It has become clear that BAT influences other peripheral tissues and controls their functions and systemic homeostasis of energy and metabolic substrates, suggesting BAT as a metabolic regulator, other than for thermogenesis. This notion is supported by discovering that various paracrine and endocrine factors are secreted from BAT.

We review the current understanding of BAT pathophysiology, particularly focusing on its role as a metabolic regulator in small rodents and also in humans. Keywords : Adipocytes, beige ; Adipose tissue ; Adipose tissue, brown ; Energy metabolism ; Thermogenesis ; Uncoupling protein 1.

Uncoupling protein 1 UCP1 -dependent and independent thermogenesis in brown and beige adipocytes. UCP1, a protein located in the mitochondrial inner membrane, has the ability to leak proton gradient across the mitochondrial membrane, and thereby uncouples oxidative phosphorylation to generate heat.

Thus, UCP1 thermogenesis is not dependent on adenosine triphosphate ATP. On the other hand, thermogenesis by the futile cycles of creatine and creatine phosphate, release and re-uptake of calcium, and triglyceride TG hydrolysis and fatty acid FA re-esterification is dependent on the breakdown of ATP to adenosine diphosphate ADP.

These thermogenic mechanisms are activated by cold exposure primarily through the sympathetic nerve activation. RyR, ryanodine receptor; SERCA, sarco-endoplasmic reticulum ATPase. Cod-induced uncoupling protein 1 UCP1 -dependent and -independent metabolic changes in brown adipose tissue BAT.

Cold exposure triggers triglyceride TG hydrolysis, fatty acid FA uptake, oxidation of FA via β-oxidation and tricarboxylic acid TCA cycle, and UCP1 activation. These are intimately associated with anaerobic glycolysis, and uptake of succinate and glutamine.

In UCP1-KO brown adipocytes, cold exposure triggers TG hydrolysis, FA uptake, and β-oxidation of FA, similarly in wild-type brown adipocytes. Resulting acetyl-coenzyme A CoA is not oxidized by TCA cycle but used to re-synthesis of FA and TG.

αKG, α-ketoglutaric acid. Endocrine actions of brown adipose tissue BAT -derived factors. Citations Citations to this article as recorded by. PubReader ePub Link Cite CITE. The biogenesis of different adipocytes and their characteristics.

The three mature adipocytes including white adipocytes, beige adipocytes, and brown adipocytes can derive from progenitors via de novo differentiation. Importantly, white adipocytes can reinstall the thermogenic program by mitochondria biogenesis in response to cold and certain other stimuli.

When external stimuli are withdrawn, mitochondria-enriched beige adipocytes transform into dormant adipocytes that resemble white adipocytes. In addition, the three types of adipocytes have distinct morphology and anatomical location. White adipocytes are mostly distributed in white adipose tissue, existing in various subcutaneous and intra-abdominal depots and contributing to the storage and release of energy.

Stimulated by beigeing factors, beige adipocytes appear in white adipose tissue sporadically. Compared with beige adipocytes, brown adipocytes are an embryonic-origin cell type and cluster in designated depots like interscapular brown adipose tissue depots of mice and infants.

However, both brown and beige fat cells are capable of thermogenesis because they have multilocular lipid droplets and densely packed mitochondria. Part of the HE images in this figure is generated from the Human Protein Atlas.

This figure was created on BioRender. com with permission for publication. In mammals, the developmental origin of classical brown fat cells is evolutionally conserved.

Concretely, brown adipocytes develop prenatally, and their fate is determined by mid-gestation. It implies that the thermogenic function of brown adipose tissue BAT is completely activated at birth, which is of supreme importance to newborn animals because neonates of many larger animals including humans are based on the non-shivering thermogenesis of BAT to maintain normal body temperature.

Some of the BAT depots in humans are anatomically analogous to those in rodents. In addition to the three pads mentioned above, humans also possess BAT depots in four anatomic regions, such as abdominal, mediastinal, supraclavicular, and paraspinal.

