Brown and beige adipose tissues: phenotype and metabolic potential in mice and men

With the recent rediscovery of brown fat in adult humans, our outlook on adipose tissue biology has undergone a paradigm shift. While we attempt to identify, recruit, and activate classic brown fat stores in humans, identification of beige fat has also raised the possibility of browning our white fat stores. Whether such transformation of human white fat depots can be achieved to enhance the whole body oxidative potential remains to be seen. Evidence to date, however, largely points toward a major oxidative role only for classic brown fat depots, at least in rodents. White fat stores seem to provide the main fuel for sustaining thermogenesis via lipolysis. Interestingly, molecular markers consistent with both classic brown and beige fat identity can be observed in human supraclavicular depot, thereby complicating the discussion on beige fat in humans. Here, we review the recent advances made in our understanding of brown and beige fat in humans and mice. We further provide an overview of their plausible physiological relevance to whole body energy metabolism.

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Essential role of systemic iron mobilization and redistribution for adaptive thermogenesis through HIF2-α/hepcidin axis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2109186118 ◽

2021 ◽

Vol 118 (40) ◽

pp. e2109186118

Author(s):

Jin-Seon Yook ◽

Mikyoung You ◽

Jiyoung Kim ◽

Ashley M. Toney ◽

Rong Fan ◽

...

Keyword(s):

Energy Homeostasis ◽

Iron Homeostasis ◽

Regulatory Protein ◽

Hypoxia Inducible Factor ◽

Whole Body ◽

Iron Mobilization ◽

Adaptive Thermogenesis ◽

Beige Fat ◽

Biogenesis Of Mitochondria ◽

Body Energy

Iron is an essential biometal, but is toxic if it exists in excess. Therefore, iron content is tightly regulated at cellular and systemic levels to meet metabolic demands but to avoid toxicity. We have recently reported that adaptive thermogenesis, a critical metabolic pathway to maintain whole-body energy homeostasis, is an iron-demanding process for rapid biogenesis of mitochondria. However, little information is available on iron mobilization from storage sites to thermogenic fat. This study aimed to determine the iron-regulatory network that underlies beige adipogenesis. We hypothesized that thermogenic stimulus initiates the signaling interplay between adipocyte iron demands and systemic iron liberation, resulting in iron redistribution into beige fat. To test this hypothesis, we induced reversible activation of beige adipogenesis in C57BL/6 mice by administering a β3-adrenoreceptor agonist CL 316,243 (CL). Our results revealed that CL stimulation induced the iron-regulatory protein–mediated iron import into adipocytes, suppressed hepcidin transcription, and mobilized iron from the spleen. Mechanistically, CL stimulation induced an acute activation of hypoxia-inducible factor 2-α (HIF2-α), erythropoietin production, and splenic erythroid maturation, leading to hepcidin suppression. Disruption of systemic iron homeostasis by pharmacological HIF2-α inhibitor PT2385 or exogenous administration of hepcidin-25 significantly impaired beige fat development. Our findings suggest that securing iron availability via coordinated interplay between renal hypoxia and hepcidin down-regulation is a fundamental mechanism to activate adaptive thermogenesis. It also provides an insight into the effects of adaptive thermogenesis on systemic iron mobilization and redistribution.

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Sympathetic Denervation of One White Fat Depot Changes Norepinephrine Content and Turnover in Intact White and Brown Fat Depots

Obesity ◽

10.1038/oby.2012.95 ◽

2012 ◽

Vol 20 (7) ◽

pp. 1355-1364 ◽

Cited By ~ 23

Author(s):

Ruth B.S. Harris

Keyword(s):

Brown Fat ◽

Sympathetic Denervation ◽

Fat Depots ◽

Norepinephrine Content ◽

Fat Depot ◽

White Fat

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Breaking BAT: can browning create a better white?

