Insulin sensitivity and glucose uptake -
Glucose uptake was quantitated immediately thereafter in both legs using [18F]- fluoro-deoxy-glucose [18F]FDG and PET. min in the obese subjects. min, bradykinin and insulin versus insulin leg. These data demonstrate that obesity is characterized by two distinct defects in skeletal muscle: insulin resistance of cellular glucose extraction and impaired endothelium-dependent vasodilatation.
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Published in Volume , Issue 5 on March 1, J Clin Invest. Since, a growing body of evidence support circuit-style RT as an effective training modality to enhance metabolic health components, such as whole-body glucose homeostasis Kolahdouzi et al.
One clear advantage of such a training protocol is its similarity to aerobic exercise from the perspective of the broad continuum of the energy systems, according to its ability to induce an elevated cardiovascular response Gotshalk et al.
Given the irrefutable relevance of increasing peripheral IS in prediabetic and T2D populations, a large number of studies have conducted exercise trials in those populations in an attempt to identify the optimal RT exercise prescription Praet and Van Loon, Cuff et al.
Changes in SM cross-sectional area, as well as SM normal density therefore fat-free tissue were both strongly correlated with changes in glucose uptake during the IS assessment. Cauza et al. CT-scan derived muscle cross-sectional area showed significant increases in quadriceps size after the intervention.
Furthermore, there were significant improvements in HbA1C and fasting blood glucose, lowered body fat percentage higher lower-limb strength. Unfortunately, none of these outcomes were significantly correlated with increases in quadriceps cross-sectional area.
Findings in line with those of Cauza et al. Mavros et al. Their results revealed that, in the high-intensity group, changes in SM mass were significantly and inversely correlated with HOMA2-IR.
Conversely, in the low intensity group, there was no such association. In addition, in the high-intensity group, only participants who had an increase in SM mass had a HbA1c reduction.
Surprisingly, participants in the low intensity group whom SM mass increased did not show improvements in any glycemic control outcomes. In T2D individuals, SM quantitative changes in response to RT do not always occur and are presumably unpredictable despite the application of a proper training stimulus according to population studies.
A systematic review conducted by Gordon et al. Nonetheless, the aforementioned review strongly supports a favorable effect of RT on whole-body glycemic control, IS and SM strength in people with T2D, again displaying a discrepancy between SM improvements in IS and whole-body glucose homeostasis in response to RT.
In sum, one plausible explanation of a higher efficiency of one exercise protocol over another might be total training load, i. The association between increases in SM and glucose homeostasis may also be highly relative to inter-population variability. Table 1 provides a brief overview of highly cited studies investigating FFM quantitative changes and glucose homeostasis in response to either resistance or mixed training intervention, or a comparison of the two, in different population studies.
Aside from a few exceptions Cuff et al. Amongst others, areas where counter-intuitive results have been found include post-menopausal women and women with PCOS. For instance, Kogure et al. Indeed, women and men differ not only in physical attributes but also in their SM substrates metabolism Ansdell et al.
Indeed, these different metabolic features are thought to be in part driven by enhanced SM estrogen signaling Ikeda et al. In contrast, Bucci et al. Furthermore, there was a significant and positive correlation between increases in glucose uptake and increases in absolute SM mass.
While indices of SM quality, such as absolute and relative strength, were not measured in the latter study, these results might suggest that increasing SM in the context of frailty, or pathological losses of SM such as sarcopenia may improve glucose homeostasis, as it has been suggested before Lexell, ; Volpi et al.
Table 1. Summary of studies that has investigated fat-free mass quantitative changes and glucose homeostasis in response to either resistance or mixed training intervention or a comparison.
In weight loss trials, a great deal of attention is directed toward the importance of SM mass maintenance in order to counter any loss in resting metabolic rate and therefore, energy expenditure. It is hypothesized that the reduced energy expenditure due to reduced SM mass will contribute to weight regain and deterioration of body composition, a phenomenon coined fat overshooting.
However, this fat overshooting phenomenon appears to be attenuated in obese individuals Jacquet et al. They also speculated that a high SM mass was associated with a lower density tissue in obese individuals, impaired strength-to-size ratio as well as a lower mitochondrial density and capillarization.
Taken together, these factors compromised SM work capacity. Considering those speculations, although SM is a functional physiological reserve in many circumstances, more does not necessarily mean better. In line with this, a study from Ghachem et al.
Fukushima et al. Leon et al. Before the intervention, the authors noted that appendicular SM mass was proportional to the level of obesity and was also proportionally related to fasting insulin levels.
In a large intervention study, Amankwaah et al. Unexpectedly, SM hypertrophy did not contribute to improvements in glucose homeostasis. Furthermore, the authors mentioned that the relationship between changes in SM mass and some cardiometabolic indices HDL-Cholesterol and IS index was inconsistent across different expressions of SM mass.
This suggests that the observed changes in cardiometabolic health indices were predicted by changes in fat mass rather than quantitative changes in SM.
Given the paucity of findings with regards to the implications of SM hypertrophy in response to exercise in different populations and study design, the exercise physiology community would likely benefit from a more in-depth understanding of the mechanisms involved in such adaptations, as well as their implications.
Herein, we thus suggest moving the debate forward by examining if and how the presence or the absence of SM hypertrophy influences glucose delivery and utilization in response to exercise interventions. The reader is directed toward Table 2 , which provides a brief overview of studies simultaneously reporting insulin-sensitizing SM metabolic properties, FFM quantitative changes and glucose homeostasis parameters changes in the context of exercise interventions.
Table 2. Summary of studies reporting insulin-sensitizing skeletal muscle metabolic properties, fat-free mass quantitative changes, and glucose homeostasis parameters.
Adequate perfusion is critical for efficient glucose delivery toward SM tissue. For instance, both the architecture of the microvasculature and its adaptability to vasodilation cues orchestrate glucose delivery from the circulation to the cytoplasm Schalkwijk and Stehouwer, ; Sjøberg et al. The sophisticated network of mechanisms behind insulin-stimulated vasodilation and recruitment of the vasculature being beyond the scope of the current review, readers are directed toward other excellent reviews for a more extensive discussion of these topics Cocks and Wagenmakers, ; Lenasi and Klonizakis, ; Olver and Laughlin, Capillary rarefication applies a physical barrier to adequate substrate flow toward SM tissue and is consequently an early indicator of SM-IR Lillioja et al.
Conversely, exercise-induced increases in capillary density allows for enlargement of the diffusible surface area, which promotes greater IS at the SM level Akerstrom et al.
In response to chronic AT, SM capillarity indexes i. and IS have been found to both increase in a positive and linear fashion Prior et al.
On another hand, collective evidence on vascular adaptations to exercise suggests a plausible relationship between total SM mass, SM fiber-type characterization and capillary density indexes. Interestingly, the impact of SM hypertrophy per se on SM capillary architecture has only been explored by a few trials.
In those studies, individuals with lower total SM mass had distinct characterizations of SM fiber type Trappe et al. For example, capillary density has been found to be significantly higher in endurance athletes compared to age-matched powerlifting athletes with substantially higher SM mass Tesch et al.
In a previous study, Green et al. More recently, Holloway et al. Not only did they see significant hypertrophy of type I and type II muscle fibers, but they also measured a concomitant increase in capillary-to-fiber ratio in type I muscle fibers. The findings from this study suggest SM hypertrophy may not be a limiting factor for SM angiogenesis in type I muscle fibers.
Noteworthy, these conclusions were not supported by an association between the observed changes in fiber size and capillarization indexes. In the same line, interesting results from Snijders et al. Contrasting with the results of Holloway et al.
By the same token, a recent study of Moro et al. Overall, those findings suggest that improving SM perfusion capacity for glucose, insulin and other growth factors transport may be paramount to SM hypertrophy.
The other side of the coin of these findings is that improving muscle quality first, by improving capillarity, could be the most efficient strategy regardless of the ultimate goal being SM hypertrophy, enhanced glucose homeostasis, or both.
Even though the aforementioned findings revealed important insights on how microvascular adaptations may influence SM mass quantitative changes, few investigations showed a comprehensive assessment of the implications for IS.
Yet, only a few trials and reviews have previously shed light on potential hypotheses. A study by Cocks et al. They found no significant differences in either capillary contacts or number of capillaries per fiber after the intervention, although participants saw significant improvement in post absortive glucose tolerance.
Previously, a review by Deschenes and Kraemer reported that RT-induced SM adaptation generally resulted in a reduction in relative capillarization when SM hypertrophy also occurs Deschenes and Kraemer, However, according to a later review from Harris this interpretation is highly conditional to the ways in which muscle capillarity is expressed Harris, When assessing capillarization as a matter of capillary contacts, hence the number of capillaries per myofiber, it rather seems that RT has a positive impact.
It is generally accepted that these adaptations are the direct consequence of an elevated local oxygen O 2 demand from the SM — that is greater oxidative phosphorylation OXPHOS rates Guyton et al. Likely, the ideal RT prescription for improving microvascular function and SM-IS has not been identified yet Olver and Laughlin, In all likelihood, there exist an important interplay between SM angiogenesis and the mitochondrial biogenesis transcription factors.
Irrefutably, PGC-1α transcription is likely one of the main drivers of mitochondrial biogenesis Tiraby and Langin, and has been shown to play a significant role in microvascular reactivity and adaptations, through eNOS phosphorylation and vascular endothelial growth factor VEGF transcription pathways Arany et al.
Moreover, PGC-1α transcription has been shown to reflect Hypoxia Inducible Factor-1α HIF-1α activity, hence SM local O 2 demand Gorski and De Bock, Indeed, endurance exercise generates continuous blood flow elevation toward SM for adequate O 2 and substrate delivery Andersen and Saltin, As a response, the capillary network surface increases in order to enlarge the perfusion surface available.
These adaptations seem highly dependent on PGC-1α transcription Arany et al. As high-load, low-rep or hypertrophy-driven RT generally elicits short duration muscle contractions and an intermittent elevation of blood flow comparatively to AT, it may be an insufficient physiological stimulus to promote PGC-1α-driven angiogenesis.
By the same token, results from Mortensen et al. In their recent review, Olver and Laughlin provided in-depth analysis of the impact of different exercise modes on microvascular dysfunction in T2D Olver and Laughlin, and stated that:. Such a statement reinforces the hypothesis that RT solely centered on SM hypertrophy may not be the most appropriate stimulus for microvascular adaptations and SM IS.
A unique study of Hansen et al. In short, they compared the two exercise modalities with regards to their effect on glucose metabolism in a sample of 18 older men and women with impaired glucose tolerance. In insulin resistant states, capillary blood volume and flow do not increase normally in response to insulin, which is likely to contribute to abnormal glucose homeostasis Lenasi and Klonizakis, To date, the exact effect of SM hypertrophy on the SM microvasculature response to vasodilation physiological cues remains unclear, although RT has been found to exert significant benefits Olver and Laughlin, Using an ultrasound method, Cohen et al.
Another recent study from Russell et al. Changes in fasting blood glucose, HbA1c and glucose area under the curve during an oral glucose tolerance test were all induced by a higher microvascular blood flow adjusted for percent SM, body mass index, brachial blood flow and mean arterial pressure. It is therefore legitimate to debate which one of those two improvements is more related to enhanced glucose homeostasis, relative strength being an important feature of muscle quality Barbat-Artigas et al.
