Importance of adipocyte browning in the evolution of endothermy

Endothermy changes the relationship between organisms and their environment fundamentally, and it is therefore of major ecological and evolutionary significance. Endothermy is characterized by non-shivering thermogenesis, that is metabolic heat production in the absence of muscular activity. In many eutherian mammals, brown adipose tissue (BAT) is an evolutionary innovation that facilitates non-shivering heat production in mitochondria by uncoupling food-derived substrate oxidation from chemical energy (ATP) production. Consequently, energy turnover is accelerated resulting in increased heat release. The defining characteristics of BAT are high contents of mitochondria and vascularization, and the presence of uncoupling protein 1. Recent insights, however, reveal that a range of stimuli such as exercise, diet and the immune system can cause the browning of white adipocytes, thereby increasing energy expenditure and heat production even in the absence of BAT. Here, we review the molecular mechanisms that cause browning of white adipose tissue, and their potential contribution to thermoregulation. The significance for palaeophysiology lies in the presence of adipose tissue and the mechanisms that cause its browning and uncoupling in all amniotes. Hence, adipocytes may have played a role in the evolution of endothermy beyond the more specific evolution of BAT in eutherians. This article is part of the theme issue ‘Vertebrate palaeophysiology’.

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KCTD10 regulates brown adipose tissue thermogenesis and metabolic function via Notch Signaling

Journal of Endocrinology ◽

10.1530/joe-21-0016 ◽

2021 ◽

Author(s):

Mingsheng Ye ◽

Liping Luo ◽

Qi Guo ◽

Guanghua Lei ◽

Chao Zeng ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Notch Signaling ◽

Molecular Mechanisms ◽

Uncoupling Protein ◽

Notch Signaling Pathway ◽

Whole Body ◽

Brown Adipocyte ◽

Metabolic Function ◽

Brown Adipose

Brown adipose tissue (BAT) is emerging as a target to beat obesity through the dissipation of chemical energy to heat. However, the molecular mechanisms of brown adipocyte thermogenesis remain to be further elucidated. Here, we show that KCTD10, a member of the polymerase delta-interacting protein 1 (PDIP1) family, was reduced in BAT by cold stress and a β3 adrenoceptor agonist. Moreover, KCTD10 level increased in the BAT of obese mice, and KCTD10 overexpression attenuates uncoupling protein 1 (UCP1) expression in primary brown adipocytes. BAT-specific KCTD10 knockdown mice had increased thermogenesis and cold tolerance protecting from high fat diet (HFD)-induced obesity. Conversely, overexpression of KCTD10 in BAT caused reduced thermogenesis, cold intolerance, and obesity. Mechanistically, inhibiting Notch signaling restored the KCTD10 overexpression suppressed thermogenesis. Our study presents that KCTD10 serves as an upstream regulator of notch signaling pathway to regulate BAT thermogenesis and whole-body metabolic function.

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Brown Adipose Tissue: Function and Physiological Significance

Physiological Reviews ◽

10.1152/physrev.00015.2003 ◽

2004 ◽

Vol 84 (1) ◽

pp. 277-359 ◽

Cited By ~ 3585

Author(s):

BARBARA CANNON ◽

JAN NEDERGAARD

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Heat Production ◽

Uncoupling Protein ◽

Sympathetic Nerves ◽

Physiological Significance ◽

Metabolic Efficiency ◽

Transfer Energy ◽

Brown Adipose ◽

Evolutionary Success

Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.