However, some of the BAT depots regress and are absent in adults, for example, the BAT depot in the interscapular region is most dominant in infants and gradually declines with growing. Although beige adipocytes share many morphological and biochemical characteristics with classical brown adipocytes, they have distinguishing phenotypic and functional features.

Primarily, beige fat cells can arise via de novo differentiation from adipocyte progenitors. Then, the rouse of the thermogenic phenotype by dormant cells also contributed to the recruitment of beige adipocytes in WAT depots. As an illustrative example, cold, as the most well-known thermogenic stimulus, can promote de novo beige adipocyte differentiation from α smooth muscle actin αSMA -positive stromal progenitor cells through triggering intracellular signaling, including cyclic adenosine monophosphate cAMP signaling via stimulation of β-adrenergic receptor β-AR.

It is universally accepted that beige adipocytes exist mainly in subcutaneous WAT, including anterior subcutaneous and inguinal WAT, and suprascapular fat depots. For example, perivascular adipose tissue PVAT was widely perceived to be brown fat depots.

Nevertheless, recent studies suggest that PVAT shows characteristics of beige adipose tissue in humans and BAT-like in mice. More precisely, PVAT is not always brown-like in mice or beige-like in humans, depending on the anatomic location and environmental or metabolic context.

In sum, the reinstallation and loss of thermogenesis in beige fat are adapted to altered external conditions. The mechanism of recruiting beige adipocytes may vary depending on the nature of the stimulus and of heterogeneity beige adipocytes in various metabolic diseases including cancer, which will be infusive areas for future research.

The most important biological role of brown and beige fat cells is to participate in the process of non-shivering thermogenesis that involves uncoupling protein 1 UCP1, a characterized thermogenic factor highly expressed in beige and brown adipocytes -dependent and UCP1-independent mechanisms.

Moreover, thermogenic fat considered a secretory organism can secrete various molecules to mediate communication with diverse organs and tissues via autocrine, paracrine, and endocrine. Instead, we focus on the influence caused by breaking brown and beige fat homeostasis on metabolic diseases Fig.

The multiple roles of thermogenic adipocytes in metabolic homeostasis. Thermogenic fat is generally considered a metabolic sink for glucose, lipid, and BCAAs.

In addition, brown or beige adipocytes have an impact on neighbor cells by secreting batokines. Moreover, thermogenic adipose tissue is also recognized as an endocrine organ, regulating the gene expression or functions in distant organs, such as the heart, liver, muscle, and brain.

The mechanisms of thermogenesis consist of classical UCP1-dependent and novel UCP1-independent pathways. Intimately closed to the malfunction of thermogenesis, obesity is often described as a disorder of energy intake and expenditure. For example, inhibition of the key transcriptional factor PRDM16 or reduction of UCP1 which is both involved in the UCP1-dependent pathway can drive obesity.

For instance, genetic depletion of creatine metabolism in adipocytes impairs diet-induced thermogenesis that limits weight gain in response to caloric excess and then develops obesity. As an important substrate for fueling thermogenesis, glucose can be actively transported into thermogenic adipocytes which is a common characteristic.

Typically, glucose uptake in beige and brown adipocytes is stimulated by insulin. Insulin stimulation of glucose uptake via glucose transporters in fat tissues is essential for regulating systemic blood glucose levels. Indeed, evidence from an early study demonstrated that genetic deletion of brown adipocytes leads to the development of obesity.

For example, treatment with the β3-adrenergic receptor β3-AR agonist, such as mirabegron which was approved for treating overactive bladder, can improve glucose and insulin homeostasis.

Although thermogenic fat is characterized by a high rate of glucose uptake, FAs are generally recognized as the primary fuel for mitochondrial uncoupling respiration.