Additionally, the heterogeneity of blood flow distribution between muscle fiber types is likely to play an important role in the insulin-mediated vasoreactivity. Heinonen et al. Thus, it is likely that these SM fibers display less upregulation of vasodilation mediated by endothelial factors, as well as an elevated α-adrenergic-mediated vasoconstriction, compared to type I fibers.
Previous data suggested that obese Krotkiewski et al. Admittedly, one could hypothesize that targeting SM hypertrophy might not be ideal in order to improve SM mechanisms of IS. Amongst the vast array of insulin-sensitizing adaptations from chronic exercises, enhanced oxidative capacity is one of the most regarded.
Indeed, a high SM mitochondrial density has been relentlessly highlighted as a univocal feature of SM-IS Gouspillou et al. Conversely, mitochondrial dysfunction has been related to loss of SM mass Gouspillou et al.
In brief, elevated peripheral oxidative capacity is thought to be one of the strongest predictors of whole-body-IS in virtue of a higher total substrate utilization Bruce et al. A recent study of Zampino et al. Nonetheless, whether exercise-induced SM hypertrophy leads to significant mitochondrial adaptations with regards to improved IS remains unclear.
A comprehensive study of St-Jean-Pelletier et al. Interestingly, they also found to significant relationship between mitochondrial and lipid content St-Jean-Pelletier et al. Sparks et al. Interestingly, participants in the ATRT group displayed no significant changes in SM mass. According to the authors, this could be explained by a broader recruitment of the musculoskeletal system and potentially, a greater total exercise workload.
Recently, Parry et al. Although the contribution of SM mitochondrial dilution on IS needs further investigations, one could hypothesize that since lower mitochondrial activity is a well-known feature of IR Petersen et al. In line with those speculations, a study from Burd et al. A reduced turnover rate of intramuscular triglycerides IMTG is also a hallmark of SM-IR Petersen et al.
Conversely, an elevated IMTG turnover rate is associated with greater SM-IS, irrespective of the magnitude of IMTG pools Goodpaster et al. Although the relevance of both aerobic and resistance exercises is no longer to be proven regarding enhanced IMTG metabolism, it remains unknown whether quantitative changes in SM play a role in those molecular adaptations.
However, it is generally accepted that hypertrophied SM contains proportionally more type IIA and IIB than type I fibers Karp, Nonetheless, these types of muscle fibers are thought to display a lower oxidative capacity Henriksson and Reitman, A study of Shepherd et al.
In short, their results demonstrated an increase in lipid droplet-associated proteins 2 and 5 PLIN2 and PLIN5 covering lipid droplets, as well as an increase in intramuscular triglyceride utilization during a 1-h moderate intensity cycling session after a 6-week RT protocol in lean, healthy young men.
Furthermore, there was an increase in the expression of cytochrome oxidase COX; a marker of SM oxidative capacity in both type I and II fibers. There was also a slight increase in total SM mass.
But most importantly, all adaptations occurred in both type I and type II muscle fibers. In sum, the current body of evidence suggests that even if the importance of AT and RT in glucose metabolism is no longer to be proven regarding IMTG metabolism, it has yet to be confirmed whether quantitative changes in SM mass further drives those adaptations in other populations, such as individuals with metabolic impairments.
Body weight management and exercise are amongst the most promising strategies to improve and maintain overall metabolic health Tuomilehto et al. However, it is still unclear if the current focus on SM hypertrophy, or the prevention of SM losses during weight loss trials is appropriate amongst all populations.
In contrast, studies aiming at increasing muscle quality, regardless of quantity, are currently scarce Barbat-Artigas et al.
This can be achieved with low-load-high repetition RT, which is an overlooked exercise modality in metabolically impaired populations. Further studies that will seek to determine the real contribution of quantitative changes of SM on glucose homeostasis in populations who would benefit from an optimal exercise prescription for this purpose, such as prediabetic, T2D or metabolically impaired individuals, are highly warranted.
Regular exercise, be it AT or RT, has repetitively been associated with improved IS through various mechanisms. However, the mechanisms underlying a relationship between SM hypertrophy and whole-body glucose homeostasis have not been demonstrated without doubt.
A fundamental mechanism that could contribute to IS improvements is greater SM capillarity i. The associated increase in blood-flow and diffusion surface for O 2 support improved SM OXPHOS capacity and intramuscular lipid turnover.
We argue that RT protocols both involving a high O 2 demand and aiming to improve muscle function have the highest potential to induce SM adaptations in favor to an improved IS.
With this in mind, SM hypertrophy ability to equivocally improve whole-body glucose homeostasis might be re-evaluated in specific populations. Moreover, in virtue of better known intersex- and age- related physiological differences in response to acute and chronic exercise Lundsgaard and Kiens, ; Hughes et al.
Finally, while RT is a highly relevant and proven strategy to prevent T2D Bird and Hawley, ; Pesta et al. ID and MB had the idea of the article and supervised JP in the writing. JP performed the literature search, article analysis and wrote the whole manuscript and tables.
J-CL critically revised the manuscript and tables. All authors contributed to the article and approved the submitted version. JP has received a doctoral scholarship from Fonds de recherche en santé du Québec-Santé FRQ-S. J-CL has received a doctoral scholarship from Instituts de recherche en santé du Canada IRSC.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Thank senzitivity for glucsoe nature. You are using sesnitivity browser Amazon Cyber Monday with limited support for Glucosse. To obtain Insulin sensitivity and glucose uptake best experience, we Kale and beet recipes you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. The central nervous system CNS has an important role in the regulation of peripheral insulin sensitivity and glucose homeostasis.Natural remedies for sunburn relief Chemistry and Metabolism Unit, Glucoes. Vincent's Institute Insulin sensitivity and glucose uptake Medical Sejsitivity, Fitzroy, Australia. Download Gluxose.
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Uptwke author: Hayley M. Vincent's Institute of Medical Research, sensiticity Princes Sensitigity, Fitzroy, VictoriaAustralia. honeill upgake. ABSTRACT AMPK Joint health strength an kptake conserved glucowe of cellular glucosse status that is activated during exercise. Pharmacological activation of AMPK promotes glucose uptake, sensitifity acid oxidation, mitochondrial biogenesis, and insulin sensitivity; processes that are reduced in Optimizing nutrient bioavailability processes and contribute Insulln the swnsitivity of insulin resistance.
AMPK deficient mouse models have been used to sensutivity direct genetic evidence either supporting or refuting a role for AMPK in regulating these processes. Exercise promotes glucose uptake by an insulin dependent mechanism involving AMPK. Exercise is important for improving insulin sensitivity; however, it is not known if AMPK is required for these improvements.
Understanding how these metabolic processes are regulated is important for the development of new strategies that target obesity-induced insulin resistance.
This review will discuss the involvement of AMPK in regulating skeletal muscle metabolism glucose uptake, glycogen synthesis, and insulin sensitivity. Keywords : AMPK ; Exercise ; Glucose uptake ; Insulin resistance ; Obesity.
Insulin stimulates glucose uptake by binding to the insulin receptor IRthis promotes autophosphorylation and subsequent activation of insulin receptor substrate 1 IRS1 and PI3 kinase via SH2 interaction with regulatory p85 and catalytic p subunits.
Once glucose enters the cell it can be metabolized through glycolysis to produce ATP or utilized for glycogen synthesis. Glycogen synthesis involves phosphorylation and inhibition of glycogen synthase kinase 3 GSK3 by Akt, which activates glycogen synthase GS ; promoting the conversion of glucose-6 phosphate G6P to G1P then uridine diphosphoglucose UDP-Gwhich is targeted towards glycogen.
AMPK can phosphorylate and inhibit GS; however, G6P can override this inhibitory effect. PTG, protein targeting to glycogen. AMPK can phosphorylate both TBC1D4 and TBC1D1; however, recent studies have shown that during contraction there is a strong correlation between AMPK phosphorylation of TBC1D1 and binding proteins that are proposed to be important for regulation of GAP function of TBC1D1 upon phosphorylationwhich allows dissociation of Rab proteins and glucose transporter 4 GLUT4 translocation to the plasma membrane and glucose uptake.
AK, adenylate kinase, the enzyme required for generation of AMP. Table 1 AMPK isoform heterotrimer distribution in mouse glycolytic extensor digitorum longus EDL and oxidative soleus muscle.