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Hypothalamic signaling in anorexia induced by indispensable amino acid deficiency

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00427.2012 ◽

2012 ◽

Vol 303 (12) ◽

pp. E1446-E1458 ◽

Cited By ~ 10

Author(s):

Xinxia Zhu ◽

Stephanie M. Krasnow ◽

Quinn R. Roth-Carter ◽

Peter R. Levasseur ◽

Theodore P. Braun ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Amino Acid ◽

Food Intake ◽

Molecular Mechanisms ◽

Uncoupling Protein ◽

Deficient Diet ◽

Indispensable Amino Acid ◽

Brown Adipose ◽

Melanocortin Signaling

Animals exhibit a rapid and sustained anorexia when fed a diet that is deficient in a single indispensable amino acid (IAA). The chemosensor for IAA deficiency resides within the anterior piriform cortex (APC). Although the cellular and molecular mechanisms by which the APC detects IAA deficiency are well established, the efferent neural pathways that reduce feeding in response to an IAA-deficient diet remain to be fully characterized. In the present work, we investigated whether 1) central melanocortin signaling is involved in IAA deficiency-induced anorexia (IAADA) and 2) IAADA engages other key appetite-regulating neuronal populations in the hypothalamus. Rats and mice that consumed a valine-deficient diet (VDD) for 2–3 wk exhibited marked reductions in food intake, body weight, fat and lean body mass, body temperature, and white adipose tissue leptin gene expression, as well as a paradoxical increase in brown adipose tissue uncoupling protein-1 mRNA. Animals consuming the VDD had altered hypothalamic gene expression, typical of starvation. Pharmacological and genetic blockade of central melanocortin signaling failed to increase long-term food intake in this model. Chronic IAA deficiency was associated with a marked upregulation of corticotropin-releasing hormone expression in the lateral hypothalamus, particularly in the parasubthalamic nucleus, an area heavily innervated by efferent projections from the APC. Our observations indicate that the hypothalamic melanocortin system plays a minor role in acute, but not chronic, IAADA and suggest that the restraint on feeding is analogous to that observed after chronic dehydration.

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PACAP is essential for the adaptive thermogenic response of brown adipose tissue to cold exposure

Journal of Endocrinology ◽

10.1530/joe-14-0316 ◽

2014 ◽

Vol 222 (3) ◽

pp. 327-339 ◽

Cited By ~ 10

Author(s):

Abdoulaye Diané ◽

Nikolina Nikolic ◽

Alexander P Rudecki ◽

Shannon M King ◽

Drew J Bowie ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Metabolic Rate ◽

Brown Adipose Tissue ◽

Cold Exposure ◽

Molecular Mechanisms ◽

Uncoupling Protein ◽

Morphological Properties ◽

Brown Adipose ◽

Thermogenic Response

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a widely distributed neuropeptide that acts as a neurotransmitter, neuromodulator, neurotropic factor, neuroprotectant, secretagogue,and neurohormone. Owing to its pleiotropic biological actions, knockout ofPacap(Adcyap1) has been shown to induce several abnormalities in mice such as impaired thermoregulation. However, the underlying physiological and molecular mechanisms remain unclear. A previous report has shown that cold-exposedPacapnull mice cannot supply appropriate levels of norepinephrine (NE) to brown adipocytes. Therefore, we hypothesized that exogenous NE would rescue the impaired thermogenic response ofPacapnull mice during cold exposure. We compared the adaptive thermogenic capacity ofPacap−/−toPacap+/+mice in response to NE when housed at room temperature (24 °C) and after a 3.5-week cold exposure (4 °C). Biochemical parameters, expression of thermogenic genes, and morphological properties of brown adipose tissue (BAT) and white adipose tissue (WAT) were also characterized. Results showed that there was a significant effect of temperature, but no effect of genotype, on the resting metabolic rate in conscious, unrestrained mice. However, the normal cold-induced increase in the basal metabolic rate and NE-induced increase in thermogenesis were severely blunted in cold-exposedPacap−/−mice. These changes were associated with altered substrate utilization, reduced β3-adrenergic receptor (β3-Ar(Adrb3)) and hormone-sensitive lipase (Hsl(Lipe)) gene expression, and increased fibroblast growth factor 2 (Fgf2) gene expression in BAT. Interestingly,Pacap−/−mice had depleted WAT depots, associated with upregulated uncoupling protein 1 expression in inguinal WATs. These results suggest that the impairment of adaptive thermogenesis inPacapnull mice cannot be rescued by exogenous NE perhaps in part due to decreased β3-Ar-mediated BAT activation.

