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Beige Adipocytes Are A Distinct Type Of Thermogenic Fat Cell In Mouse And Human Pdf

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A new hypothesis based on structural and molecular heterogeneity of thermogenic adipocytes suggests that regulated thermogenesis in mammalian adipose tissues involves two structural-functional levels. The first level comprises typical brown fat and beige adipocytes of subcutaneous white fat depots. Being a part of the functional thermoregulatory system, this level of heat production is controlled by the appropriate hypothalamic centers. The second level is represented by visceral beige adipocytes with a relatively low total thermogenic capacity which provide a fine local adjustment of thermal optima for cell renewal processes.

Two-Level Organization of Thermogenesis in Adipose Tissue: a Morphofunctional Hypothesis

Promotion of brown adipose tissue BAT activity or browning of white adipose tissue has shown great potential as anti-obesity strategy in numerous preclinical models. The discovery of active BAT in humans and the recent advances in the understanding of human BAT biology and function have significantly propelled this field of research. Pharmacological stimulation of energy expenditure to counteract obesity has always been an intriguing therapeutic concept; with the identification of the specific molecular pathways of brown fat function, this idea has now become as realistic as ever.

Two distinct strategies are currently being pursued; one is the activation of bone fide BAT, the other is the induction of BAT-like cells or beige adipocytes within white fat depots, a process called browning. Recent evidence suggests that both phenomena can occur in humans. Cold-induced promotion of BAT activity is strongly associated with enhanced thermogenesis and energy expenditure in humans and has beneficial effects on fat mass and glucose metabolism.

Despite these encouraging results, a number of issues deserve additional attention including the distinct characteristics of human vs rodent BAT, the heterogeneity of human BAT depots or the identification of the adipocyte precursors that can give rise to thermogenic cells in human adipose tissue. In addition, many pharmaceutical compounds are being tested for their ability to promote a thermogenic program in human adipocytes. This review summarizes the current knowledge about the various cellular and molecular aspects of human BAT as well as the relevance for energy metabolism including its therapeutic potential for obesity.

There is now a large body of evidence — at least in rodents — that the actions of brown adipose tissue BAT or the browning of white adipose tissue WAT can protect against obesity and related complications 1 , 2 , 3. The molecular mechanisms that are responsible for the energy-dissipating qualities of brown fat have been studied in detail 4 , 5. Uncoupling protein-1 UCP-1 has been identified as the key factor controlling the thermogenic capacity of brown adipocytes 6.

UCP-1 disrupts the electrochemical gradient across the mitochondrial membrane by allowing protons to reenter the mitochondrial matrix. Consequently, mitochondrial fatty acid oxidation is increased and chemical energy is wasted through heat production thermogenesis 4 , 7. This process has long been believed to occur exclusively in brown adipocytes; however, in recent years, a large number of studies have reported about the emergence of UCPpositive cells in WAT with very similar properties as BAT cells 3 , 8 , 9.

A hallmark of beige adipocytes is their potential to take on a thermogenic phenotype in response to various stimuli such as cold, chemical compounds or genetic factors. Under basal conditions, beige cells express very similar molecular markers as classic white adipocytes with low UCP-1 levels ; however, when appropriately stimulated, they acquire a thermogenic signature with high UCP-1 expression and increased energy consumption similar to bone fide brown adipocytes 2 , 3 , 10 , 11 , 12 , Despite some mutual features, brown and beige adipocytes also have very distinct characteristics.

For instance, they differ in their anatomical location; whereas beige cells emerge within WAT, particularly in the subcutaneous depots, classic brown adipocytes reside within bone fide BAT typically located in the interscapular region in rodents and human infants 3 , 13 , Another difference between brown and beige adipocytes pertains to their developmental origin.

Classical brown adipocytes originate from precursor cells in the embryonic mesoderm that express the transcription factor myogenic factor 5 MYF5 and can give rise to either brown adipocytes or myocytes. The transcriptional co-regulator PR domain containing 16 PRDM16 has been shown to control the switch between myogenic vs adipogenic differentiation in the MYF5-positive precursors 15 , In contrast, beige adipocytes are believed to come from a MYF5-negative lineage. However, the exact origin of beige adipocytes still remains a matter of great debate given that recent lineage tracing studies in rodents provide evidence for two fundamentally different concepts 3.

One is the so-called precursor model because it implies that beige adipocytes are derived from a distinct progenitor cell population by de novo differentiation in response to distinct stimuli such as prolonged cold exposure or certain genetic modifications. The other concept proposes that mature white adipocytes can transdifferentiate into beige adipocytes when appropriately challenged and has therefore been termed transdifferentiation or more accurately interconversion model 8 , 17 , Given the context in which these fate-mapping studies have been performed, it is possible that both developmental models are correct and that additional factors such as the environment e.