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: Insulin sensitivity and glucose uptake| Article PDF | Role Kale and beet recipes mitochondrial dysfunction in insulin sensitivoty. Lipotoxic heart disease in obese Ijsulin implications for human obesity. Joint health strength studies, which have been Strength-focused nutrition replicated senstiivity, have contributed abd the hypothesis that RT targeting SM hypertrophy could be as efficient as aerobic exercise performed alone for improving SM insulin sensitivity IS Dela and Kjaer, ; Pesta et al. Selected major risk factors and global and regional burden of disease. Westergren HU, Svedlund S, Momo RA, Blomster JI, Wahlander K, Rehnstrom E, Greasley PJ, Fritsche-Danielson R, Oscarsson J, Gan LM. |
| Background | However, there is still controversy around whether this fuel shift is adaptive or maladaptive. The ketogenic diet effect can be mediated by suppressing longevity-related insulin signaling and mTOR pathway, and activation of peroxisome proliferator activated receptor α PPARα , the master regulator that switches on genes involved in ketogenesis [ ]. Several reports suggest that ketogenic diet may be associated with a decreased incidence of risk factors of cardiovascular disease such obesity, diabetes, arterial blood pressure and cholesterol levels, but these effects are usually limited in time [ ]. However other reports indicated that cardiac risk factor reductions corresponded with weight loss regardless of a type of diet used [ ]. Excessive production of ROS leads to protein, DNA, and membrane damage. In addition, ROS exerts deleterious effects on the endoplasmic reticulum. This also contributes to diabetic cardiomyopathy pathogenesis [ , ]. Insulin essentially provides an integrated set of signals allowing the balance between nutrient demand and availability. Impaired nutrition contributes to hyperlipidemia and insulin resistance causing hyperglycemia. This condition alters cellular metabolism and intracellular signaling that negatively impact cells. In the cardiomyocyte, this damage can be summarized into three actions: 1 alteration in insulin signaling. All these effects induce cellular events including: 1 gene expression modifications, 2 hyperglycemia and dyslipidemia, 3 activation of oxidative stress and inflammatory response, 4 endothelial dysfunction, and 5 ectopic lipid accumulation, which, favored by obesity, perpetuates the metabolic deregulation. Overall, insulin resistance contributes to generate CVD via two independent pathways: 1 atheroma plaque formation and 2 ventricular hypertrophy and diastolic abnormality. Both effects lead to heart failure. 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VO, SN, OE, CA and FZ conducted a review of the literature and contributed to conception and design and wrote the first draft the review; CS contributed to conception and design of the article and critically reviewed the drafts of the manuscript. All authors read and approved the final manuscript. This study was supported by Fondo Nacional de Desarrollo Científico y Tecnológico FONDECYT , Lions Medical Research Foundation Australia , and Diabetes Australia. Whereas the field has largely focused on direct effects of obesity-associated alterations in peripheral tissues such as liver, skeletal muscle and adipose tissue Fig. Recently, an important role for the CNS in the regulation of peripheral insulin sensitivity and glucose homeostasis has been unravelled. We review the progress made in this research field and place particular emphasis on the central control of liver and brown adipose tissue BAT as well as pancreatic islet function in control of glucose metabolism. We provide an update on the key brain regions, neurons and molecular mechanisms in these neurons and the downstream neurocircuitries identified, as well as outline relevant peripheral mediators that act on the these brain circuits in the control of glucose homeostasis. We also review recent literature on how obesity perturbs CNS-dependent control of glucose metabolism, and highlight the potential clinical relevance of these regulatory CNS pathways in T2D. Solid evidence for a role of CNS circuits in regulating systemic glucose homeostasis dates back to the s Box 1. Today, a large literature substantiates energy-regulatory capabilities of a plethora of areas in the rodent brain Fig. Among those, several nuclei residing in the hypothalamus stand out, of which the arcuate nucleus ARH , the ventromedial nucleus VMH and lateral hypothalamic area LHA have received most attention. We now recognize a neuroregulatory network governing control over feeding, peripheral insulin sensitivity and glucose metabolism extending beyond the ARH, VMH and LHA Table 1. These regulatory centres also include a number of extra-hypothalamic nuclei, such as sensory and integrative clusters in the hindbrain 6 , 7 , as well as autonomic, parasympathetic and sympathetic preganglionic brainstem neurons 8 , 9. Owing to the application of cell-specific chemogenetic and optogenetic techniques 10 , 11 , several of these nuclei were initially documented to orchestrate the behavioural and autonomic repertoire that controls feeding Table 2 and some of these neurons have more recently been assigned gluco-regulatory properties beyond and even independent of their food intake-regulatory function. Schematic representing a sagittal section of a mouse brain in which critical brain regions controlling glucose homeostasis and peripheral insulin sensitivity as well as brown fact activity are depicted. Three main regions are highlighted: the bed nucleus of the stria terminalis BNST , the hypothalamus and the medulla. In the caudal part the brain, the medulla contains key areas such as the dorsal vagal complex DVC and the raphe pallidus nucleus RPA. The ARH is located at the floor of the third ventricle, leveling with the base of the pituitary stalk a funnel of nerves connecting the brain with the pituitary gland and bridges with the median eminence. ARH neurons sense peripheral substances that signal the energy state of the organism. In line with their ability to integrate peripheral signals and adapt their electrical activity according to energy availability, chronic manipulations of hormonal and nutrient signalling in POMC and AgRP neurons affect glucose metabolism in peripheral tissues 12 , However, whether POMC or AgRP neuron firing acutely controls glucose metabolism was not established until recently. Using cell-specific excitatory techniques, acute activation of AgRP neurons was found to impair systemic insulin sensitivity and glucose tolerance after acutely raising insulin or glucose in the bloodstream Specifically, AgRP-neuron activation halved insulin-stimulated glucose uptake selectively into BAT, likely through re-programming the gene expression profile towards a myogenic signature The most strongly upregulated gene in BAT was myostatin, a molecule previously linked to abnormal glucose metabolism Indeed, acute induction of myostatin partially explained the insulin resistance downstream of AgRP-neuron stimulation Previous studies showed that acute activation of AgRP neurons reduces energy expenditure 16 , whereas mice genetically modified to lack AgRP neurons burn slightly more calories 17 , indicating a relationship between AgRP neurons and brown fat function. Consistent with these observations, acute activation of AgRP neurons decreased the activity in sympathetic nerves supplying BAT, and a lower β-adrenergic tone contributed to the development of systemic insulin resistance upon AgRP-neuron activation Activating this projection in the vlBNST did not induce a feeding response however With respect to appetite control, activation of long- and short-range outputs from distinct subpopulations of AgRP neurons to several downstream sites is sufficient to evoke feeding alone. These observations point to a parallel and redundant organization of AgRP neuronal circuits that controls feeding behaviour Although all AgRP neuron projections sites potentially controlling systemic glucose metabolism have not yet been probed, the data available thus suggest that peripheral insulin sensitivity is controlled by less redundant AgRP neuron circuits compared to those in control of feeding behaviour. By contrast, acute activation of POMC neurons had no effect on glucose metabolism in these studies 14 , suggesting that acute AgRP neuron activation controls peripheral insulin sensitivity without interfering with the melanocortin pathway. Experiments defining melanocortin-dependent feeding behaviour have shown that the hypophagia from stimulating POMC neurons is prevented in A y mice, in which AgRP constitutively blocks melanocortin signalling. By contrast, the hyperphagia from activating AgRP neurons is intact in A y mice 19 , and melanocortin receptor blockade cannot prevent the hypophagic response upon AgRP neuron ablation Taken together, AgRP neurons may similarly control glucose metabolism independently of melanocortin signalling. To this end, AgRP neurons also synthesize NPY and GABA, and whereas AgRP through its action on MC4Rs is sufficient to trigger sustained but delayed increase in food intake, both NPY and GABAergic signalling contribute to the rapid hyperphagia observed upon AgRP neuron excitation 21 , AgRP neurons may thus govern control over glucose metabolism through NPY, GABA receptor signalling, or a combination of both. Interestingly, induced NPY expression specifically from the ARH reduces energy expenditure and decreases BAT thermogenesis via NPY1-receptor signalling in key nuclear relay stations, including the locus coeruleus, solitary tract nucleus and ventrolateral medulla in the hindbrain, some of which modulate sympathetic outflow to BAT These observations indicate that NPY-receptor signalling downstream of AgRP neurons may explain some of the effects on brown fat physiology exerted by AgRP neurons, and possibly systemic insulin sensitivity. Finally, although acute activation of POMC neurons was ineffective in affecting glucose metabolism in these studies, it is noteworthy that a recent study reported that chemogenetic activation of POMC ARH neurons markedly and rapidly within minutes increases BAT temperature by several degrees 24 , demonstrating that POMC ARH neurons promote BAT thermogenesis. The reasons why POMC-positive ARH cells potently affect BAT temperature without clear effects on insulin sensitivity are currently unknown, and future studies will be needed to address the nature of this divergence. The activity of POMC and AgRP neurons bi-modally and rapidly controls appetitive behavior even upon mere sensory perception of food Activation of POMC ARH neurons selectively suppresses appetite 19 , 98 Table 2 , and mutations in the POMC gene are associated with obesity in a range of species including humans, mice and dogs Best known for signaling satiety, recent intriguing data reveal a previously unprecedented function of a subset of POMC neurons to promote feeding behavior through cannabinoid-receptor mediated release of β-endorphin, an endogenous opioid neuropeptide originating from the POMC precursor molecule By contrast, AgRP neurons are hunger sensitive and signal energy deficits: their activation rapidly evokes eating and their ablation in the adult animal causes rapid weight loss due to cessation of feeding 16 , 19 , , Mechanistically, the neuropeptide AgRP competes with α-melanocyte-stimulating hormone α-MSH released from POMC neurons for binding sites on the melanocortin 4-receptor MC4R , blocks the coupling to a G αs signaling pathway, and promotes feeding when AgRP has the upper hand. Besides the canonical view of neuronal MC4R signaling, new fascinating data however suggest that AgRP can act independently of G αs and through regulating the pore state of an inwardly rectifying potassium channel, Kir7. According to these results, binding of AgRP onto MC4R opens Kir7. The brain launches an adaptive and protective counter-regulatory response when glucose levels fall out of range. The VMH Fig. In mice that are hypoglycemic owing to a high dose of insulin, the ability to normalize glycaemia fails when SF-1 neurons are optogenetically inhibited, as the anticipated rebound from hypoglycemia elicited by insulin is attenuated In turn, optogenetic activation of SF-1 neurons increases blood glucose, and causes profound hyperglycaemia when blood glucose levels are elevated either by stimulating HGP or by injecting glucose into mice The differential responses may stem from a failure of stimulating glucagon and corticosterone release when SF-1 neurons are inhibited , or from the inability to balance glucagon and corticosterone secretion and control HGP when SF-1 neurons are stimulated. It is conceivable that photostimulation of SFexpressing neurons mimics a state of glucodeprivation in the VMH since they stimulate the counter-regulatory response to hypoglycemia, including effects on pancreas and liver. Thus, a defined circuit spanning from glucose-sensing VMH neurons to the aBNST specifically regulates expression of key genes for hepatic gluconeogenesis and influences the abundance of counter-regulatory hormones striving to restore glycaemia. In another study, investigators used radiowaves to manipulate glucokinase-expressing VMH neurons engineered to respond to an electromagnetic field, and showed that activation of VMH neurons robustly elevates blood glucose and glucagon concentrations in the circulation as well as drives the expression of key hepatic gluconeogenic genes, whereas inhibition quells these responses These findings further substantiate a role for the VMH in the control of peripheral glucose metabolism, and the authors describe a novel technique, dubbed magnetogenetics, to affect neuronal activity through a genetically encoded fusion protein between the iron-binding protein ferritin and a thermo-sensitive ion channel protein. Although the paper describes a way to remotely manipulate the electrical activity of neurons in mice with a very clear outcome 28 and whereas a string of recent articles report the successful use of magnetogenetics, the way the underlying operative mechanism biophysically