Lifestyle modifications largely designed to alter fat mass and distribution are the cornerstone of these interventions and have been shown to delay the onset of hyperglycemia in individuals at high risk for the disease 20 , Similarly, chronic CR has dramatic beneficial effects on glucose tolerance and insulin action in rodents 12 and in primates Importantly, reduction in visceral adiposity is a common feature of all these interventions.

However, it has been difficult to discern whether a reduction in the size of intra-abdominal fat depots plays a causative role or is simply a covariant tightly associated with one or more causative factors.

Here, we show that surgical removal of two intra-abdominal fat depots prevents the onset of age-dependent insulin resistance and markedly delays the onset of glucose intolerance and diabetes in a rodent model of obesity and diabetes. Our findings indicate that a modest decrease in total fat mass per se does not have a significant impact on insulin action.

However, not all fat depots have equal metabolic import. Adipose tissue from different anatomical sites has markedly different effects on metabolic outcomes. In fact, removal of a similar amount of adipose tissue from the peri-renal and peri-epididymal sites VF led to dramatic improvements in peripheral and hepatic insulin sensitivity and glucose tolerance.

The onset of diabetes in the ZDF rats tracked very closely with the regeneration of VF several weeks after its surgical removal. Our results may provide useful information in the contentious debate regarding the mechanism s by which CR improves metabolic parameters and extends life in rodent models Until recently, the effects of CR on life extension 24 , 25 were related directly to the decreased intake of nutrients rather than to secondary effects on body weight, fat mass, or distribution of body fat.

This study documents that insulin action can be improved in the absence of CR, challenging the notion that nutrient excess per se is the prominent cause of insulin resistance in this aging model. Overall, the dramatic improvement in peripheral and hepatic insulin action after removal of visceral but not SC adipose tissue resembles the effects of prolonged CR in aging rodents However, a closer look at other associated variables in the two intervention models also reveals striking differences.

CR results in marked reductions in body weight, total fat mass, and lean body mass. Conversely, the surgical removal of VF markedly improves metabolic parameters in the absence of any detectable changes in body weight, fat mass, and lean body mass.

Furthermore, the reduction in VF is the result of a proportional decrease in all VF depots with CR, whereas it is entirely due to decreased epididymal and perinephric fat in our surgical model.

Thus, decreased VF could largely account for the beneficial metabolic effects of chronic CR. However, our results cannot quantify the relative contribution of mesenteric, epididymal, and perinepric fat depots in mediating these effects. Insulin resistance is a major risk factor for the development of diabetes in humans and animals Here, we used the Zucker Fatty rat model, which resembles common features of obese patients developing type 1 diabetes This model is characterized by marked hyperinsulinemia and insulin resistance Thus, removal of VF dramatically improved insulin sensitivity in Zucker Fatty rats.

Thus, selective intra-abdominal fat depots play a major role in modulating insulin action and glucose tolerance in these two animal models. Can we speculate on potential mechanism s by which these depots regulate insulin action in distant sites? One possibility is that increased plasma levels of FFAs and glycerol impair insulin action in both the liver and muscle 29 — In fact, it has been suggested that VF is resistant to the antilipolytic effects of insulin, and its removal may have decreased the flux of FFAs and glycerol to these target organs However, the concentrations of FFAs and glycerol were unchanged in these experimental models at both basal conditions and during the studies.

It should also be pointed out that the venous drainage of the mesenteric fat is portal, whereas that of the epididymal and perinephric fat is caval. Recent evidence indicates that adipose cells are also capable of biosynthesis and secretion of several metabolically active factors Some of these factors circulate in plasma and are active at distant targets 19 , In this regard, it is of interest that the mRNA encoding for the novel circulating protein resistin was much higher in epididymal and perinephric adipose tissue than in SC adipose tissue.

The extraction of VF also resulted in marked changes in the expression of the fat-derived peptide TNF-α in the SC adipose tissue. TNF-α may be directly involved in the development of insulin resistance in obesity through its effects on insulin signaling VF removal was also associated with decreased plasma concentrations of both insulin and leptin.

Leptin mRNA in SC adipose tissue was also decreased. The decline in circulating levels of these hormones may simply reflect their improved biological action.

However, it is also likely that a decrease in plasma insulin concentrations and perhaps decreased carbon flux into the hexosamine pathway may account for the decreased expression of leptin in SC adipose tissue after VF removal Finally, removal of VF resulted in a significant decrease in plasma Acrp30 levels.

Thus, because Acrp30 normally induces a potentiation of insulin action, the improvements in systemic insulin sensitivity seen with VF removal was probably mediated through mechanisms distinct from an increase in circulating Acrp30 levels.

Our results indicate that the surgical removal of selective intra-abdominal fat depots prevents the age-related decrease in peripheral and hepatic insulin action and may regulate gene expression in SC adipose tissue. Furthermore, removal of VF delays the onset of diabetes in the ZDF model of obesity and diabetes.

Thus, we propose that specific interventions designed to reduce intra-abdominal adiposity will greatly improve insulin action. Further studies will be necessary to identify the specific fat-derived signals by which selective depots of adipose tissue regulates glucose fluxes and gene expression at distant sites.