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Standardized Hydrangea serrata (Thunb.) Ser. Extract Ameliorates Obesity in db/db Mice

Nutrients ◽

10.3390/nu13103624 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3624

Author(s):

Hee-Soo Han ◽

Kyung-Sook Chung ◽

Yu-Kyoung Shin ◽

Sun Hee Lee ◽

Kyung-Tae Lee

Keyword(s):

Adipose Tissue ◽

Gut Microbiota ◽

Molecular Mechanisms ◽

Body Weight Gain ◽

Binding Protein ◽

Uncoupling Protein ◽

Liver Steatosis ◽

Water Extract ◽

Sirtuin 1 ◽

Brown Adipose

We previously reported the potential anti-obesity effects of the water extract of Hydrangea serrata (Thunb.) Ser. leaves (WHS) in high-fat diet-induced obese mice. As an extension of our previous study, we investigated the anti-adipogenic and anti-obesity effects of WHS and its underlying molecular mechanisms in 3T3-L1 preadipocytes and genetically obese db/db mice. WHS attenuated the gene expression of adipogenic transcription factors, CCAAT/enhancer binding protein (C/EBP)α, peroxisome proliferator-activated receptor (PPAR)γ, and sterol regulatory element binding protein (SREBP)-1. Moreover, WHS inhibited the mitotic clonal expansion of preadipocytes by inducing G1 cell cycle arrest. Oral administration of WHS alleviated body weight gain and body fat accumulation in vivo. In addition, adipocyte hypertrophy and liver steatosis were ameliorated by WHS treatment. WHS reduced C/EBPα, PPARγ, and SREBP-1 expression and activated AMPKα phosphorylation in both white adipose tissue (WAT) and liver tissue. WHS also mildly upregulated the expression of thermogenic proteins, including uncoupling protein-1, PPARs, PPARγ coactivator-1α, and sirtuin-1, in brown adipose tissue (BAT). Furthermore, WHS altered the gut microbiota composition to resemble that of wild-type mice. Taken together, our findings suggest that WHS could alleviate adiposity by inhibiting adipogenesis in WAT and the liver and modulating the gut microbiota.

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Brown adipose tissue development and function and its impact on reproduction

Journal of Endocrinology ◽

10.1530/joe-18-0084 ◽

2018 ◽

Vol 238 (1) ◽

pp. R53-R62 ◽

Cited By ~ 6

Author(s):

Michael E Symonds ◽

Peter Aldiss ◽

Neele Dellschaft ◽

James Law ◽

Hernan P Fainberg ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Heat Production ◽

Maternal Obesity ◽

Thermal Environment ◽

Uncoupling Protein ◽

The Body ◽

Substantial Impact ◽

Brown Adipose ◽

Fat Depot

Although brown adipose tissue (BAT) is one of the smallest organs in the body, it has the potential to have a substantial impact on both heat production as well as fat and carbohydrate metabolism. This is most apparent at birth, which is characterised with the rapid appearance and activation of the BAT specific mitochondrial uncoupling protein (UCP)1 in many large mammals. The amount of brown fat then gradually declines with age, an adaptation that can be modulated by the thermal environment. Given the increased incidence of maternal obesity and its potential transmission to the mother’s offspring, increasing BAT activity in the mother could be one mechanism to prevent this cycle. To date, however, all rodent studies investigating maternal obesity have been conducted at standard laboratory temperature (21°C), which represents an appreciable cold challenge. This could also explain why offspring weight is rarely increased, suggesting that future studies would benefit from being conducted at thermoneutrality (~28°C). It is also becoming apparent that each fat depot has a unique transcriptome and show different developmental pattern, which is not readily apparent macroscopically. These differences could contribute to the retention of UCP1 within the supraclavicular fat depot, the most active depot in adult humans, increasing heat production following a meal. Despite the rapid increase in publications on BAT over the past decade, the extent to which modifications in diet and/or environment can be utilised to promote its activity in the mother and/or her offspring remains to be established.