works is unclear and has turned into a subject of debate To ensure that the field strength was adequate to affect neuronal activity, while permitting assessments of its impact on glucose metabolism in vivo , the mice had to be anesthetized in those studies Although the findings obtained from manipulating VMH neurons were the expected, whether exactly the same outcome is present in awake mice could not be proven with the confines of the method, as narcosis might have intrinsic effects on neural activity and glucose homeostasis. Thus, refinements of the necessary equipment for electromagnetics is required for large-scale use and to set the stage for further exciting discoveries. Moreover, future studies are encouraged to define the precise mechanism of magnetogenetics. Although recent research has provided a wealth of information, the functional organization of the neurocircuity influencing counter-regulatory mechanisms of glycemic control remains to be better understood, and electromagnetics is hoped to provide more answers on the neuroendocrine components and architecture contributing. While the aBNST has surfaced as a key integrative glucoregulatory node, the details about this system remain to be specified. Specifically, which descending neural network downstream of the aBNST, tethering it do BAT glucose utilization, insulin sensitivity and counter-regulatory responses, as well as the exact cellular phenotype of the crucial aBNST neurons are issues that clearly call for additional study. Located along the midline of the anterior hypothalamus, the preoptic area PoA is situated closely below the anterior commissure where nerve bundles pass between the two brain hemispheres and above the optic chiasm where optic nerve fibres from the retinas cross between the two hemispheres Fig. The PoA regulates BAT heat production, a process that depends on the metabolism of significant amounts of glucose and triglycerides 30 , 31 , Nevertheless, the thermoregulatory function of this brain region has been primarily studied in the context of fever, which is driven by prostaglandin signalling in the median preoptic subnucleus 33 and activates brown fat thermogenesis via a neural pathway including the rostral raphe pallidus Fig. Surgical or electric manipulations of the LHA neurons over 50 years ago were shown to control food intake. We now know that a part of this effect is explained by an inhibitory synaptic innervation from the BNST to glutamatergic LHA neurons, eliciting voracious feeding in mice that are already satiated when optogenetically manipulated In food-deprived animals, inhibiting this input onto the LHA conversely suppresses feeding Furthermore, projections to the LHA from AgRP neurons impair systemic insulin sensitivity when activated So far, recent observations point toward a critical role for MC4R signalling in the LHA in control of glucose homeostasis By reconstituting MC4R expression specifically in LHA neurons of obese mice carrying a null MC4R allele MC4R LHA , Morgan et al. were able to improve glucose tolerance and glycaemia in both normal chow and high-fat diet HFD -fed mice independent of changes in body weight, adiposity or insulin concentrations Activation of the MC4R using an α-melanocyte stimulating hormone α-MSH analogue in mice with MC4Rs re-expressed in the LHA increased glucose uptake specifically into brown fat; this effect correlated with subtle increments in glucose transporter 4 GLUT-4 gene expression and upregulation of a thermogenic gene expression programme in BAT Consistent with the idea that MC4R LHA signalling facilitates BAT glucose utilization via the sympathetic nervous system, nerves innervating BAT showed normal spiking responses to a MC4R agonist in mice carrying a reactivated MC4R gene in the LHA, in contrast to the nerves in obese whole-body MC4R knockouts that were insensitive, and surgically eliminating BAT from sympathetic input furthermore impaired the improved glucose tolerance obtained from MC4R LHA reactivation Thus, MC4R LHA signalling activates sympathetic outflow to BAT, and intact sympathetic control over BAT glucose uptake is required to rescue the glucose tolerance when the MC4R is gone in every cell but in LHA neurons, as judged from this comprehensive study in mice In the s, physiologist Claude Bernard observed that manipulation to the floor of the fourth ventricle in the hindbrain of experimental animals caused blood glucose levels to rise above normal, and that the excess sugar was excreted in the urine Walter Bradford Cannon later conceptualized and developed it further. With diminished enthusiasm for the brain as an interesting target for intervention, research was now devoted to deciphering insulin action in peripheral organs and defects in pancreatic insulin secretion. In hindsight, however, and considering that the brain governs control of most homeostatic networks, it seems improbable that glucose metabolism would be controlled by mechanisms independent of the CNS. In humans, the quantity of BAT correlates inversely with BMI, BAT is highly responsive to cold and diet exposure, an adaptive response that is reduced in obese and overweight subjects, and insulin 36 , 37 , 38 , 39 , There is evidence that BAT is less active in diabetics 41 and that BAT activation improves whole-body glucose homeostasis and insulin sensitivity Such observations have fostered the notion that strong actuators of BAT activity could be used to treat obesity and diabetes. Brown fat function is often studied under cold conditions, a state that does not allow capturing whether BAT plays a role in glucose metabolism at euthermia. To measure whether metabolic activity in human BAT affects blood glucose levels over time and depending on feeding state and circadian rhythm, Lee and colleagues measured the temperature profile of the skin overlying supraclavicular BAT as a surrogate of conventional fluorodeoxyglucose positron emission tomography FDG-PET imaging At thermoneutrality, supraclavicular BAT temperature progressively rose during a glucose load, indicating that BAT utilizes glucose. The authors also observed a noteworthy rhythmicity in glucose uptake into human brown adipocytes, especially after insulin stimulation, together with oscillating trafficking of GLUT-4 to the plasma membrane, which mirrored the fluctuations in glucose uptake and generated heat In humans normal weight, non-diabetic men in their mid-twenties with larger than average active BAT depots, changes in BAT thermogenesis predicted subcutaneous blood glucose levels, whereas BAT thermogenic activity responded to systemic changes in glycaemia in individuals with comparatively small amounts of BAT Notably, men devoid of supraclavicular BAT exhibited the largest glycemic variability. Conceivably, human BAT glucose utilization is linked to thermogenesis, and BAT shows a glucose-responsive rhythm entrained by circadian oscillations in GLUT-4 in a similar manner as mechanisms coordinating body temperature rhythmicity and responses to cold In light of these findings, whether greater fluctuations in glucose levels as a consequence of the amount of functionally active BAT pre-dispose for diabetes warrant further investigations. Afferent hormonal and nutritional cues provide feedback signals to the brain that are crucial for systemic glucose homeostasis. On the other hand, efferent signalling from the brain to peripheral tissues is promoted via the autonomic nervous system, for example to control HGP, BAT activity and pancreatic hormone secretion Fig. However, several discoveries made in the past 20 years have reignited interest in this concept. Firstly, activation of the IR, which is widely expressed throughout the CNS, was shown to curb eating. Secondly, manipulation of key IR signalling components such as PI3 kinases , activation of neuronal ATP sensitive potassium channels 45 , or depletion of functional IRs from the brain 46 , affect not only energy homeostasis but also systemic glucose metabolism. In humans, insulin quenches HGP via the same class of potassium channels K ATP as it does in rodents Insulin activates K ATP channels in a PI3 kinase-dependent manner resulting in hyperpolarization of neurons 13 , However, how various hypothalamic neurons respond electrically to insulin might differ, as exemplified by the recent findings that insulin can excite POMC neurons via activation of canonical transient receptor potential channels in a PI3 kinase-dependent manner Similarly, insulin promotes PI3 kinase signalling in melanin-concentrating hormone MCH neurons in the LHA and increases their excitability Physiologically, insulin-dependent activation of these neurons impairs locomotor activity and glucose homeostasis by controlling hepatic insulin sensitivity and HGP in mice fed a HFD. Given that the phenotypic alterations dependent on IR signalling in MCH neurons were observable in HFD-fed mice but not lean mice fed a normal mouse chow suggest that this mechanism is engaged only during conditions when insulin levels rise. Consistent with this, HFD feeding associated with hyperinsulinemia increases PI3-kinase activity in MCH neurons via the IR The central nervous system contains high density of receptors for the white adipose tissue WAT -derived hormone leptin as well as receptors for the pancreatic hormone insulin. Leptin and insulin act on specific brain regions that will in turn modulate glucose utilization and production in peripheral tissue via the autonomic nervous system. Notably, the vagus nerve links brain insulin action and the liver in the control of hepatic gluconeogenesis. At the pancreatic level, the autonomic nervous system is involved in pancreatic hormone secretion. The brown adipose tissue BAT receives sympathetic innervation which activity directly control BAT glucose uptake. NA, noradrenaline. The insulin-dependent effects on MCH-expressing cells supports the existence of selective hormone resistance, which describes the occurrence of insulin resistance in cell types within the CNS with simultaneous retained or even over-activated insulin action in other CNS cell types. Indeed, the manifestation of selective CNS resistance to insulin represents a rule rather than exception In fact, insulin activates PI3K signalling and reduces the firing rate of a proportion of SF-1 VMH neurons through K ATP channel activation Mice lacking the IR on these subsets of neurons are partially protected from diet-induced obesity upon HFD feeding, associated with reduced systemic insulin levels and improved glucose metabolism Thus, the hyperinsulinemia present under prolonged HFD feeding predictably silences the SF-1 neurons, and IR signalling via the PI3K pathway in SF-1 VMH neurons mediates systemic insulin resistance and obesity in response to a HFD. Thus, the manifestation of selective insulin resistance clearly necessitates work on the underlying molecular mechanisms. Future studies should focus on region-specific mechanisms of selective hormone resistance, and, ultimately, to develop cell-specific insulin de sensitizers in the treatment of obesity-associated alterations such as uncontrolled HGP. Chronically elevated HGP contributes significantly to the hyperglycaemia associated with T2D ref. Understanding how the liver fails to respond to insulin and to the efferent signals originating from the CNS in the regulation of this process is thus of great importance. Pharmacological approaches were the first to document a role for central insulin signalling in the control of peripheral glucose homeostasis, as infusion of insulin into the cerebral ventricle adjacent to the hypothalamus suppresses HGP and lowers blood glucose A key observation in the search for the neuronal substrate explaining how brain IR signalling can inhibit HGP came from mice genetically modified to lack the IR specifically in AgRP neurons. Here, Könner et al. observed that failure to activate IR signalling in AgRP neurons substantially reduced the ability of peripherally applied insulin to suppress HGP under a euglycemic-hyperinsulinemic clamp. These findings thus demonstrated that the site for central insulin signalling to inhibit HGP is, indeed, AgRP neurons In agreement with these data, selective restoration of the IR specifically in AgRP neurons in addition to liver and pancreatic β-cells rescues the ability of insulin to curb HGP, whereas selective re-expression of the IR to POMC neurons in otherwise IR-deficient mice exacerbates insulin resistance and increases HGP Thus, these findings suggest a functional dichotomy in regulation of HGP originating from POMC and AgRP neurons, similar to their opposing effect on feeding and energy expenditure 19 Box 2. In addition, hypothalamic insulin action reduces the breakdown of lipids lipolysis and promotes fatty acid and triglyceride synthesis lipogenesis in adipocytes through a reduction in the sympathetic tone to white adipose tissue The vagus nerve the tenth cranial nerve innervates large parts of the viscera and has been suggested to create the critical interface between the brain and the liver Fig. The vagus nerve also links brain IR signalling to gluconeogenesis, as central insulin action requires intact hepatic vagal nerve branches to suppress HGP 6 , Insulin hyperpolarizes AgRP neurons and inhibits their firing frequency through opening of K ATP channels The reduced activity of AgRP neurons, in turn, results in ILmediated activation of STAT3 signalling in the liver, and downregulates the abundance of key gluconeogenic genes, including Pepck and G6Pase 13 , 45 , 53 , 56 , These data suggest that diet-induced obesity blunts hypothalamic IR signalling and inhibits its control of HGP, substantiating a role for central insulin resistance in obese, diabetic animals. S6K1 signalling in POMC neurons is, however, also reported to suppress HGP in hyperinsulinemic clamps The disparate outcome from these experiments may not be mutually exclusive and differences in cells targeted because of varying methodology adenoviral-based, acute pan-neuronal overexpression versus chronic POMC cell-specific gene inactivation are likely one explanation to these seemingly discordant findings, especially considering