In general, upon activation by long-chain FAs, UCP1 increases the conductance of the inner mitochondrial membrane IMM to make thermogenic adipocytes mitochondria generate heat. By contrast, promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane can increase FAs uptake into thermogenic adipocytes.

Given the fact that the FAs constitute a preferred energetic substrate for most thermogenic adipocytes, increasing evidence has shown that thermogenic fat exerts effects on systemic lipid metabolism.

As illustrative examples, BAT activity can control vascular lipoprotein homeostasis by boosting triglyceride-rich lipoproteins TRL turnover and channeling lipids into BAT, and this process crucially relies on local lipoprotein lipase LPL activity and CD36 in mice models by short-term cold exposure.

Of note, current research also emphasizes the importance of UCP1-independent thermogenesis based on ATP-dependent futile cycling, and how it impacts the whole-body lipid homeostasis dynamically remains unclear.

Apart from glucose and FAs, BCAAs including valine, leucine, and isoleucine have also been demonstrated to support thermogenesis in mice and humans, and active BCAAs oxidation is required for optimal thermogenesis in turn. Moreover, defective BCAAs catabolism in beige and brown adipose tissue causes impaired thermogenesis.

Further, decreased SIRT4 expression is found in the adipose tissue of diabetic mouse models. So to comprehensively understand the roles they play calls for further experiments and clinical trials.

Beyond heat generation, solid evidence has suggested that some of the physiological effects of beige and brown adipocytes are mediated by releasing small molecules, defined as batokines.

Some of the adipokines released by brown or beige adipocytes have been identified by the transcriptomic, proteomic, and metabolomic analysis, including proteins, lipids, and metabolites.

Furthermore, the broad number of articles suggest that these secretory batokines mainly act in an autocrine, paracrine, or endocrine manner to regulate neighboring cells and distant organs.

Generally, batokines can act on cells within the adipose tissue and promote adipogenesis, angiogenesis, neurite outgrowth, and immune cell interactions. In particular, the thermogenic activity of beige and brown fat cells can be enhanced by bone morphogenetic protein-8b BMP8b , fibroblast growth factor FGF21 , Follistatin-like 1 FSTL1 , and the cytokine interleukin-6 IL-6 , or inhibited by the soluble form of the LDL receptor 11 sLR11 , which are secreted by themselves with autocrine actions.

Beyond these local effects, batokines can impact distant tissues in an endocrine fashion, such as the liver, heart, skeletal muscle, and central nervous system CNS. Furthermore, batokines such as FGF21 might influence sympathetic nervous system activity and circadian behavior.

As an illustrative example, researchers newly have demonstrated that a population of GABAergic neurons in the dorsolateral portion of the dorsal raphe nucleus DRN is capable of regulating thermogenesis through both direct and indirect pathways. Preclinical experiments have suggested that some of the factors released by thermogenic fat cells such as FGF21 increase cardiac substrate oxidation and protect the heart from hypertensive cardiac remodeling.

More precisely, activated thermogenic adipocytes secret neuregulin 4 NRG4 , which then acts on hepatocytes to decrease de novo lipogenesis and protect the liver from damage.

For instance, the FA derivative 12,dihydroxy- 9Z -octadecenoic acid 12,diHOME is increased within beige and brown fat in response to exercise or cold exposure to enhance thermogenesis, leading to the enhanced FAs uptake and oxidation of myocytes in an endocrine manner.

Collectively, these publications have identified plenty of candidate batokines from mammals, and some of them remain mysterious. Further research is warranted into this aspect to comprehensively understand the secretome of beige or brown adipocytes, and describe the action mode of each of these molecules in every single metabolic disease, including malignancy which is seem to be forgotten by researchers studying thermogenic fat.

Currently, it is widely accepted that the activity of thermogenic adipose tissue declines during the development of metabolic disorders. Examples, overeating like emotional eating, peer pressure, snacking , low energy expenditure like aging, neuroendocrine factors, sarcopenia, and medications , or physical inactivity like chronic fatigue, low fitness level, emotional barriers, and joint pain can influence the chronic positive energy balance, thus subsequently causing obesity.