Journal of Endocrinology ◽

10.1530/joe-15-0408 ◽

2015 ◽

Vol 228 (1) ◽

pp. R19-R29 ◽

Cited By ~ 24

Author(s):

Amy Warner ◽

Jens Mittag

Keyword(s):

Energy Expenditure ◽

Metabolic Diseases ◽

Uncoupling Protein ◽

Whole Body ◽

Direct Stimulation ◽

White Adipocytes ◽

Beige Adipocytes ◽

Beige Fat ◽

Underlying Mechanisms ◽

Body Energy

Obesity and its comorbidities are a growing problem worldwide. In consequence, several new strategies have been proposed to promote weight loss and improve insulin sensitivity. Recently, it has been demonstrated that certain populations of white adipocytes can be ‘browned’, i.e., recruited to a more brown-like adipocyte, capable of thermogenesis through increased expression of uncoupling protein 1. The list of browning agents that induce these so-called beige adipocytes is growing constantly. However, the underlying mechanisms are often poorly understood, with the possibility that some of these agents cause browning as a secondary effect. Moreover, it remains unclear whether beige adipocytes can contribute sufficiently to affect whole-body energy expenditure in a functionally significant manner. This review presents an overview of the different molecular pathways leading to the induction of beige fat, including direct stimulation and indirect actions on the CNS or the immune system. We discuss the available evidence on the capacity of beige adipocytes to influence whole-body energy expenditure in rodents, and lastly outline the potential problems of translating browning capacity into the potential treatment of human metabolic diseases.

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Trans-Cinnamic Acid Stimulates White Fat Browning and Activates Brown Adipocytes

Nutrients ◽

10.3390/nu11030577 ◽

2019 ◽

Vol 11 (3) ◽

pp. 577 ◽

Cited By ~ 14

Author(s):

Nam Kang ◽

Sulagna Mukherjee ◽

Jong Yun

Keyword(s):

Cinnamic Acid ◽

Immunoblot Analysis ◽

Brown Fat ◽

Mechanistic Study ◽

Brown Adipocytes ◽

Ampk Signaling ◽

White Adipocytes ◽

Beige Fat ◽

Polymerase Chain ◽

White Fat

Recently, pharmacological activation of brown fat and induction of white fat browning (beiging) have been considered promising strategies to treat obesity. To search for natural products that could stimulate the process of browning in adipocytes, we evaluated the activity of trans-cinnamic acid (tCA), a class of cinnamon from the bark of Cinnamomum cassia, by determining genetic expression using real time reverse transcription polymerase chain reaction (RT-PCR) and protein expression by immunoblot analysis for thermogenic and fat metabolizing markers. In our study tCA induced brown like-phenotype in 3T3-L1 white adipocytes and activated HIB1B brown adipocytes. tCA increased protein content of brown-fat-specific markers (UCP1, PRDM16, and PGC-1α) and expression levels of beige-fat-specific genes (Cd137, Cidea, Cited1, Tbx1, and Tmen26) in 3T3-L1 white adipocytes, as well as brown-fat-specific genes (Lhx8, Ppargc1, Prdm16, Ucp1, and Zic1) in HIB1B brown adipocytes. Furthermore, tCA reduced expression of key adipogenic transcription factors C/EBPα and PPARγ in white adipocytes, but enhanced their expressions in brown adipocytes. In addition, tCA upregulates lipid catabolism. Moreover, mechanistic study revealed that tCA induced browning in white adipocytes by activating the β3-AR and AMPK signaling pathways. tCA can induce browning, increase fat oxidation, reduce adipogenesis and lipogenesis in 3T3-L1 adipocytes, and activate HIB1B adipocytes, suggesting its potential to treat obesity.

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The characterization and energetic potential of brown adipose tissue in man

Clinical Science ◽

10.1042/cs0690343 ◽

1985 ◽

Vol 69 (3) ◽

pp. 343-348 ◽

Cited By ~ 70

Author(s):

S. Cunningham ◽

P. Leslie ◽

D. Hopwood ◽

P. Illingworth ◽

R. T. Jung ◽

...