neuronal heterogeneity, that is, existence or different subpopulations of functionally distinct POMC neurons. Insulin is not the only hormone that affects systemic glucose homeostasis through CNS-mediated mechanisms. For example, glucagon-like peptide 1 GLP-1 augments glucose-stimulated insulin secretion and reduces HGP, likely mediated by GLP-1 receptor signalling in the ARH The peptide hormone glucagon secreted from pancreatic alpha-cells Fig. Hypothalamic glucagon receptor activation was found to inhibit HGP through a K ATP channel-dependent mechanism, and the increase in HGP from raising peripheral glucagon concentrations could be abated by blocking glucagon action in the CNS 62 , These data led to the conclusion that, in contrast to its direct actions on the liver, hypothalamic glucagon signalling inhibits HGP 62 , This was surprising, because glucagon drives HGP by direct effects on hepatocytes Fig. That a peptide promotes HGP through its stimulatory effects on the liver, and on the other hand inhibits the very same process through effects on the brain may seem counter-intuitive, as these two forces are counteracting. The findings may however point to the existence of a self-regulatory feedback loop to fine-tune HGP, in which central glucagon signalling explains why the hepatic effect of high glucagon concentration on HGP is transient, tapering off within hours even during continuous glucagon infusion. A monomeric peptide conjugate between glucagon, GLP-1 and GIP glucose-dependent insulinotropic polypeptide that acts as an agonist at each receptor vastly improves metabolic and glycemic control in obese and diabetic rodents As judged from its impact on whole-animal physiology increased energy expenditure, reduced caloric intake and better glycemic control , it is reasonable to believe that the triple agonist exerts some of its key functions by acting on the brain. Finally, whether the data in rodents on central glucagon action, with the purpose of limiting its own effects on the liver, extend to humans is important to investigate. Whether insulin action in the CNS is relevant for day-to-day or acute control of blood glucose in humans has been a matter of intense discussions While causally proving the existence of a CNS-dependent mechanism of insulin action to inhibit HGP in humans is inherently challenging, administering insulin through a spray formulation into the nose has shed some light on the physiological relevance of insulin signalling in the human brain. Intranasal application of insulin rapidly elevates levels of the hormone in the cerebrospinal fluid at concentrations that are too low to be detected in the blood, suggesting that insulin penetrated directly into the brain from the nose without increasing insulin levels in the systemic circulation Daily intranasal insulin administration over 8 weeks reduces body fat and weight in healthy men but not woman ranging between 0. Importantly, Heni et al. In their study, lean individuals required more glucose to maintain euglycemia after intranasal delivery of insulin in a clamp setting compared with placebo-treated individuals in the presence of similar venous insulin levels. These data indicated improvements in whole-body insulin sensitivity, and the amount of glucose infused interestingly correlated with increased hypothalamic activity and indices of increased parasympathetic descending vagal nerve activity Therefore, the authors concluded that short-term insulin action as a result of intranasal application of insulin improves systemic insulin sensitivity in humans, possibly via a hypothalamic-mediated vagal mechanism like in rodents 6 , However, these studies do not provide definitive evidence that endogenously produced insulin has a similar physiological role in the human brain. The responses to intranasal insulin therapy, and the cortical response to systemic hyperinsulinemia are weaker in obese humans, suggesting that obesity renders the brain less responsive to insulin 69 , This phenomenon also occurs in animals with reduced amounts of IR protein in the ARH, a situation that is accompanied by a failure to efficiently suppress HGP and whole-body insulin resistance Besides being a methodological bedrock for experiments aiming to elucidate the role of insulin signalling in the brain, the question is whether nasal insulin administration therefore represents an attractive alternative medical regimen to current therapies to treat obesity-associated diabetes. The development of T2D can be preceded by defects in not only insulin-dependent but also in insulin-independent glucose uptake more than a decade before the disease is diagnosed Thus, how efficiently glucose promotes its own disposal unrelated to insulin action predicts the future risk of developing glucose intolerance. Secreted from white adipose tissue in proportion to fat mass, leptin is intimately linked to CNS-dependent control of glucose homeostasis; as such leptin administration has been reported to rescue insulin-deficient diabetes Thus, leptin receptor signalling in the brain appears to normalize diabetic hyperglycaemia across different tissues and mechanisms, giving rise to the idea that leptin compensates for the lack of insulin in animal models of diabetes where loss of islet β-cell function is prominent In addition, combined leptin and insulin signalling in POMC neurons is broadly accepted to regulate peripheral glucose metabolism. Supporting this notion, mice lacking both the insulin and leptin receptors on POMC neurons do not suppress HGP normally, an effect associated with systemic glucose intolerance and insulin resistance Reconstitution of leptin receptor signalling on the same neurons conversely normalizes blood glucose and increases hepatic insulin sensitivity Collectively, these data point to a key role for leptin action in the ARH. However, hypoinsulinaemia as a consequence of islet failure does not seem to increase compensatory leptin receptor signalling in the CNS with the purpose of rescuing euglycemia as the hyperglycaemia usually persists in conditions characterized by insulin deficiency. Whether leptin alone can replace or compensate for insulin deficiency can thus be debated. The islets of the pancreas are subject to regulation by insulin signalling in the brain, and their connection with the CNS and the efferent arm of the autonomic nervous system is remarkably vulnerable during a specific developmental time window of the hypothalamic neurocircuitry Work from Vogt et al. has shown that feeding mothers a HFD exclusively during the lactation period leads to abnormal formation of axons from POMC neurons to the posterior part of the paraventricular nucleus of the hypothalamus PVH Fig. Ultimately, these perturbations are associated with obesity, impaired glucose-stimulated insulin secretion as well as glucose intolerance in the offspring that received fat milk On the other hand, pups genetically modified to lack the IR in POMC neurons were protected from disturbances in glucose homeostasis in response to maternal HFD feeding during lactation Thus, hyperinsulinemia may predispose the progeny of an overnutritioned breast-feeding mother for future long-lived metabolic disease through hypothalamic IR signalling, whereas the inability to sense the abnormally high levels of insulin acting on POMC neurons during lactation prevents it. Given the escalating numbers of obese and diabetic pregnant or breast-feeding women, a better understanding of metabolic, developmental programming is thus urgently needed. Recent results obtained by combining neural tracing experiments and functional interventions directed to different hypothalamic nuclei provided new insights into the innervation of the pancreas and its influence over glucose metabolism Backtracking the CNS sites innervating the pancreas provide the evidence that glucokinase-expressing neurons in the ARH send signals via multiple synapses to this tissue Functionally, inhibiting glucose sensing in the ARH reduced insulin secretion and led to glucose intolerance, demonstrating a causal relationship between the innervation and pancreatic secretory function As the intervention was not directed towards a specific sub-set of neurons in the ARH, the identity of the neurons regulating pancreatic function remains unknown. POMC and AgRP neurons are both known to change their excitability to fluctuations in extracellular glucose concentrations in electrophysiological studies. POMC neurons are glucose excited, driven by closing of K ATP channels. When POMC neurons lost the ability to sense glucose, through genetically preventing ATP-mediated closure of K ATP channels, or made defective via HFD feeding, glucose tolerance is impaired Whether the effect seen stems from a failure to correctly regulate insulin secretion, however, currently remains unclear. Other than in the ARH, Pomc mRNA is only expressed in the nucleus of the solitary tract within the CNS, and thus shows a very restricted expression pattern. This is in contrast to the MC4R distribution, the receptor for POMC-derived α-MSH, which is broadly expressed in the brain, including in nuclear groups in the medulla oblongata. Deletion of the MC4R in the dorsal motor nucleus of the vagus nerve DMV , part of the dorsal vagal complex DVC Fig. In agreement with these findings, in obese, glucose intolerant and hyperinsulinemic MC4R-null mice, selective restoration of MC4R expression to DMV neurons attenuated the hyperinsulinemia without affecting body weight 8. Thus, DMV MC4R signalling has an essential role in regulating blood insulin levels. Given the dissociation between improvements in insulin levels and lack of body weight reduction, these data also support the existence of divergent melanocortin pathways in control of glucose metabolism and energy balance. Possibly linking hypothalamic neurons to regulation of insulin secretion are insulin-sensitive GLUTexpressing neurons of the hypothalamus GLUT-4 HYPO. Cre-dependent viral tracing experiments have provided evidence that GLUT-4 HYPO neurons project to the DMV, and mice in which GLUT-4 HYPO neurons have been ablated present with elevated plasma glucose and reduced insulin levels but normal pancreatic beta-cell morphometry Accordingly, mice devoid of GLUT-4 HYPO neurons display impaired glucose tolerance. To that end, the authors suggested that the hyperglycaemia is a consequence of impaired insulin secretion involving a GLUT-4 HYPO to DMV projection While the data clearly define a role for GLUT-4 HYPO neurons in the control of energy and glucose metabolism, the experimental approach relied on the death of GLUT-4 HYPO neurons, and did not permit an evaluation on the role of GLUT-4 neurons in discrete hypothalamic areas. Genetic cell ablation may not come without caveats, such as gliosis see below appearing following GLUT-4 HYPO neuron ablation, and a vast array of neurons are GLUTexpressing, making the application of cell-specific excitatory or inhibitory control of viable GLUT-4 HYPO neurons an attractive complement for further expansion of our knowledge on their role in energy metabolism and insulin signalling The reduced propensity of the CNS to respond to hormones during obesity has been extensively studied; the resistance to insulin and leptin within the melanocortin circuitry in the hypothalamus being best defined 82 , 83 , Moreover, in the CNS, activation of inflammatory processes is a key event in the manifestation of peripheral insulin resistance in obese animals 85 , Inflammatory insults to AgRP neurons have a dominant role in these processes 87 as attenuation of the neuroinflammatory response by depriving AgRP neurons of the inhibitor of nuclear factor kappa-B kinase 2 IKK-β gene, an essential trigger of the immune response, protects against obesity and systemic glucose intolerance from HFD feeding Moreover, c-Jun N-terminal kinase 1- and IKK-β-dependent inflammatory signalling is sufficient to drive neuronal and systemic leptin or insulin resistance, respectively, even in the absence of HFD feeding when constitutively activated in AgRP neurons The onset of hypothalamic inflammation is rapid. Gliosis, the process of glial cells in the central nervous system reacting and proliferating to a trauma or injury and a prominent feature of neurodegenerative diseases , surrounding AgRP neurons can be seen within three days and before fat accumulation is measurable in rodents confronted acutely to a HFD Such observations have fostered the hypothesis that neuroinflammation is an actuator of obesity development rather than a secondary consequence of weight gain. The acute HFD-induced gliosis gradually tapers off in rodents 90 , 91 , indicative of an induction of a neuroprotective mechanism, but that is eventually overridden as gliosis, leptin resistance and glucose intolerance persist upon chronic HFD feeding unless the unhealthy diet is discontinued Similar signs of inflammation have been reported in obese humans from neuroradiologic assessments of gliosis 90 , and gliosis has recently been found to associate with higher BMI, fasting insulin and HOMA-IR Homeostatic Model Assessment, a model to assess beta-cell function and insulin resistance in obese humans. Insulin levels and HOMA-IR did not correlate with BMI in these investigations, suggesting a link between gliosis, pancreatic responses and insulin resistance unrelated to the degree of adiposity Recent observations offer evidence in support of a neuroprotective mechanism clearly linked to inflammatory signalling, characterized by similar temporal dynamics and kinetics as the onset and disappearance of HFD-induced gliosis Here, perivascular macrophages are recruited to the blood—brain barrier of the cerebral blood vessels when the brain is challenged with a HFD to limit central inflammation. Via local vascular endothelial growth factor production and increased expression of glucose transporters GLUT-1 , these events are believed to warrant cerebral glucose homeostasis during consumption of energy-dense foods Despite the existences of mechanisms offering acute protection of neuronal function, the extent of the exposure to fatty food is a denominator for the magnitude of