During the development of obesity, adipose tissue can expand by de novo synthesis and enlargement of existing adipocytes, whereas the mass of activated thermogenic fat is decreased. Compared with white fat, brown and beige adipose tissue is beneficial for combating obesity by enhanced lipolysis of triglycerides and the oxidation of FAs.

Give an illustrative example, selectively genetic depletion of glycine amidinotransferase GATM in fat Adipo-Gatm KO or the cell surface creatine transporter CRT in fat AdCrTKO substantially reduces adipocyte creatine, inhibits thermogenesis and energy expenditure, then driving obesity as a consequence.

Mechanically, the AKG stimulates the secretion of adrenaline through 2-oxoglutarate receptor 1 OXGR1 expressed in adrenal glands and causes muscle hypertrophy and fat loss consequently. More specifically, they found that HPF directly targeted dihydrolipoamide S-acetyltransferase DLAT and thereby enhanced the capacity of heat generation by activating AMPK and PGC1A.

Polyethylene glycol PEG -crosslinked polydopamine nanoparticle PDA is a safe and injectable photothermal hydrogel that converts near-infrared NIR light input into accurately controlled temperature output. Mechanically, local hyperthermia activates heat shock factor 1 HSF1 , and enhanced HSF1 regulates Hnrnpa2b1 transcription, consequently increasing the mRNA stability of key metabolic genes.

T2DM is arguably one of the largest epidemics ever seen globally, leading to the ninth major cause of death. The number of people with T2DM has doubled in the last several decades and is projected to rise further to almost million by Accumulation of excess WAT is detrimental to metabolic health, while the activation of thermogenic fat has a beneficial influence on diabetes.

Insulin is a major regulator of glucose uptake in most tissues, including BAT, WAT, and skeletal muscle glucose. However, heat production-related glucose uptake into thermogenic fat has been suggested to be independent of insulin signaling, primarily dependent on GLUT1 transporter in an adrenergic-promoted manner.

Non-communicable diseases NCDs are the leading cause of death and ill health, which account for seven of ten deaths around the world. Further, obesity also leads to CVD mortality independently of other cardiovascular risk factors. As an active endocrine and paracrine organ, excessive adipose tissue releases multiple hormonses and cytokines, such as leptin, adiponectin, IL-6, and TNF-α, which result in diabetes, cardiovascular inflammation, increased blood pressure level, fibrinolysis, and atherosclerosis.

Generally, thermogenic fat potentially exerts beneficial metabolic and cardiovascular effects through stimulating energy expenditure, attenuating cardiac remodeling, and suppressing the inflammatory response. In animal studies, increased BAT activation stimulated by beta-adrenaline can diminish the progress of hypercholesterolemia and protect from atherosclerosis development in mice with hyperlipidemia.

Accordingly, overexpression of BMP4 in adipose tissues enhanced the thermogenic activity of PVAT and protects against atherosclerosis in mice.

Of note, epicardial adipose tissue EAT is part of the VAT that surrounds the heart, excessive accumulation of whom is considered a risk factor for the incidence of coronary artery diseases. Furthermore, thermogenic genes expressions in EAT were recongnized as protective factors against coronary artery disease and heart failure with reduced left ventricular ejection fraction.

By contrast, mice with genetic ablation of UCP1 is susceptible to hypertension, cardiomyopathy, and fibrosis. Interestingly, the cardiac parameters and survival of UCP1 knock-out mice were improved after receiving a BAT transplant from the controls. There is growing evidence to indicate that the dysregulation of adipose tissue is closely linked with metabolic diseases in rodents and humans, such as T2DM, obesity, fatty liver, and pancreatitis.

Besides, some of them have been considered high-risk factors for multiple tumors. Recently, there is a systematic understanding that WAT is capable of promoting tumor growth, metastasis, and chemoresistance.