Regardless of the precise developmental origin, the induction of thermogenically active beige adipocytes in WAT has proven to be effective in preventing or reducing obesity and diabetes in numerous preclinical models. Current research is directed at discovering the various molecular cues that induce such a browning program in WAT.

Besides chronic cold exposure, a number of transcription factors and co-regulators have been identified to control the browning process. In addition, circulating factors such as thyroid hormones, bile acids, natriuretic peptides, retinoids, fibroblast growth factor 21 FGF and various cytokines can regulate a thermogenic program in WAT 14 , 19 , 20 , 21 , 22 , Notably, physical exercise has also been demonstrated to promote WAT browning in mice through a muscle-derived hormone named irisin However, it is still a matter of investigation which of these pathways are conserved in humans and to what extent they contribute to thermogenesis and energy dissipation.

In fact, the FDG-positive fat depots have been viewed as impediment to diagnostic imaging because the signal could obscure tumor visualization or introduce false positive results 25 , Therefore, beta blockers have occasionally been used to repress the unwanted FDG uptake Notably, very early studies including one in Finnish outdoor workers had already indicated that the occurrence of BAT may be influenced by ambient temperatures In line with these early observations are newer reports of seasonal variations in BAT activity showing negative correlations with average outdoor temperatures 32 , In humans, BAT depots are typically located in the deep cervical, supraclavicular, parasternal and sometimes perirenal regions 28 , 29 , 30 , 34 and Fig.

In some rare cases of pheochromocytoma, significant FDG uptake has also been detected in visceral adipose tissue reflecting a browning of this WAT compartment due to the prolonged stimulation with endogenous catecholamines 35 , However, after surgical removal of the tumor, FDG uptake was no longer present in the visceral fat suggesting reversal of the browning process Citation: Endocrine Connections 6, 5; Other research is directed at testing alternative radiotracers beyond FDG 40 , Given that BAT is primarily utilizing fatty acids as fuel substrate, various lipid tracers such as 11 C-acetate and 18 F-fluoro-thiaheptadecanoic acid have been studied Ever since the discovery of cold-induced BAT in humans, researchers have tried to better understand the molecular characteristics of this adipose depot.

Therefore, biopsy studies of FDG-positive neck fat depots have been performed to establish the genetic signature of human BAT. By comparing the results from human fat biopsies with those from mouse fat depots, researchers have tried to address the question whether human BAT resembles the molecular and functional aspects of bone fide brown or beige fat.

Currently, there is evidence for both, which can in part be explained by the large heterogeneity of the human BAT samples studied. Depending upon the exact anatomical location, human BAT has been suggested to display either a classical brown or a beige signature or both 44 , 45 , 46 , Another important limitation besides the heterogeneous composition of human brown fat depots is the fact that the marker genes that have been used for genetic characterization of human BAT have previously been identified in mouse tissues 10 , 45 , These gene sets may not fully reproduce the molecular landscape of human BAT, which makes it more challenging to unequivocally distinguish between beige and brown fat in humans.

In this context, it is noteworthy that thermoneutral conditions occur at different ambient temperatures in mice and humans that is mice require slightly higher temperatures for thermoneutrality. Regardless of those experimental caveats, human BAT is a metabolically highly active tissue with a respiratory capacity up to fold greater than WAT and comparable to rodent BAT when normalized to the mitochondrial content Another important issue that has recently drawn a lot of interest is the capacity of human WAT to acquire BAT-like features.

Turning the large amounts of white fat, as seen in obese subjects, into energy-dissipating beige fat represents an intriguing concept with great potential for therapeutic applications. Reports from pheochromocytoma patients with FDG-positive intra-abdominal WAT depots containing adipocytes with high UCP-1 expression suggest that browning of visceral WAT can occur in response to catecholamine excess 35 , 36 , 53 , A more recent study in intensive care patients found that subcutaneous fat can also undergo significant browning under extreme conditions.

Severe burn injuries led to the emergence of UCPpositive beige cells within the subcutaneous fat with a maximum several weeks after the trauma. This observation was linked to the severe adrenergic stress and the prolonged elevation of norepinephrine levels seen after such burn injuries Likewise, a case study in a patient with papillary thyroid carcinoma found that TSH-suppressing treatment with levothyroxine T4 induced BAT activity and browning of subcutaneous adipose tissue The relevance of thyroid hormones for adipose browning in humans is also supported by findings that circulating free T4 concentrations significantly correlated with gene expression of classic brown fat markers in the subcutaneous WAT of middle-aged obese men and women Whether browning of WAT can also be induced under controlled pharmacological conditions and whether that results in increased energy wasting and body weight loss in humans is yet to be shown.