hypothalamic inflammation, as prolonged HFD feeding causes leptin and insulin resistance and disturbances in peripheral glucose homeostasis. To this end, non-neuronal cells other than astrocytes and immune cells associated to the cerebral blood vessels as described above are also involved. Evidence suggests that saturated fat can be sensed predominantly by mediobasal hypothalamic, intraparenchymal microglia Activating an inflammatory M1 cytokine response to the buildup of saturated fatty acids in microglia may set the stage for hypothalamic neuronal stress and reduced leptin responsiveness, which in turn may reduce peripheral insulin sensitivity. Understanding the pathomechanisms behind diet-induced neuroinflammation is thus of high priority in the field of metabolism research, as it has implications for our understanding of obesity and insulin resistance as well as a better comprehension of the neurological complications such as neuropathies, cognitive dysfunction and stroke associated with diabetes. Significant advancements to our understanding of how the brain influences peripheral glucose homeostasis have been made owing to studies revealing key brain regions and the identities of the neurons involved, their connectivity and the molecular components causally associated, as well as the peripheral organs and cellular events targeted by the brain. Specifically, HGP, brown fat glucose utilization and control of insulin secretion are processes importantly regulated by the CNS. Although great progress in this area of research has been made, several issues nonetheless remain to be resolved. To this end, while the application of techniques with high spatial resolution in neuroscientific research, relying on the existence of a known cell-specific promoter, has moved us several steps forward towards better control over functional neurocircuits, unique marker genes for many CNS cell-types potentially involved are yet nonetheless still inconspicuous. Moreover, there is extensive heterogeneity in gene expression within single CNS nuclei, and better characterization of this molecular diversity would subsequently improve our comprehension of the neuronal mechanisms controlling peripheral insulin sensitivity and glucose metabolism. Furthermore, a remaining challenge is to directly test whether processes regulating BAT activity and HGP can be exploited for the development of better and safer viable therapeutics. In fact, the beneficial effects of current anti-diabetic therapies, such as insulin supplementation, drugs triggering insulin release, insulin-resistance reducing agents and insulin-sensitizing medications are explained by peripheral actions, and although they successfully reduce hyperglycaemia, they were developed under the assumption that the brain has little, if any, influence on these processes. The inherent adverse effects including hypoglycemia, weight gain and gastrointestinal problems accompanying some of these medications are also problematic. To this end, identifying strong, selective actuators of BAT activation and agents dampening HGP will be important. Indeed, work on defining the neuronal mechanisms controlling BAT and liver biology may not only reveal potential CNS targets, but also facilitate the identification of pathways in liver and BAT directly controlled by the CNS. Realistically, drug candidates in the myostatin signalling cascade, well-studied in the context of muscle growth, sarcopenia and cachexia, could rapidly be advanced into clinical trials assessing their therapeutic potential to moderate insulin resistance. There is also a need to define novel regulators of key glucoregulatory neuronal populations, which may lead to innovative therapies. For instance, recent publications identified the purinergic-receptor 6 P2Y6 as novel regulator of AgRP neuron activity and further revealed that selectively abrogating P2Y6 signalling in AgRP neurons alleviates obesity-associated insulin resistance Translational studies will be necessary to validate if P2Y6-antagonism represents a pharmaceutical way for diabetic treatment. Finally, as failure to suppress HGP or impaired insulin sensitivity and glucose intolerance may develop as consequences of central hormone resistance, especially upon central inflammation, continued efforts in defining the intracellular pathways that are altered in obesity are required, and whether normalization of their function rescues energy and glucose metabolism. Ideally, this knowledge will facilitate to the development of novel pharmaceutical interventions for the treatment of obesity and diabetes. 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Science , — Article CAS ADS PubMed Google Scholar. Pocai, A. A brain-liver circuit regulates glucose homeostasis. Cell Metab. Filippi, B. Rossi, J. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. By examining MC4R signaling in various autonomic nervous system neurons, diverging pathways mediating the effects of melanocortins on energy balance and glucose homeostasis are elegantly covered. Article CAS PubMed PubMed Central Google Scholar. Berglund, E. Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia. Atasoy, D. Deconstruction of a neural circuit for hunger. Nature , — A comprehensive article defining in detail, using circuit mapping to probe a number of postsynaptic targets of starvation-sensitive nerve cells, the functional connection downstream of AgRP neurons in evoked feeding responses. Introduced a concept by which AgRP neurons target oxytocin neurons in the PVH, and inhibit these neurons to promote feeding. Article CAS ADS PubMed PubMed Central Google Scholar. Stachniak, T. Neuron 82 , — Hill, J. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Konner, A. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Steculorum, S. AgRP neurons control systemic insulin sensitivity via myostatin expression in brown adipose tissue. Cell , — Via a distinct and overlapping functional architecture of neurocircuits, this paper explains how AgRP neuron activation acutely impairs insulin sensitivity. It documented for the first time that AgRP neurons rapidly re-program BAT gene expression; a switch towards a myogenic gene profile was seen upon activation of these neurons. Guo, T. Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity. PLoS ONE 4 , e Article ADS CAS PubMed PubMed Central Google Scholar. Krashes, M. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. Joly-Amado, A. Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning. EMBO J. Betley, J. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell , — An elegant paper based on cell-type-specific circuit manipulation and projection-specific anatomical analysis, revealing that stimulation of AgRP neuron projections in numerous brain areas elicits feeding behaviour. Although AgRP neurons project broadly throughout the brain, they appear to project primarily in a one-to-one configuration, and each projection site received innervation from a distinct subgroup of AgRP neurons capable of controlling food intake alone. Aponte, Y. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Wu, Q. Starvation after AgRP neuron ablation is independent of melanocortin signaling. Natl Acad. USA , — Nakajima, K. Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Shi, Y. Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Fenselau, H. Shimazu, T. Reciprocal influences of the ventromedial and lateral hypothalamic nuclei on blood glucose level and liver glycogen content. Nature , — Klockener, T. Meek, T. Functional identification of a neurocircuit regulating blood glucose. USA , E—E A comprehensive article that covers both connectivity and functional aspects, with particular attention to a subset of VMH neurons in glucose counter-regulation. The authors identify an activating projection from the VMH to the aBNST that increases blood glucose levels; silencing the VMH neurons impaired normalization of blood glucose levels during hypoglycemia. Stanley, S. Bidirectional electromagnetic control of the hypothalamus regulates feeding and metabolism. Meister, M. Physical limits to magnetogenetics. Elife 5 , e Bartelt, A. Brown adipose tissue activity controls triglyceride clearance. Yu, S. Glutamatergic preoptic area neurons that express leptin receptors drive temperature-dependent body weight homeostasis. Nakamura, K. A thermosensory pathway that controls body temperature. Lazarus, M. EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses. Jennings, J. The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Morgan, D. Regulation of glucose tolerance and sympathetic activity by MC4R signaling in the lateral hypothalamus. Diabetes 64 , — A paper offering shedding light on the complicated topic of melanocortin signaling. Discrete MC4R restoration in the LHA was found to reduce glucose intolerance in otherwise whole-body MC4R-deficient mice; the improvement could be linked to sympathetic nervous system-dependent control of BAT glucose utilization, occurring without changes in body weight. Cypess, A. Identification and importance of brown adipose tissue in adult humans. Such data were independently described in similarly classic papers the same year in references 37—39, work that revitalized the field of brown fat research and fuelled interest in BAT glucoregulatory properties. van Marken Lichtenbelt, W. Cold-activated brown adipose tissue in healthy men. Virtanen, K. Functional brown adipose tissue in healthy adults. Saito, M. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. |
| Insulin resistance characterizes glucose uptake in skeletal muscle but not in the heart in NIDDM | Inflammatory insults to AgRP neurons have a dominant role in these processes 87 as attenuation of the neuroinflammatory response by depriving AgRP neurons of the inhibitor of nuclear factor kappa-B kinase 2 IKK-β gene, an essential trigger of the immune response, protects against obesity and systemic glucose intolerance from HFD feeding Moreover, c-Jun N-terminal kinase 1- and IKK-β-dependent inflammatory signalling is sufficient to drive neuronal and systemic leptin or insulin resistance, respectively, even in the absence of HFD feeding when constitutively activated in AgRP neurons The onset of hypothalamic inflammation is rapid. Gliosis, the process of glial cells in the central nervous system reacting and proliferating to a trauma or injury and a prominent feature of neurodegenerative diseases , surrounding AgRP neurons can be seen within three days and before fat accumulation is measurable in rodents confronted acutely to a HFD Such observations have fostered the hypothesis that neuroinflammation is an actuator of obesity development rather than a secondary consequence of weight gain. The acute HFD-induced gliosis gradually tapers off in rodents 90 , 91 , indicative of an induction of a neuroprotective mechanism, but that is eventually overridden as gliosis, leptin resistance and glucose intolerance persist upon chronic HFD feeding unless the unhealthy diet is discontinued Similar signs of inflammation have been reported in obese humans from neuroradiologic assessments of gliosis 90 , and gliosis has recently been found to associate with higher BMI, fasting insulin and HOMA-IR Homeostatic Model Assessment, a model to assess beta-cell function and insulin resistance in obese humans. Insulin levels and HOMA-IR did not correlate with BMI in these investigations, suggesting a link between gliosis, pancreatic responses and insulin resistance unrelated to the degree of adiposity Recent observations offer evidence in support of a neuroprotective mechanism clearly linked to inflammatory signalling, characterized by similar temporal dynamics and kinetics as the onset and disappearance of HFD-induced gliosis Here, perivascular macrophages are recruited to the blood—brain barrier of the cerebral blood vessels when the brain is challenged with a HFD to limit central inflammation. Via local vascular endothelial growth factor production and increased expression of glucose transporters GLUT-1 , these events are believed to warrant cerebral glucose homeostasis during consumption of energy-dense foods Despite the existences of mechanisms offering acute protection of neuronal function, the extent of the exposure to fatty food is a denominator for the magnitude of hypothalamic inflammation, as prolonged HFD feeding causes leptin and insulin resistance and disturbances in peripheral glucose homeostasis. To this end, non-neuronal cells other than astrocytes and immune cells associated to the cerebral blood vessels as described above are also involved. Evidence suggests that saturated fat can be sensed predominantly by mediobasal hypothalamic, intraparenchymal microglia Activating an inflammatory M1 cytokine response to the buildup of saturated fatty acids in microglia may set the stage for hypothalamic neuronal stress and reduced leptin responsiveness, which in turn may reduce peripheral insulin sensitivity. Understanding the pathomechanisms behind diet-induced neuroinflammation is thus of high priority in the field of metabolism research, as it has implications for our understanding of obesity and insulin resistance as well as a better comprehension of the neurological complications such as neuropathies, cognitive dysfunction and stroke associated with diabetes. Significant advancements to our understanding of how the brain influences peripheral glucose homeostasis have been made owing to studies revealing key brain regions and the identities of the neurons involved, their connectivity and the molecular components causally associated, as well as the peripheral organs and cellular events targeted by the brain. Specifically, HGP, brown fat glucose utilization and control of insulin secretion are processes importantly regulated by the CNS. Although great progress in this area of research has been made, several issues nonetheless remain to be resolved. To this end, while the application of techniques with high spatial resolution in neuroscientific research, relying on the existence of a known cell-specific promoter, has moved us several steps forward towards better control over functional neurocircuits, unique marker genes for