Firstly, white adipocytes fuel tumor growth by providing nutrients like FAs and glutamine. For example, adipocytes can decrease the natural killer cell toxicity, activate the inflammatory phenotype of macrophages, and promote fibrosis and vascularization in tumors.

The role of thermogenic adipose tissue in malignancy. Polypeptides, metabolites, or other certain mediators derived from cancerous cells initial the conversion of white-to-beige locally and distantly.

On the one hand, activated beige adipocytes in SAT lead to lipolysis and energy expenditure, subsequently contributing to cancer-associated cachexia. On the other hand, the adjacent thermogenic fat can directly promote tumor growth and metastasis by secreting specific molecules, such as lactate.

Accordingly, pharmacologically inhibiting the browning of white adipose tissue slows cancer progression and improves the outcomes for patients. ZAG zinc-α 2 -glycoprotein, PTHRP parathyroid-hormone-related protein, LIF leukemia inhibitory factor, GDF15 growth differentiation factor 15, ADM adrenomedullin, IL-6 the cytokine interleukin-6, β3-AR β3-adrenergic receptor, TKI tyrosine kinase inhibitor, Arctii Fructus the extract of Arctium lappa.

Cancer-associated cachexia is a multifactorial syndrome characterized by weakness, loss of fat, and muscle wasting, which is driven by a variable combination of reduced food intake and metabolic changes, such as elevated energy expenditure, excess catabolism, and systemic inflammation.

Moreover, cancer cachexia has commonly been considered the main inducement of complications in patients with malignancy, leading to reduced quality of life and poor outcomes. Thus, a switch from white to thermogenic fat contributes to cancer cachexia by increasing systemic energy expenditure.

Notably, the WAT browning generally takes place during the initial steps of cancer cachexia, preceding the loss of muscle.

The adipose tissue microenvironment ATME consists of multiple cell types, such as adipocytes, stromal cells, immune cells, vascular endothelial cells, and fibroblasts. First, adipocytes can secrete nutrients and adipokines into the microenvironment, contributing to cancer cell proliferation and invasion.

For instance, adipocytes release cellular contents into the microenvironment through pyroptosis or necrosis in response to external clues like hypoxia or low pO 2 and mechanical stress, then triggering the accumulation of phagocytic macrophages consequently. Besides, the elastase of neutrophils causes insulin resistance and elevated levels of free insulin by cleaving insulin receptor substrate 1 IRS1 , contributing to enhanced phosphoinositide 3-kinase PI3K signaling within tumor cells.

On the one hand, adipocytes in ATME strongly support tumor growth and enhanced angiogenesis by releasing particular molecules directly in hepatocellular carcinoma.

Moreover, the interaction between pancreatic stellate cells and adipocytes promotes matrix remodeling and impairs vascular perfusion, leading to tumor growth and ineffective chemotherapy.

Nevertheless, how the thermogenic adipocytes in ATME affect tumor development and metastasis is mysterious. To make it clear, we may need to identify subpopulations of adipocytes in tumor-associated ATME by single-nucleus sequencing sNuc-seq or single-cell RNA sequencing scRNA-seq technique.

The interaction except cachexia between thermogenic adipose tissue and cancer cells differs in tumor types. Nowadays, our understanding of it is limited but promising, which is expected to provide a novel strategy for diagnosis, therapy, or prognosis.

Hepatic carcinoma is the fourth leading cause of cancer-related mortality worldwide, which generally arises in a background of hepatitis and cirrhosis. Primary liver cancer commonly consists of hepatocellular carcinoma HCC , intrahepatic cholangiocarcinoma iCCA , and other rare tumors like hepatoblastoma and fibrolamellar carcinoma.