Keyword(s):

Animal Studies ◽

Visual Inspection ◽

Uncoupling Protein ◽

Brown Fat ◽

Whole Body ◽

Cold Adapted ◽

Fat Depots ◽

Brown Adipose ◽

Perinephric Fat ◽

Body Response

1. In adult man, brown fat can be detected in perinephric fat depots by visual inspection, electron microscopy and nucleotide binding to the tissue-specific uncoupling protein. 2. The 32 kDa uncoupling protein is functionally active, showing a nucleotide-sensitive conductance to protons and an uncoupling response to fatty acids. 3. The amount of uncoupling protein in human mitochondria is equivalent to that in a partially cold-adapted guinea pig, indicating some potential for thermogenesis. 4. Respiratory capacity measurements indicate that the total perinephric fat in adult man can only account for one-fivehundredth of the whole-body response to infused noradrenaline. Thus, although brown fat has been found to be quantitatively important in animal studies, considerable caution must be exercised in extrapolating its significance to adult man.

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ACETATE-1-C14 UTILIZATION BY BROWN FAT FROM HAMSTERS IN COLD EXPOSURE AND HIBERNATION

Canadian Journal of Biochemistry ◽

10.1139/o64-151 ◽

1964 ◽

Vol 42 (10) ◽

pp. 1397-1401 ◽

Cited By ~ 5

Author(s):

Joan Baumber ◽

Arliss Denyes

Keyword(s):

Cold Exposure ◽

Lipid Production ◽

Primary Response ◽

Brown Fat ◽

Cervical Tissue ◽

Tissue Samples ◽

Fat Depots ◽

Highly Active ◽

White Fat

The in vitro conversion of acetate-1-C14 to C14O2 and C14-lipid by the interscapular and cervical brown fat depots of cold-exposed golden hamsters was measured. Tissue samples were taken from animals after 48 hours, 3 weeks, and 6–8 weeks in the cold, in hibernation, and arousing from hibernation and immediately after arousal. There was a depression in C14O2 production by cervical tissue after 48 hours in the cold, and by interscapular tissue after 3 weeks in the cold. C14O2 production by both depots remained low throughout acclimation, hibernation, and arousal. C14-Lipid production by both depots increased after 48 hours in the cold and remained high during acclimation. C14-Lipid production was depressed during hibernation and arousal, with recovery to acclimated levels at the end of arousal in the interscapular, but not in the cervical depot. Cervical brown fat had a higher conversion to both C14O2 and C14-lipid than interscapular brown fat. Qualitatively, but not quantitatively, brown fat behaved similarly to white fat. It was concluded that increased lipogenic capacity is not a primary response of brown fat to cold exposure of the animal, but that some other pathway becomes highly active.

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Indispensable role of mitochondrial UCP1 for antiobesity effect of β3-adrenergic stimulation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00105.2005 ◽

2006 ◽

Vol 290 (5) ◽

pp. E1014-E1021 ◽

Cited By ~ 82

Author(s):

Ken-ichi Inokuma ◽

Yuko Okamatsu-Ogura ◽

Asako Omachi ◽

Yukiko Matsushita ◽

Kazuhiro Kimura ◽

...

Keyword(s):