many CNS cell-types potentially involved are yet nonetheless still inconspicuous. Moreover, there is extensive heterogeneity in gene expression within single CNS nuclei, and better characterization of this molecular diversity would subsequently improve our comprehension of the neuronal mechanisms controlling peripheral insulin sensitivity and glucose metabolism. Furthermore, a remaining challenge is to directly test whether processes regulating BAT activity and HGP can be exploited for the development of better and safer viable therapeutics. In fact, the beneficial effects of current anti-diabetic therapies, such as insulin supplementation, drugs triggering insulin release, insulin-resistance reducing agents and insulin-sensitizing medications are explained by peripheral actions, and although they successfully reduce hyperglycaemia, they were developed under the assumption that the brain has little, if any, influence on these processes. The inherent adverse effects including hypoglycemia, weight gain and gastrointestinal problems accompanying some of these medications are also problematic. To this end, identifying strong, selective actuators of BAT activation and agents dampening HGP will be important. Indeed, work on defining the neuronal mechanisms controlling BAT and liver biology may not only reveal potential CNS targets, but also facilitate the identification of pathways in liver and BAT directly controlled by the CNS. Realistically, drug candidates in the myostatin signalling cascade, well-studied in the context of muscle growth, sarcopenia and cachexia, could rapidly be advanced into clinical trials assessing their therapeutic potential to moderate insulin resistance. There is also a need to define novel regulators of key glucoregulatory neuronal populations, which may lead to innovative therapies. For instance, recent publications identified the purinergic-receptor 6 P2Y6 as novel regulator of AgRP neuron activity and further revealed that selectively abrogating P2Y6 signalling in AgRP neurons alleviates obesity-associated insulin resistance Translational studies will be necessary to validate if P2Y6-antagonism represents a pharmaceutical way for diabetic treatment. Finally, as failure to suppress HGP or impaired insulin sensitivity and glucose intolerance may develop as consequences of central hormone resistance, especially upon central inflammation, continued efforts in defining the intracellular pathways that are altered in obesity are required, and whether normalization of their function rescues energy and glucose metabolism. Ideally, this knowledge will facilitate to the development of novel pharmaceutical interventions for the treatment of obesity and diabetes. Such discoveries are also expected to furnish our understanding of neuronal control mechanisms of whole-body insulin sensitivity and glucose metabolism. How to cite this article: Ruud, J. et al. Neuronal control of peripheral insulin sensitivity and glucose metabolism. Ng, M. Global, regional, and national prevalence of overweight and obesity in children and adults during a systematic analysis for the Global Burden of Disease Study Lancet , — Article PubMed PubMed Central Google Scholar. Wild, S. Global prevalence of diabetes: estimates for the year and projections for Diabetes Care 27 , — Article PubMed Google Scholar. Stevens, J. The effect of age on the association between body-mass index and mortality. Article CAS PubMed Google Scholar. Ezzati, M. Comparative Risk Assessment Collaborating G. Selected major risk factors and global and regional burden of disease. Kasuga, M. Insulin stimulates the phosphorylation of the 95,dalton subunit of its own receptor. Science , — Article CAS ADS PubMed Google Scholar. Pocai, A. A brain-liver circuit regulates glucose homeostasis. Cell Metab. Filippi, B. Rossi, J. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. By examining MC4R signaling in various autonomic nervous system neurons, diverging pathways mediating the effects of melanocortins on energy balance and glucose homeostasis are elegantly covered. Article CAS PubMed PubMed Central Google Scholar. Berglund, E. Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia. Atasoy, D. Deconstruction of a neural circuit for hunger. Nature , — A comprehensive article defining in detail, using circuit mapping to probe a number of postsynaptic targets of starvation-sensitive nerve cells, the functional connection downstream of AgRP neurons in evoked feeding responses. Introduced a concept by which AgRP neurons target oxytocin neurons in the PVH, and inhibit these neurons to promote feeding. Article CAS ADS PubMed PubMed Central Google Scholar. Stachniak, T. Neuron 82 , — Hill, J. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Konner, A. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Steculorum, S. AgRP neurons control systemic insulin sensitivity via myostatin expression in brown adipose tissue. Cell , — Via a distinct and overlapping functional architecture of neurocircuits, this paper explains how AgRP neuron activation acutely impairs insulin sensitivity. It documented for the first time that AgRP neurons rapidly re-program BAT gene expression; a switch towards a myogenic gene profile was seen upon activation of these neurons. Guo, T. Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity. PLoS ONE 4 , e Article ADS CAS PubMed PubMed Central Google Scholar. Krashes, M. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. Joly-Amado, A. Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning. EMBO J. Betley, J. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell , — An elegant paper based on cell-type-specific circuit manipulation and projection-specific anatomical analysis, revealing that stimulation of AgRP neuron projections in numerous brain areas elicits feeding behaviour. Although AgRP neurons project broadly throughout the brain, they appear to project primarily in a one-to-one configuration, and each projection site received innervation from a distinct subgroup of AgRP neurons capable of controlling food intake alone. Aponte, Y. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Wu, Q. Starvation after AgRP neuron ablation is independent of melanocortin signaling. Natl Acad. USA , — Nakajima, K. Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Shi, Y. Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Fenselau, H. Shimazu, T. Reciprocal influences of the ventromedial and lateral hypothalamic nuclei on blood glucose level and liver glycogen content. Nature , — Klockener, T. Meek, T. Functional identification of a neurocircuit regulating blood glucose. USA , E—E A comprehensive article that covers both connectivity and functional aspects, with particular attention to a subset of VMH neurons in glucose counter-regulation. The authors identify an activating projection from the VMH to the aBNST that increases blood glucose levels; silencing the VMH neurons impaired normalization of blood glucose levels during hypoglycemia. Stanley, S. Bidirectional electromagnetic control of the hypothalamus regulates feeding and metabolism. Meister, M. Physical limits to magnetogenetics. Elife 5 , e Bartelt, A. Brown adipose tissue activity controls triglyceride clearance. Yu, S. Glutamatergic preoptic area neurons that express leptin receptors drive temperature-dependent body weight homeostasis. Nakamura, K. A thermosensory pathway that controls body temperature. Lazarus, M. EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses. Jennings, J. The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Morgan, D. Regulation of glucose tolerance and sympathetic activity by MC4R signaling in the lateral hypothalamus. Diabetes 64 , — A paper offering shedding light on the complicated topic of melanocortin signaling. Discrete MC4R restoration in the LHA was found to reduce glucose intolerance in otherwise whole-body MC4R-deficient mice; the improvement could be linked to sympathetic nervous system-dependent control of BAT glucose utilization, occurring without changes in body weight. Cypess, A. Identification and importance of brown adipose tissue in adult humans. Such data were independently described in similarly classic papers the same year in references 37—39, work that revitalized the field of brown fat research and fuelled interest in BAT glucoregulatory properties. van Marken Lichtenbelt, W. Cold-activated brown adipose tissue in healthy men. Virtanen, K. Functional brown adipose tissue in healthy adults. Saito, M. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58 , — Orava, J. 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Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, Cologne, , Germany. Johan Ruud, Sophie M. Policlinic for Endocrinology, Diabetes and Preventive Medicine PEDP , University Hospital Cologne, Kerpener Strasse 26, Cologne, , Germany. Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases CECAD and Center for Molecular Medicine Cologne CMMC , University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, , Germany. National Center for Diabetes Research DZD , Ingolstädter Land Strasse 1, Neuherberg, , Germany. You can also search for this author in PubMed Google Scholar. Correspondence to Jens C. This work is licensed under a Creative Commons Attribution 4. Reprints and permissions. Ruud, J. Nat Commun 8 , Download citation. Received : 28 September Accepted : 14 March Published : 04 May Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. nature nature communications review articles article. Download PDF. Subjects Metabolism Neuroscience. Figure 1: Glucoregulatory roles of the pancreatic-derived hormones insulin and glucagon. Full size image. Key CNS sites in control of glucose metabolism Solid evidence for a role of CNS circuits in regulating systemic glucose homeostasis dates back to the s Box 1. Figure 2: Key brain nuclei and areas involved in CNS control of glucose homeostasis. Full size table. Table 2 Cell type-specific manipulations reported to alter food intake. Box 2: AgRP and POMC ARH neurons are key regulators of food intake. Box 1: Claude Bernard revisited. Brown fat activity and humans In humans, the quantity of BAT correlates inversely with BMI, BAT is highly responsive to cold and diet exposure, an adaptive response that is reduced in obese and overweight subjects, and insulin 36 , 37 , 38 , 39 , Hormonal signalling to the brain and effects on glucose metabolism Afferent hormonal and nutritional cues provide feedback signals to the brain that are crucial for systemic glucose homeostasis. Figure 3: Pathways involved in the control of glucose homeostasis. Central control of pancreatic islet function The islets of the pancreas are subject to regulation by insulin signalling in the brain, and their connection with the CNS and the efferent arm of the autonomic nervous system is remarkably vulnerable during a specific developmental time window of the hypothalamic neurocircuitry Obesity perturbs CNS control of peripheral glucose metabolism The reduced propensity of the CNS to respond to hormones during obesity has been extensively studied; the resistance to insulin and leptin within the melanocortin circuitry in the hypothalamus being best defined 82 , 83 , Future directions Significant advancements to our understanding of how the brain influences peripheral glucose homeostasis have been made owing to studies revealing key brain regions and the identities of the neurons involved, their connectivity and the molecular components causally associated, as well as the peripheral organs and cellular events targeted by the brain. Additional information How to cite this article: Ruud, J. References Ng, M. Article PubMed PubMed Central Google Scholar Wild, S. Article PubMed Google Scholar Stevens, J. Article CAS PubMed Google Scholar Ezzati, M. Article PubMed Google Scholar Kasuga, M. Article CAS ADS PubMed Google Scholar Pocai, A. Article CAS PubMed Google Scholar Filippi, B. Forty percent were healthy control participants i. None had a clinical diagnosis of neurologic disease. Patients with T2D used either metformin 1—3 g daily , or a combination of metformin and dipeptidyl peptidase-4 inhibitors. Patients receiving insulin treatment were excluded. All participants underwent a screening visit before inclusion in the study. Metformin was withheld 24—72 h and dipeptidyl peptidase-4 inhibitors 24 h before the metabolic study. Prior to inclusion, each participant gave written consent. Each protocol included in this study was approved by the Ethics Committee of the Hospital District of Southwest Finland Turku, Finland and conducted in accordance with the Declaration of Helsinki. The anthropometric and metabolic characteristics of all study participants are listed by study in Supplementary Table 1. In this cohort, BGU was quantified only during a euglycemic hyperinsulinemic clamp. The euglycemic hyperinsulinemic clamp was performed as previously described Plasma glucose levels were measured every 5—10 min throughout the clamp. During the clamp, samples for plasma insulin and serum FFA measurement were taken at baseline and at 30 and 60 min, respectively, thereafter. Of note, the Gjedde-Patlak analysis and FUR strongly correlate with each other For the early scans, the FUR calculation was restricted between 30 and 40 min. For the late scans, all frames were included. To account for possible differences between early and late studies, we derived a regularization parameter from an ad hoc experiment, as described in the Supplementary Material. Meta-analytic uniformity maps of the four selected key cognitive domains were downloaded. This approach examines the extent to which M-value—dependent BGU effects correspond with cerebral localization of different cognitive functions. We explored variables influencing BGU using Bayesian hierarchical modeling. We estimated varying intercepts and slopes for each brain lobe and varying intercepts for the participants. To capture project-specific variation unrelated to variables of interest e. late scans , we also estimated varying intercepts for the projects. The following variables were included in the model: insulin sensitivity as indexed by the M value , age, sex, steady-state insulin level, and presence of T2D. BMI was not included in the model, because of its high collinearity with the M value Supplementary Fig. Including all these predictors in the same model allowed us to identify the unique contribution of each of these variables while adjusting for the others. BGU values were log transformed because posterior predictive checking indicated that log transformation significantly improves model fit. For regularizing purposes, we used the standard normal distribution as the prior distribution for regression coefficients. We also provided an informative prior for the difference between early and late scans see Supplementary Material for more details on priors and the statistical modeling. Otherwise, we used the default prior distributions of the BRMS package. These effects were estimated by adding each of these three variables, in turn, to the main model to use maximal amount of data for each variable while adjusting for all the variables included in the main model. Linear regressions were performed in statistical parametric mapping SPM12 toolbox for Matlab to evaluate correlations between BGU and single regressors M value, age, T2D, sex. The data set comprised of participants. Data on the anthropometric and metabolic characteristics of all study participants are reported as means and ranges in Table 1. Plasma glucose levels were maintained throughout the studies at mean ± SD 5. M value correlated negatively with steady-state insulin A and steady-state FFA levels B during the clamp. No correlation was found between M value and plasma glucose levels during the clamp C. BGU was negatively associated with M value and age. For M value, the effect was similar across all the brain lobes. This finding was also confirmed in the statistical parametric mapping analysis Fig. For age, however, there was regional variation: the effect was strongest in limbic and temporal lobes, whereas the frontal and parietal lobes only showed a negative trend. We could not find evidence for age dependency of BGU in the occipital lobe. Sex did not affect BGU. The data also suggest that T2D, adjusting for insulin sensitivity, is associated with elevated BGU. There is, however, uncertainty about the magnitude of the effect as indicated by the wide posterior intervals. Steady-state insulin levels did not make an independent contribution to BGU. Posterior intervals of the regression coefficients for the variables of interest predicting BGU. ss, steady state. Brain clusters as defined by false discovery rate—corrected statistical parametric mapping one-sample t test for the association between BGU during clamp and M value and the corresponding scatterplots. These results show how well the M value—dependent BGU effects correspond with cerebral localization of different cognitive functions. The main finding of our study was that insulin sensitivity, assessed using the gold standard M value from a euglycemic clamp, correlates negatively with BGU under conditions of insulin stimulation and is the strongest predictor of BGU among all parameters investigated. We also found that presence of T2D further contributes to increased BGU. To our knowledge, the present data set comprises information on the largest cohort of people with apparently normal cognitive function whose BGU has been studied under euglycemic hyperinsulinemia, and our findings are in line with previous reports of other research groups in both humans and animals 18 , It appears to be a consistent finding that during euglycemic hyperinsulinemia, BGU correlates inversely with insulin sensitivity. The underlying mechanisms for this characteristic of brain metabolism are not known. Some authors have speculated that insulin resistance does not have an effect on the expression of GLUT transporters in the brain, whereas their expression is markedly reduced in skeletal muscle in insulin resistance In line with this, findings of a preclinical study indicated that whereas fasting and diabetes markedly decreased GLUT4 expression in adipose tissue, brain GLUT4 expression was only marginally affected by the same conditions On the basis of recent evidence that the [ 18 F]-FDG uptake in the brain is driven by astrocytes 28 and that a high-fat diet leads to astrocyte proliferation and activation called astrogliosis 29 , we hypothesize that the increased BGU in insulin resistance is driven by brain inflammation. We are investigating this hypothesis in a clinical trial Clinical trial reg. NCT, clinicaltrials. However, if astrogliosis is one part of the picture, hyperinsulinemia is a prerequisite for the higher BGU in the context of insulin resistance, because in the fasting conditions, neither we, studying humans 16 , nor Bahri et al. In turn, systemic hyperinsulinemia may either activate central circuits directly or this effect could be mediated by the periphery through retrograde signaling to the brain. Of note, it has been shown that insulin stimulates glucose uptake in cultured glial cells from brain tissue 30 and that human astrocytes, upon insulin stimulation, synthesize glycogen and proliferate All in all, astrocytes represent optimal candidate cells to explain this peculiar brain characteristic regarding BGU during insulin stimulation, but more research is warranted to reveal the underlying cellular mechanisms. Even though the relevance of our findings under clamp conditions may be criticized because of their experimental nature, systemic insulin levels achieved during euglycemic hyperinsulinemic clamps were those typically seen in the postprandial state. Information about brain glucose metabolism in more physiologic conditions is scanty, but Daniele et al. Previous studies in patients prone to AD under fasting conditions have reported that insulin resistance associates with brain hypometabolism in key brain areas that are affected in AD 14 , Regarding the insulin effect, seminal work by Talbot et al. Accumulating evidence supports the notion that AD may be considered a metabolic disease of the brain, in which brain glucose use is impaired and, whereas early brain glucose hypermetabolism i. Similar temporal paradoxical patterns have been described in other neuroimaging studies, in which memory-related functional MRI showed hyperactivation in less-impaired patients with MCI and hypoactivation in more-impaired patients with MCI More research is definitely warranted to clarify the complex pathophysiology that links systemic metabolic and central disorders. In this context, we think a cross-sectional and longitudinal comparison of brain glucose metabolism in conditions of euglycemic clamp between BMI and age-matched individuals with normal cognition, MCI, and AD could aid understanding of the present findings. BGU decreased with advancing age, and this effect was especially evident in the limbic lobe, in line with previous studies showing that fasting BGU decreases with aging Thus, we extend this finding to the insulin-stimulated state. Several other parameters were tested for their contribution to BGU. Presence of T2D seemed to further increase BGU, although there was uncertainty about the magnitude of this effect, as indicated by the wide posterior intervals. This finding is in line with the established notion that worse metabolic control is associated with more severe insulin resistance. FFAs cross the blood-brain barrier, and we have previously shown that obese patients have increased brain FFA uptake as compared with lean individuals On the basis of previous studies showing that hypothalamic sensing of circulating FFAs is important in the control of nutrient intake and energy balance 37 , we hypothesized that FFAs could be key players in the cross-talk between brain and peripheral tissues in the context of insulin resistance. However, our data showed that when accounting for insulin resistance, steady-state FFA levels were not an independent predictor of BGU. Likewise, we did not find any evidence for an association between plasma insulin levels and BGU. In clamp experiments, a feature of patients with insulin resistance is higher plasma insulin levels compared with insulin-sensitive patients, as also seen in our study, despite similar rates of exogenous insulin infusion. Despite being higher in patients with insulin resistance, plasma insulin levels did not correlate with BGU. In a previous study, researchers showed that whereas obese patients had increased plasma insulin levels, they had relative lower central nervous system insulin levels compared with lean individuals 38 , suggesting that the central effects of insulin cannot be predicted by the peripheral plasma insulin levels. BGU in the insulin-stimulated state was not significantly affected by sex. Previous studies regarding the effect of sex on BGU have yielded mixed results 39 , In our data, men tended to have lower BGU across all brain regions examined. However, as shown in Fig. Strengths of our study are its large size across a wide range of insulin sensitivity and age; the application of Bayesian hierarchical model for the investigation of the effects not only of insulin sensitivity but also of other potential effectors of brain glucose uptake; and the application of gold standard techniques i. Our study has also limitations. First, the current analysis documents associations but does not explain the mechanisms underlying the observed increase in BGU in the context of insulin resistance. Second, we combined data from several projects that originally focused on different research questions, and the data, therefore, are not optimally balanced across different covariates. However, we used a large sample, analyzed all data with the same approach, and accounted for differences in the projects using statistical modeling. Even though the FUR is considered a less accurate method, it correlates very well with Patlak 23 and is a valid alternative of quantification of PET data, which could be applied more often in research settings. The individuals included in the current data set had apparent normal cognitive function, but cognitive function testing was not performed. Still, we used a meta-analytic approach that showed that BGU clusters with domains of cognitive function. Unfortunately, this type of analysis does not allow an evaluation of the brain areas involved. This further underlines the need for studies to investigate how BGU is linked to cognitive function and whether an increased BGU at baseline can predict cognitive decline in the long term. Finally, due to the physics of the PET, small brain areas such as the hypothalamus cannot be examined. Even though the study of the hypothalamus is of special interest in metabolic investigation, our results demonstrate that the interplay between insulin resistance and BGU is present at the whole-brain level. In conclusion, in a large sample of participants across a wide range of age and insulin sensitivity, we have shown that insulin-stimulated BGU correlates negatively with the degree of insulin sensitivity. Presence of T2D was also associated with enhanced BGU and, as expected, age was a negative independent predictor of BGU. As the incidence of metabolic and neurodegenerative disorders increases, there is a compelling need to identify the common pathophysiologic pathways of these conditions, which may eventually lead to efficient treatments and prevention. The authors thank the staff of the Turku PET Centre for performing the PET imaging. The study was conducted within the Center of Excellence in Cardiovascular and Metabolic Diseases, supported by the Academy of Finland, the University of Turku, Turku University Hospital, Åbo Akademi University, Finnish Diabetes Foundation, Sigrid Juselius Foundation, and Finnish Cultural Foundation. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. conceived the study design. analyzed data and literature and drafted the manuscript. conducted the clinical positron emission tomography studies. analyzed the compartmental data analyses. reviewed the manuscript. All authors approved the final version of the manuscript. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the Keystone Symposium Bioenergetics and Metabolic Disease, Keystone, CO, 21—25 January ; and at the 54th European Association for the Study of Diabetes annual meeting, Berlin, Germany, 1—5 October Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Diabetes Care. Advanced Search. User Tools Dropdown. |
| Insulin Resistance and Diabetes | Cancer Res — The euglycemic hyperinsulinemic clamp was performed as previously described Volume 53, Issue 2. Performed the experiments: AM EA. Functionally, inhibiting glucose sensing in the ARH reduced insulin secretion and led to glucose intolerance, demonstrating a causal relationship between the innervation and pancreatic secretory function Article CAS PubMed Google Scholar Ono, H. Cerebral glucose metabolic rates in normal human females versus normal males. |
| Association between insulin resistance and the development of cardiovascular disease | Clinical Science , — In subjects with type 2 diabetes, hepatic uptake of VLDL, IDL, and LDL is decreased, resulting in increased residence time of these lipoproteins in the plasma [ 96 ]. Glucose fluctuations and hyperglycemia trigger inflammatory responses via mitochondrial dysfunction and endoplasmic reticulum stress. View author publications. The failing heart relies on ketone bodies as a fuel. |
Molecular Insylin volume 10uptwke 65—71 Cite this Insulin sensitivity and glucose uptake. Metrics details. Gaps remain in our understanding of Joint health strength Guarana for Mental Clarity molecular sensitivuty by which insulin regulates glucose uptake in fat and muscle cells. Recent evidence suggests that insulin action involves multiple pathways, each compartmentalized in discrete domains. Upon activation, the receptor catalyzes the tyrosine phosphorylation of a number of substrates. One family of these, the insulin receptor substrate IRS proteins, initiates activation of the phosphatidylinositol 3-kinase pathway, resulting in stimulation of protein kinases such as Akt and atypical protein kinase C.
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