These chronic inflammation originate from hepatitis B or C virus HBV or HCV infections, metabolic disorders including excess body weight, diabetes, impaired glucose tolerance, metabolic syndrome, alcoholic steatohepatitis ASH , and nonalcoholic fatty liver disease NAFLD , smoking, chronic toxin exposure, and parasite infection, and the majority of them are potentially modifiable risk factors.

Recently, there are some great reviews summarizing the pathogenetic mechanisms of the transition from NAFL to NASH and even HCC. According to recent investigations, thermogenic fat is induced to increase the energy expenditure of the whole body, and then alleviate obesity and hepatic steatosis simultaneously.

Mechanically, increased succinate in liver tissue drives inflammation through blinding to succinate receptor 1 SUCNR1 in liver-resident stellate cell and macrophage populations and activated thermogenic adipocytes in mice protect against SUCNR1-dependent inflammatory infiltration in the liver. By contrast, the crosstalk between thermal adipocytes and hepatic cancer cells is barely revealed.

Just one previous research found that the thermogenesis signaling pathway was upregulated in HCC patients without fibrosis by functional enrichment analysis, which might predict survival in HCC patients.

Epidemiologically, represents the sixth most frequently diagnosed cancer in men and the tenth in women, respectively, and its incidence rates have been increasing. Based on histological and cytogenetic signatures, RCC is divided into several subtypes. For example, recent research has shown that melatonin promotes tumor slimming and suppress tumor progression by activating transcriptional coactivator PGC1A and lipid browning programs.

Specifically, researchers used RNA-Seq analysis to find that PRDM16 disrupts the transcriptome of cancer cells like semaphorin 5B SEMA5B , which is a hypoxia-inducible factor HIF target gene highly expressed in RCC that promotes in vivo tumor growth. More precisely, ccRCC cells activate PAT browning through the secretion of PTHRP, then the thermogenic adipocytes increase lactate secretion and promote ccRCC cell proliferation.

Notably, tyrosine kinase inhibitors TKI often used to treat ccRCC, such as sunitinib, have been shown to activate adipocytes browning, and the combination therapy of TKI plus browning inhibitor present a more-complete suppression of ccRCC.

and 7. Besides, extensive research has shown that PC also ranks 4th and 6th the cancer-associated deaths in the U. and China, respectively. by In addition, SAT wasting was likely related to the browning of adipocytes, because overexpression of UCP1 in SAT exposed to PC exosomes was tested in mice and patients with PC.

However, hyperglycemia is detected in quite a few PC patients before or after the diagnosis of PC, although the browning of SAT is considered a phenomenon of decreasing blood glucose.

In addition to SAT, pancreatic fat accumulation is linked to chronic pancreatitis, pancreatic neoplasms, disturbed glucose metabolism, and impaired insulin secretion.

Given that some cancers have been observed to promote browning of adjacent WAT, whether the browning of intrapancreatic adipose tissue occurs and the crosstalk between brown pancreatic fat and tumor required further research.

Breast cancer BC is the most common cancer diagnosed in many countries including the US excluding skin cancers and China, which is the second leading cause of cancer death among women after lung cancer and remains the primary tumor-associated cause of disease burden for women.

In addition, it is important to notice that BC is also the most commonly diagnosed cancer type in young adults aged 30 to 39 years. Moreover, the breast adipose tissue is impacted by surrounding cancer cells, and vice-versa modifies the TME in favor of cancer via browning of WAT.

Furthermore, activated thermogenic adipocytes in the breast can modulate the behavior of mammary epithelial cells and promote tumor progression in both tumor and non-tumor mice.

Tumors derived from the stomach are a global health problem, with more than 1 million people newly diagnosed with gastric cancer GC worldwide each year.

For instance, researchers found that exosomes released from GC cells could deliver circular RNAs into preadipocytes, promoting the differentiation of preadipocytes into mature adipocytes with thermogenic phenotype via stimulating PRDM16 and suppressing miR Colorectal cancer CRC is the main contributor to global cancer mortality, accounting for roughly 1.