Soon after the detection of cold-induced BAT in human adults in , numerous follow-up studies confirmed that activated BAT contributed to non-shivering thermogenesis and oxidative metabolism in humans.

The reduction in fat mass was greater in subjects with higher BAT activity and correlated with the degree of cold-induced thermogenesis Both, glucose and fatty acid uptake contribute to increased BAT oxidative metabolism in humans 42 , 60 , 61 , Using hyperinsulinemic—euglycemic clamp studies, BAT activation was shown to improve whole-body glucose disposal and insulin sensitivity confirming its relevance for total energy metabolism 58 , However, rapidly elevated BAT radiodensity after short-term cold exposure led to the hypothesis that acute BAT thermogenesis is fueled predominantly by fatty acids hydrolyzed from intracellular triglycerides.

Not only did nicotinic acid administration suppress cold-induced BAT oxidative metabolism and glucose uptake in healthy men, but it also led to an increase in skeletal muscle shivering intensity. These results suggest that intracellular triglyceride lipolysis is likely essential for BAT thermogenesis and provide experimental evidence for a reciprocal role of non-shivering thermogenesis in BAT and shivering thermogenesis in skeletal muscle. In recent years, the importance of BAT as a major site for lipoprotein metabolism has been increasingly appreciated thanks largely to mouse models that demonstrated that cold-activated BAT can effectively clear plasma triglycerides predominantly through the actions of lipoprotein lipase and CD36 64 , 65 , Moreover, BAT activation mitigates hypercholesterinemia and atherosclerotic plaque formation 66 , 67 , suggesting a potential cardioprotective role, possibly independent of increased energy expenditure and weight loss.

Whether this concept holds true for cardiovascular disease in humans is yet to be shown. Interestingly, the recruitment of BAT during cold acclimation was not associated with any elevation in energy expenditure, which may be a consequence of the modest increase in BAT activity observed in this study.

However, when comparing BAT-positive with BAT-negative subjects, there is a plethora of evidence for higher cold-induced thermogenesis, enhanced energy expenditure and improved whole-body glucose homeostasis in those with active BAT irrespective of the body mass 58 , 59 , 68 , Interestingly, enhanced skeletal muscle glucose uptake due to elevated GLUT4 translocation seemed to account for majority of the glycemic effects seen in this study, raising the possibility that activated BAT may release endocrine factors that engage other metabolic tissues such as skeletal muscle.

Recent evidence suggests that BAT is indeed a source of hormone production and that these BAT-derived factors may play a role in systemic energy metabolism.

In addition to its function as a thermogenic organ, BAT has recently been identified as a tissue with high secretory capacity. Accumulating evidence from preclinical studies suggests that molecules released from BAT differ significantly from those released from WAT. Most of the autocrine and paracrine molecules such as nerve growth factor, fibroblastic growth factor 2 and vascular endothelial growth factor-A promote BAT growth, vascularization, innervation and blood flow, processes that are important for BAT recruitment during thermogenic stimulation The transplantation of BAT into diabetic or diet-induced obese mice significantly improved glycemic conditions, WAT inflammation and systemic adipokine profiles 72 , 73 , Secretion of insulin-like growth factor 1 has been proposed as one endocrine mechanism for the antidiabetic actions of transplanted BAT Morphological and molecular studies from transplanted BAT revealed larger adipocyte size and decreased thermogenic gene expression in comparison to endogenous BAT These findings suggested that the beneficial effects of BAT transplantation may not primarily be driven by the intrinsic thermogenic activity but by endocrine factors released from the transplant.

Additional support for this concept came from a study showing that the favorable metabolic effects of BAT transplantation were lost when interleukin-6 IL-6 -deficient mice were used as donors, suggesting IL-6 as another endocrine mediator of transplanted BAT IL-6 has previously been identified to be secreted form activated brown adipocytes The role of IL-6 as a classic pro-inflammatory cytokine has to be reconsidered in light of recent data that IL-6 signaling can promote insulin sensitivity in skeletal muscle and adipose tissue of mice 76 , The importance for BAT as secretory organ has also been highlighted by a recent report identifying BAT as a source for circulating exosomal miRNAs, which function as negative regulators of translation.

Transplantation of BAT into mice lacking the miRNA-processing enzyme Dicer restored the levels of numerous circulating miRNAs that are associated with an improvement in glucose tolerance In this context, a new class of lipids has been identified, that is released from tissues and acts locally or systemically on energy turnover, glucose metabolism and inflammatory pathways 80 , One of these so-called lipokines is the BAT-derived 12,dihydroxy-9Z-octadecenoic acid 12,diHOME , which is increased in response to cold exposure and promotes BAT activation in a feedforward mechanism These findings highlight the promising developments in the identification of novel non-invasive markers for the prediction of metabolically active BAT in humans.