Peripheral insulin sensitivity in aging rats. Shown are results for young 2-month-old and old month-old F1 hybrids of F and Brown Norway rats. Hepatic insulin sensitivity in aging rats. The ability of insulin to suppress EGP was studied using glucose tracer methodology see research design and methods.

R a , rate of EGP. Development of diabetes and the regrowth of VF in ZDF rats. Six rats from each group were studied using a pancreatic clamp, and the rest were monitored for 4 months until they developed diabetes.

Gene expression of TNF-α and leptin. RT and real-time PCR analysis for TNF-α, leptin, and β-actin are described in research design and methods. B : Analysis of all real-time PCR data obtained in all rats, corrected for intensity of β-actin and presented in arbitrary units.

mesenteric fat. Gene expression of resistin A and ACRP30 B. B : Real-time PCR data obtained from all rats corrected for the intensity of β-actin and presented in arbitrary units. M and SC. young 2-month-old , and old month-old F1 hybrids of F and Brown Norway rats were used in these experiments.

The table depicts the amounts of VF or SC removed at the surgery, body weight, lean body mass, non-VF fat mass, total VF, and epididymal, perinephric, and mesenteric fat, which were determined at killing after the experiments.

Plasma glucose, insulin, FFA concentrations, basal rate of EGP R a , glucose infusion rate GIR , glycolysis Gly , and glycogen synthesis GS during the basal period and during the pancreatic euglycemic clamp are shown.

These parameters were measured at basal conditions and during the insulin clamps see group description in research design and methods. The table depicts the amounts of VF removed at surgery, body weight, lean body mass, non-VF fat mass, and total VF, epididymal, perinephric, and mesenteric fat that were detected after the study.

This work was supported by grants from the National Institutes of Health Paul Beeson Physician Faculty Scholar in Aging Award and RO1-AG to N. and RDK and ROI-DK to L. Address correspondence and reprint requests to Nir Barzilai, Institute for Aging Research, Belfer Bldg.

E-mail: barzilai aecom. CR, caloric restriction; dsDNA, double-stranded DNA; EGP, endogenous glucose production; FFA, free fatty acid; SC, subcutaneous; TNF-α, tumor necrosis factor-α; VF, visceral fat. Sign In or Create an Account. Search Dropdown Menu.

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Article Information. Article Navigation. Obesity Studies October 01 Removal of Visceral Fat Prevents Insulin Resistance and Glucose Intolerance of Aging : An Adipokine-Mediated Process?

Ilan Gabriely ; Ilan Gabriely. Third, some key data regarding items such as details of diabetes medications, eating behaviors, and nutritional status were not collected. Future prospective studies including these data are also needed. Appropriate estimated VFA cut-off points for DM are As SFA was associated with DM only in women, the appropriate estimated cut-off is Our results suggest that it is important to consider both SFA and VFA, especially in women, for primary and secondary prevention of DM.

The ethics committee imposed restrictions to data access and sharing. Individuals who wish to access our data must obtain further permission from the committee, which can be achieved by contacting the corresponding author. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al.

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BMC Cardiovasc Disord. Download references. The authors thank all participants who underwent the voluntary medical check-ups and the data collection staff at Juntendo University Hospital. Department of General Medicine, Juntendo University Faculty of Medicine, Hongo , Bunkyo-ku, Tokyo, , Japan.

Department of General Medicine, Juntendo University School of Medicine, Hongo , Bunkyo-ku, Tokyo, , Japan. You can also search for this author in PubMed Google Scholar.

HY, HF, and TN participated in the design of the study. HY, HF, MS, KG, TK, TM, YT, CH, and YH participated in data collection and revised the manuscript.

HY, HF, and TN conceived the study, participated in its design, and revised the manuscript. HY participated in analysis of the data and revised the manuscript. Current DPP4 inhibitors do not reduce inflammation in fat or improve insulin resistance. Many patients with type 2 diabetes are given oral DPP4 inhibitors known as gliptins to help manage their disease.

These drugs lower blood sugar by preventing DPP4 from interfering with a hormone that stimulates insulin production. But surprisingly, these drugs had no effect on inflammation in the abdominal fat of obese mice, the researchers found.

The reason for this shortcoming of gliptins, Tabas believes, may be related to their effects in the gut versus the liver. But we have some evidence that DPP4 inhibitors in the gut also end up promoting inflammation in fat. That cancels out the anti-inflammatory effects the drugs may have when they reach inflammatory cells, called macrophages, in the fat.

When the researchers selectively blocked DPP4 production inside liver cells, they were able to reduce fat inflammation and improve insulin resistance, while also lowering blood sugar.

The findings suggest that DPP4 inhibitors could be more potent if they were redirected to liver cells and away from the gut. In theory, current DPP4 inhibitors could potentially be redirected by packaging the drug into nanoparticles that are delivered to the liver.

However, the CUIMC team is studying an alternate approach that uses small interfering RNAs siRNAs —snippets of genetic material that silence particular genes—to turn off liver cell DPP4.