Optimistically, the incidence and mortality are gradually stable and even slightly declined in developed countries owing to nationwide screening programs and increased uptake of colonoscopy in general.

Nevertheless, new cases of early-onset CRC generally defined as CRC diagnosed before the age of 50 years have recently been increasing globally, which exhibits different clinical manifestations, pathological characteristics, and molecular features compared to later-onset CRC patients.

As with most cancers, body fat and obesity are modifiable risk factors increasing CRC incidence. Give an example, they find that intestinal disease tolerance is preferentially established in thermoneutral mice, protecting them from injury-induced colitis and inflammation-induced colon cancer.

Besides, the underlying mechanism is mediated by an unexpected crosstalk between thermogenic adipocytes and intestinal epithelial cells. The clue of thermogenic adipose tissue is indirect and scattered in the rest of the cancers, thus which will not be discussed here.

Collectively, cancer cachexia is the most common and mechanically clear impact caused by WAT browning. In contrast, the local inter-communication between thermogenic adipocytes and other cells in TME-like immune cells is unrevealed.

Therefore, future research on this topic should be encouraged. Findings over the past two decades have comprehensively described the multiple functions of thermogenic adipocytes in mice and humans.

Significantly, their abnormal activity is closely related to cancer and other metabolic diseases. Accordingly, investigators have been actively searching for effective tools and pharmacologic agents to identify and manipulate activated thermogenic fat, respectively, holding promise for combating malignancy and metabolic disorders clinically.

Different from WAT, thermogenic fat has distinctive features of ontogeny, bioenergetics, and physiological functions. These characteristics provide an opportunity to differentiate thermogenic fat from WAT by using imaging tools. Additionally, some novel molecular imaging modalities will be enumerated in Table 1.

Clinicians can identify suspected malignancies and metastases by measuring the uptake of radiolabelled glucose. Moreover, investigators developed Brown Adipose Reporting Criteria in Imaging Studies BARCIST 1. Compared with PET, MRI has better spatial resolution at a lower cost and is much safer as they do not involve the injection of radioactive tracers.

Apart from PET and MRI, plenty of other modalities have been developed to identify thermogenic adipose tissue, such as single-photon emission computerized tomography SPECT , near-infrared fluorescence imaging NIRFI , contrast-enhanced ultrasound CEUS , near-infrared spectroscopy NIRS , infrared thermography IRT.

Given the role of thermal fat in nutrient metabolism and energy expenditure as well as its impact on other tissues, activating thermogenic adipose tissue provides a promising therapeutic strategy for curbing obesity, T2DM, and other metabolic diseases.

Although the overwhelming benefits have been demonstrated in some metabolic diseases, the adverse side effects of browning should not be ignored, like cachexia and cardiovascular events in hypermetabolic conditions. In turn, blocking WAT browning might be exploited for clinical benefit in hypermetabolic patients.

Collectively, we have to figure out how we can preserve the therapeutic effects by manipulating thermogenesis, while also eliminating many of the unexpected side effects. In addition, we also cite some evidence to show the therapeutic potential of brown and beige fat in humans with malignancy.

Activating the browning of adipose tissue is emerging as an interesting and promising method to curb metabolic disorders like obesity and T2DM because of its unique capacity to upregulate non-shivering thermogenesis. Moreover, it has been demonstrated that exercise can stimulate the browning of WAT and increase energy consumption by promoting the expression of hypothalamic brain-derived neurotrophic factor BDNF.

For instance, capsaicin and its analog capsinoids mimic the effects of cold exposure to decrease body fatness through the activation and recruitment of BAT through activating transient receptor potential TRP channels. Remarkably, recent preclinical investigations have shown that successful BAT transplantation models display improvements in glucose metabolism and insulin sensitivity, as well as reductions in body mass and decreased adiposity in recipients.