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Novel Browning Agents, Mechanisms, and Therapeutic Potentials of Brown Adipose Tissue

BioMed Research International ◽

10.1155/2016/2365609 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 32

Author(s):

Umesh D. Wankhade ◽

Michael Shen ◽

Hariom Yadav ◽

Keshari M. Thakali

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Energy Homeostasis ◽

Therapeutic Potential ◽

Uncoupling Protein ◽

Brown Adipocytes ◽

Atp Production ◽

Obesity And Diabetes ◽

Brown Adipose ◽

Beige Adipocytes

Nonshivering thermogenesis is the process of biological heat production in mammals and is primarily mediated by brown adipose tissue (BAT). Through ubiquitous expression of uncoupling protein 1 (Ucp1) on the mitochondrial inner membrane, BAT displays uncoupling of fuel combustion and ATP production in order to dissipate energy as heat. Because of its crucial role in regulating energy homeostasis, ongoing exploration of BAT has emphasized its therapeutic potential in addressing the global epidemics of obesity and diabetes. The recent appreciation that adult humans possess functional BAT strengthens this prospect. Furthermore, it has been identified that there are both classical brown adipocytes residing in dedicated BAT depots and “beige” adipocytes residing in white adipose tissue depots that can acquire BAT-like characteristics in response to environmental cues. This review aims to provide a brief overview of BAT research and summarize recent findings concerning the physiological, cellular, and developmental characteristics of brown adipocytes. In addition, some key genetic, molecular, and pharmacologic targets of BAT/Beige cells that have been reported to have therapeutic potential to combat obesity will be discussed.

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Alternative Polyadenylation and Differential Regulation of Ucp1: Implications for Brown Adipose Tissue Thermogenesis Across Species

Frontiers in Pediatrics ◽

10.3389/fped.2020.612279 ◽

2021 ◽

Vol 8 ◽

Author(s):

Wen-Hsin Lu ◽

Yao-Ming Chang ◽

Yi-Shuian Huang

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Molecular Mechanisms ◽

Uncoupling Protein ◽

Alternative Polyadenylation ◽

Proton Channel ◽

Inner Mitochondrial Membrane ◽

Brown Adipose ◽

Brown Adipose Tissue Thermogenesis ◽

Ucp1 Expression

Brown adipose tissue (BAT) is a thermogenic organ owing to its unique expression of uncoupling protein 1 (UCP1), which is a proton channel in the inner mitochondrial membrane used to dissipate the proton gradient and uncouple the electron transport chain to generate heat instead of adenosine triphosphate. The discovery of metabolically active BAT in human adults, especially in lean people after cold exposure, has provoked the “thermogenic anti-obesity” idea to battle weight gain. Because BAT can expend energy through UCP1-mediated thermogenesis, the molecular mechanisms regulating UCP1 expression have been extensively investigated at both transcriptional and posttranscriptional levels. Of note, the 3′-untranslated region (3′-UTR) of Ucp1 mRNA is differentially processed between mice and humans that quantitatively affects UCP1 synthesis and thermogenesis. Here, we summarize the regulatory mechanisms underlying UCP1 expression, report the number of poly(A) signals identified or predicted in Ucp1 genes across species, and discuss the potential and caution in targeting UCP1 for enhancing thermogenesis and metabolic fitness.