Uncoupling Protein ◽

Plasma Free Fatty Acid ◽

Brown Fat ◽

Whole Body ◽

Adrenergic Stimulation ◽

Fat Pad ◽

Mitochondrial Uncoupling ◽

Mitochondrial Uncoupling Protein ◽

White Fat

Mitochondrial uncoupling protein-1 (UCP1) has been thought to be a key molecule for thermogenesis during cold exposure and spontaneous hyperphagia and thereby in the autonomic regulation of energy expenditure and adiposity. However, UCP1 knockout (KO) mice were reported to be cold intolerant but unexpectedly did not get obese even after hyperphagia, implying that UCP1 may not be involved in the regulation of adiposity. Treatment of obese animals with β3-adrenergic agonists is known to increase lipid mobilization, induce UCP1, and, finally, reduce body fat content. To obtain direct evidence for the role of UCP1 in the anti-obesity effect of β3-adrenergic stimulation, in the present study, UCP1-KO and wild-type (WT) mice were fed on cafeteria diets for 8 wk and then given a β3-adrenergic agonist, CL-316,243 (CL), or saline for 2 wk. A single injection of CL increased whole body oxygen consumption and brown fat temperature in WT mice but not in KO mice, and it elicited almost the same plasma free fatty acid response in WT and KO mice. WT and KO mice increased similarly their body and white fat pad weights on cafeteria diets compared with those on laboratory chow. Daily treatment with CL resulted in a marked reduction of white fat pad weight and the size of adipocytes in WT mice, but not in KO mice. Compared with WT mice, KO mice expressed increased levels of UCP2 in brown fat but decreased levels in white fat and comparable levels of UCP3. It was concluded that the anti-obesity effect of β3-adrenergic stimulation is largely attributable to UCP1, but less to UCP2 and UCP3, and thereby to UCP1-dependent degradation of fatty acids released from white adipose tissue.

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Brown Adipose YY1 Deficiency Activates Expression of Secreted Proteins Linked to Energy Expenditure and Prevents Diet-Induced Obesity

Molecular and Cellular Biology ◽

10.1128/mcb.00722-15 ◽

2015 ◽

pp. MCB.00722-15 ◽

Cited By ~ 4

Author(s):

Francisco Verdeguer ◽

Meghan S. Soustek ◽

Maximilian Hatting ◽

Sharon M. Blättler ◽

Devin McDonald ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

Brown Fat ◽

Secreted Proteins ◽

Fat Depots ◽

Diet Induced Obesity ◽

Brown Adipose ◽

White Fat

Mitochondrial oxidative and thermogenic function in brown and beige adipose tissues modulate rates of energy expenditure. It is unclear, however, how beige or white adipose tissue contributes to brown fat thermogenic function or compensate for partial deficiencies in this tissue and protect against obesity. Here, we show that the transcription factor YY1 in brown adipose tissue activates the canonical thermogenic and uncoupling gene expression program. In contrast, YY1 represses a series of secreted proteins including FGF21, BMP8b, GDF15, Angptl6, Neuromedin B and Nesfatin linked to energy expenditure. Despite substantial decreases in mitochondrial thermogenic proteins in brown fat, mice lacking YY1 in this tissue are strongly protected against diet-induced obesity, exhibit increased energy expenditure and oxygen consumption in beige and white fat depots. The increased expression of secreted proteins correlates with elevation of energy expenditure and promotion of beige and white fat activation. These results indicate that YY1 in brown adipose tissue controls antagonistic gene expression programs associated with energy balance and maintenance of body weight.

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Transcription Regulators and Hormones Involved in the Development of Brown Fat and White Fat Browning: Transcriptional and Hormonal Control of Brown/Beige Fat Development

Physiological Research ◽

10.33549/physiolres.933650 ◽

2018 ◽

pp. 347-362 ◽

Cited By ~ 7

Author(s):

J. ZHANG ◽

H. WU ◽

S. MA ◽

F. JING ◽

C. YU ◽

...

Keyword(s):

Adipose Tissue ◽

Hormonal Control ◽

Brown Fat ◽

Metabolic Complications ◽

Adipose Tissues ◽

Brown Adipose ◽

Beige Adipocytes ◽

New Strategy ◽

Beige Fat ◽

White Fat

The high prevalence of obesity and related metabolic complications has inspired research on adipose tissues. Three kinds of adipose tissues are identified in mammals: brown adipose tissue (BAT), beige or brite adipose tissue and white adipose tissue (WAT). Beige adipocytes share some characteristics with brown adipocytes such as the expression of UCP1. Beige adipocytes can be activated by environmental stimuli or pharmacological treatment, and this change is accompanied by an increase in energy consumption. This process is called white browning, and it facilitates the maintenance of a lean and healthy phenotype. Thus, promoting beige adipocyte development in WAT shows promise as a new strategy in treating obesity and related metabolic consequences. In this review, we summarized the current understanding of the regulators and hormones that participate in the development of brown fat and white fat browning.

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