These beneficial effects are mediated by several different mechanisms, including endocrine effects via the release of batokines. Give an illustrative example, human adipose-derived stem cells were differentiated into brown adipocytes with rosiglitazone and then injected into mice every other week over 10 weeks, then the models injected with the thermogenic cells showed a loss of body weight and enhanced glucose tolerance.

Although driving thermogenesis in preclinical and clinical studies of metabolic diseases like obesity showed exciting results, its beneficial effects on cancer patients have not been reported yet. Regarding previous investigations, the abnormal accumulation of WAT promotes tumorigenesis, progression, invasion, and metastasis.

All of these hypotheses require strong evidence. On present evidence, hypermetabolic conditions including burns and cancer in which browning is detrimental to patient outcome. In the skin tumor mice model, investigators found that WAT browning was an early event in the pathophysiology of cancer cachexia, and treatment with the selective β3-AR antagonist or nonsteroidal anti-inflammatory drug sulindac could ameliorate cachexia owing to the reduction of browning in subcutaneous WAT.

The primary reason is that Metformin can inhibit the electron transport chain ETC and ATP synthesis, and it also can regulate AMP-activated protein kinase AMPK and mTORC1 in multiple ways. Thermogenic adipocytes including brown and beige adipocytes have garnered considerable attention recently, mainly because both of them have similar impacts on thermoregulation and nutrient utilization.

Although brown and beige adipocytes come from distinct origins during embryonic development and locate in different positions anatomically, they have multilocular lipid droplets, abundant mitochondria, and highly expressed UCP1.

Of note, beige fat cells are reproducible in adults. More precisely, the emergence of beige adipocytes is an inducible process stimulated by external clues such as cold, exercise, and fasting. Therefore, manipulating the thermogenic program provide a promising therapeutic strategy for combating obesity, T2DM, cancer, and other diseases.

Although multiple therapeutic strategies activating thermogenesis have been shown to work well in animal models, the majority of them do not apply to humans. Probably the heterogeneity in thermogenic adipose tissue between the two species make the translational application from mice to humans harder.

Moreover, it should not be ignored that targeting thermogenic fat can give rise to adverse effects in vivo, such as cachexia, heart diseases, and other hypermetabolic disorders. Collectively, investigators and clinicians must consider it prudent how we can preserve the beneficial metabolic effects of browning and meanwhile eliminate many of the unexpected side effects.

In contrast to obesity or diabetes, the influence of thermogenic adipocytes is not one-sided anymore but double-edged during the initiation and progression of the tumor.

Firstly, activated thermogenic adipocytes can prevent obesity, T2DM, and other metabolism-related diseases like NAFLD through increasing energy expenditure, enhancing glucose tolerance, or alleviating inflammation, and the majority of these metabolic diseases are generally considered high-risk factors for multiple tumors.

Specifically, enhanced thermogenesis in SAT speeds up fat mass loss and cancer cachexia, thereby contributing to the poor outcome of cancer patients. Ultimately, malignant cells are resistant to chemotherapy partly because chemotherapeutic drugs stimulate reinstallation of the thermogenic phenotype in WAT.

Although targeting thermogenic adipocytes is not a reliable treatment for cancer patients based on current research, it has already presented its therapeutic potential in other metabolic conditions.

Referring to the current status of investigating thermogenic fat, there are several aspects worth studying further in oncology.

Besides, from the perspective of translational medicine, a novel detective technology is required for precisely distinguishing thermogenic fat from tumors and continuously evaluating the capacity of thermogenesis. Moreover, it is also necessary to explore how to achieve safe and effective beige fat activation in tumors locally, because inducing thermogenesis through traditional ways like cold stimuli or beta-adrenergic signaling possibly results in potential cardiovascular hazards.

In conclusion, recent investigations provide new insights into the biology and pathology of thermogenic fat and preliminarily reveal its connection to metabolic diseases and malignancy, thereby suggesting that modulating the activity of thermogenic adipocytes holds promise for combating obesity, T2DM, cancer, and other metabolic diseases.

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