Another circulating molecule that has lately received a lot of attention is fibroblast growth factor 21 FGF21 , which is mainly secreted by the liver but also by activated brown adipocytes FGF21 regulates energy metabolism through multiple pathways including enhanced browning of WAT and accelerated lipoprotein catabolism 23 , In addition, FGF21 alters food preferences through hypothalamic signals that is decreased desire for sweets and consequently reduces carbohydrate intake in mice 86 , As a result, FGF21 actions counteract diet-induced obesity, hyperglycemia and hyperlipidemia in various animal models.

In isolated human brown adipocytes, FGF21 and the muscle-derived hormone irisin have additive effects on norepinephrine-stimulated thermogenesis Clinical trials are currently underway to test the efficacy and safety of FGF21 analogs in human metabolic disease. However, blood glucose levels were not significantly reduced, whereas markers of bone turnover increased in a dose-dependent manner, which tempered the previous enthusiasm of FGFbased treatment for metabolic disease 90 , Given the persuasive evidence from various preclinical and clinical studies that the promotion of BAT function has beneficial effects on total energy metabolism, pharmacologic activation of human BAT holds great promise as a therapeutic concept in metabolic disease.

Non-pungent capsaicin analogs capsinoids may represent an alternative therapeutic approach.

Biology of Beige Adipocyte and Possible Therapy for Type 2 Diabetes and Obesity

Brown adipose tissue: what have we learned since its recent identification in human adults. Brown adipose tissue, an essential organ for thermoregulation in small and hibernating mammals due to its mitochondrial uncoupling capacity, was until recently considered to be present in humans only in newborns. The identification of brown adipose tissue in adult humans since the development and use of positron emission tomography marked with fluorodeoxyglucose PET-FDG has raised a series of doubts and questions about its real importance in our metabolism. In this review, we will discuss what we have learnt since its identification in humans as well as both new and old concepts, some of which have been marginalized for decades, such as diet-induced thermogenesis. Arq Bras Endocrinol Metab. However, it has only been recognized as a mammal specific thermogenic organ, essential for mammalian thermoregulation, for less than half a century 2.

These two beiging triggers have been used interchangeably but whether these two stimuli may induce beiging differently at cellular and molecular levels remains unclear. Here, we found that cold-induced beige adipocyte formation requires Adrb 1, not Adrb3 , activation. In contrast, Adrb3 activation stimulates mature white adipocytes to convert into beige adipocytes. Necessity tests, using mature adipocyte-specific Prdm16 deletion strategies, demonstrated that adipocytes are required and are predominant source to generate Adrb3 -induced, but not cold-induced, beige adipocytes. Excess accumulation of a type of fat called white fat is associated with obesity and metabolic problems. White fat cells store energy.

Promotion of brown adipose tissue BAT activity or browning of white adipose tissue has shown great potential as anti-obesity strategy in numerous preclinical models. The discovery of active BAT in humans and the recent advances in the understanding of human BAT biology and function have significantly propelled this field of research. Pharmacological stimulation of energy expenditure to counteract obesity has always been an intriguing therapeutic concept; with the identification of the specific molecular pathways of brown fat function, this idea has now become as realistic as ever. Two distinct strategies are currently being pursued; one is the activation of bone fide BAT, the other is the induction of BAT-like cells or beige adipocytes within white fat depots, a process called browning. Recent evidence suggests that both phenomena can occur in humans.


Beige Adipocytes are a Distinct Type of Thermogenic Fat Cell in These data illustrate a new cell type with therapeutic potential in mouse and human. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that.


Two-Level Organization of Thermogenesis in Adipose Tissue: a Morphofunctional Hypothesis

All mammals own two main forms of fat. The classical white adipose tissue builds up energy in the form of triglycerides and is useful for preventing fatigue during periods of low caloric intake and the brown adipose tissue instead of inducing fat accumulation can produce energy as heat. Since adult humans possess significant amounts of active brown fat depots and their mass inversely correlates with adiposity, brown fat might play an important role in human obesity and energy homeostasis.

It is the best journal to keep up to date with endocrine pathophysiology both in the clinical and in the research field. It publishes the best original articles of large research institutions, as well as prestigious reviews. The Impact Factor measures the average number of citations received in a particular year by papers published in the journal during the two receding years.

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2 Comments

Susan S. 29.03.2021 at 19:51

Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin. Finally, we provide evidence that previously identified brown fat deposits in adult humans are composed of beige adipocytes.

Ytdinsuilep 03.04.2021 at 02:33

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