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Brown adipose tissue mitochondria: modulation by GDP and fatty acids depends on the respiratory substrates

Bioscience Reports ◽

10.1042/bsr20100144 ◽

2011 ◽

Vol 32 (1) ◽

pp. 53-59 ◽

Cited By ~ 9

Author(s):

Leopoldo De Meis ◽

Luisa A. Ketzer ◽

Juliana Camacho-Pereira ◽

Antonio Galina

Keyword(s):

Fatty Acids ◽

Adipose Tissue ◽

Membrane Potential ◽

Brown Adipose Tissue ◽

Heat Production ◽

Uncoupling Protein ◽

Atp Synthesis ◽

Brown Adipocytes ◽

Bat Mitochondria ◽

Brown Adipose

The UCP1 [first UCP (uncoupling protein)] that is found in the mitochondria of brown adipocytes [BAT (brown adipose tissue)] regulates the heat production, a process linked to non-shivering thermogenesis. The activity of UCP1 is modulated by GDP and fatty acids. In this report, we demonstrate that respiration and heat released by BAT mitochondria vary depending on the respiratory substrate utilized and the coupling state of the mitochondria. It has already been established that, in the presence of pyruvate/malate, BAT mitochondria are coupled by faf-BSA (fatty-acid-free BSA) and GDP, leading to an increase in ATP synthesis and mitochondrial membrane potential along with simultaneous decreases in both the rates of respiration and heat production. Oleate restores the uncoupled state, inhibiting ATP synthesis and increasing the rates of both respiration and heat production. We now show that in the presence of succinate: (i) the rates of uncoupled mitochondria respiration and heat production are five times slower than in the presence of pyruvate/malate; (ii) faf-BSA and GDP accelerate heat and respiration as a result and, in coupled mitochondria, these two rates are accelerated compared with pyruvate/malate; (iii) in spite of the differences in respiration and heat production noted with the two substrates, the membrane potential and the ATP synthesized were the same; and (iv) oleate promoted a decrease in heat production and respiration in coupled mitochondria, an effect different from that observed using pyruvate/malate. These effects are not related to the production of ROS (reactive oxygen species). We suggest that succinate could stimulate a new route to heat production in BAT mitochondria.

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Invited Review: Uncoupling proteins and thermoregulation

Journal of Applied Physiology ◽

10.1152/japplphysiol.00994.2001 ◽

2002 ◽

Vol 92 (5) ◽

pp. 2187-2198 ◽

Cited By ~ 171

Author(s):

George Argyropoulos ◽

Mary-Ellen Harper

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Uncoupling Protein ◽

Biochemical Properties ◽

Atp Production ◽

Metabolic Functions ◽

Mitochondrial Inner Membrane ◽

Brown Adipose ◽

Total Body ◽

Body Energy

Energy balance in animals is a metabolic state that exists when total body energy expenditure equals dietary energy intake. Energy expenditure, or thermogenesis, can be subcategorized into groups of obligatory and facultative metabolic processes. Brown adipose tissue (BAT), through the activity of uncoupling protein 1 (UCP1), is responsible for nonshivering thermogenesis, a major component of facultative thermogenesis in newborn humans and in small mammals. UCP1, found in the mitochondrial inner membrane in BAT, uncouples energy substrate oxidation from mitochondrial ATP production and hence results in the loss of potential energy as heat. Mice that do not express UCP1 (UCP1 knockouts) are markedly cold sensitive. The recent identification of four new homologs to UCP1 expressed in BAT, muscle, white adipose tissue, brain, and other tissues has been met by tremendous scientific interest. The hypothesis that the novel UCPs may regulate thermogenesis and/or fatty acid metabolism guides investigations worldwide. Despite several hundred publications on the new UCPs, there are a number of significant controversies, and only a limited understanding of their physiological and biochemical properties has emerged. The discovery of UCP orthologs in fish, birds, insects, and even plants suggests the widespread importance of their metabolic functions. Answers to fundamental questions regarding the metabolic functions of the new UCPs are thus pending and more research is needed to elucidate their physiological functions. In this review, we discuss recent findings from mammalian studies in an effort to identify potential patterns of function for the UCPs.

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