Thermogenesis in normal rabbits and rats: no role for brown adipose tissue?
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1. The occurrence of dietary and cold‐induced thermogenesis in young rabbits was unaffected by noradrenaline or propranolol, and it is concluded that the brown adipose tissue, although detectable histologically, is non‐functional. 2. Noradrenaline treatment caused an increase in oxygen consumption in albino, but not in hooded rats, suggesting that the former breed may possess brown adipose tissue capable of thermogenesis.PRDM16
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Studies on promoting thermogenesis of brown and beige adipose tissue have become a hot topic in various metabolic conditions, which based on the conclusions that brown and beige adipose tissue are able to facilitate weight loss and improve metabolic health. However, recent studies showed that there were several problems for the anti-obesity application via promoting brown/beige adipose tissue thermogenesis. In obese individuals, classical brown adipose tissue presents thermogenesis dysfunction. Moreover, the beige adipose tissue has significantly lower thermogenesis capability compared with brown adipose tissue. On such conditions, excessively excited sympathetic innervation is essential to increase energy consumption in obesity via increasing classic brown adipose thermogenesis and inducing white adipose tissuebrowning. However, excessive excited sympathetic nerve results in cardiovascular side effects. Additionally, excessive induction of white adipose tissuebrowningmight disrupt the white adipose tissue homeostasis and aggravate the intrinsic metabolic disorders. Therefore, solving these practical application problems of brown/beige adipose tissue is a new research area for improving metabolic disorders. (Chin J Endocrinol Metab, 2017, 33: 625-628)
Key words:
Brown adipose tissue; Beige adipose tissue; White adipose tissue browning; Obesity; Energy metabolism; Application limitations
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Increasing energy expenditure by stimulating thermogenesis through activation of brown adipose tissue (BAT) and/or induction of browning of white adipose tissue (WAT) is considered a promising strategy to treat/prevent obesity and related metabolic diseases. Whereas WAT is adapted to store energy as triglycerides, BAT produces heat (non-shivering thermogenesis). In brown adipocytes, the uncoupling protein-1 (UCP-1) regulates conversion of energy into heat by uncoupling ATP production from mitochondrial respiration. Also in WAT adaptive UCP-1 positive adipocytes (brown in white: brite or beige) can arise, predominantly in subcutaneous (s) WAT. This browning of WAT is enhanced by exposure to cold.
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OBJECTIVE White adipose tissue (WAT) and brown adipose tissue (BAT) play distinct roles in adaptation to changes in nutrient availability, with WAT serving as an energy store and BAT regulating thermogenesis. We previously showed that mice maintained on a leucine-deficient diet unexpectedly experienced a dramatic reduction in abdominal fat mass. The cellular mechanisms responsible for this loss, however, are unclear. The goal of current study is to investigate possible mechanisms. RESEARCH DESIGN AND METHODS Male C57BL/6J mice were fed either control, leucine-deficient, or pair-fed diets for 7 days. Changes in metabolic parameters and expression of genes and proteins related to lipid metabolism were analyzed in WAT and BAT. RESULTS We found that leucine deprivation for 7 days increases oxygen consumption, suggesting increased energy expenditure. We also observed increases in lipolysis and expression of β-oxidation genes and decreases in expression of lipogenic genes and activity of fatty acid synthase in WAT, consistent with increased use and decreased synthesis of fatty acids, respectively. Furthermore, we observed that leucine deprivation increases expression of uncoupling protein (UCP)-1 in BAT, suggesting increased thermogenesis. CONCLUSIONS We show for the first time that elimination of dietary leucine produces significant metabolic changes in WAT and BAT. The effect of leucine deprivation on UCP1 expression is a novel and unexpected observation and suggests that the observed increase in energy expenditure may reflect an increase in thermogenesis in BAT. Further investigation will be required to determine the relative contribution of UCP1 upregulation and thermogenesis in BAT to leucine deprivation-stimulated fat loss.
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The role of brown adipose tissue (BAT) in defending body temperature was demonstrated initially by Foster and Frydman (1) who showed that BAT was the site of cold-induced thermogenesis. This was followed by the identification that heat production occurred via the uncoupling of BAT mitochondria through uncoupling protein 1 (UCP1) (5). Finally, work from Flier and colleagues demonstrated that BAT protected mice against the development of obesity and diabetes (2) and firmly established BAT as a thermoregulatory organ that could be targeted to reduce the risk of obesity and diabetes. Around the same time it was suggested that BAT could actively defend body weight through diet-induced thermogenesis (DIT). More recently, the discovery of BAT in adult humans has renewed interest in brown fat research and in understanding ways to remodel white adipose tissue (WAT) to a phenotype more similar to BAT. This process, termed “browning,” is marked by the appearance of “beige” adipocytes in WAT that are functionally similar to brown adipocytes. Exercise had been postulated for a while to reduce BAT thermogenesis, but, somewhat surprisingly, recent work has demonstrated that endurance training promotes the browning of WAT in rodents. At first glance, exercise-induced browning of WAT seems somewhat counterintuitive; however, in the current issue of the Journal, Sepa-Kishi and Ceddia (6) discuss novel findings that might explain the opposing effects of exercise on BAT and subcutaneous WAT (scWAT) thermogenesis. Sepa-Kishi and Ceddia (6) put forth the hypothesis that remodeling of adipose tissue during exercise training functions to shift thermogenesis away from classical BAT toward scWAT, where it would not necessarily affect core body temperature. In effect, this would allow the animal to deal with greater heat production during exercise. These ideas stem from their recent study in which endurance training reduced UCP1 content and lipid oxidation in classical BAT. In contrast, exercise promoted beige adipocytes, UCP1 content, and fatty acid oxidation in scWAT. An interesting observation was that energy expenditure after exercise remained elevated despite a reduction in BAT thermogenesis, leading the authors to suggest that exercise-induced scWAT browning can compensate partially for the reduction in BAT. Similarly, scWAT browning could limit adiposity during high-fat feeding by promoting DIT. The beneficial effects of exercise on whole-body energy homeostasis are undoubtable, but the exact contribution of scWAT browning and the reality of DIT are a matter of debate (3). Indeed, exercise does suppress BAT activity in humans; however, the evidence for browning is less apparent (7). Alternatively, the reduction in BAT activity could be a means of shifting energy away from uncoupling and toward working muscle, whereas the increase in WAT fatty acid oxidation might partly support adenosine triphosphate synthesis required for greater in situ de novo lipogenesis (4). Exercise training at thermoneutrality or in UCP1 knockout mice could be useful in teasing apart UCP1-dependent versus -independent effects on whole-body energy expenditure. In addition, as stated by the authors, understanding the cellular source of beige cells and the neural circuitry involved in the downregulation of BAT and upregulation of scWAT browning could prove useful in discovering novel therapies to combat obesity and diabetes. Emilio P. Mottillo Department of Medicine McMaster University Hamilton, Ontario, Canada
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Amphetamine (0.5, 1.0, 2.0 or 4.0 mg/kg) produced dose-dependent activation of interscapular brown-adipose tissue (IBAT) in female rats anesthetized with urethane (1.2 g/kg). Amphetamine-induced thermogenesis may reflect activation of beta-adrenergic receptors as evidenced by the rapid reversal of amphetamine-induced thermogenesis by propranolol (1.0 mg/kg). The potential relation of this effect to the anorexic property of amphetamine is discussed.
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Adaptive thermogenesis is highly dependent on uncoupling protein 1 (UCP1), a protein expressed by thermogenic adipocytes present in brown adipose tissue (BAT) and white adipose tissue (WAT). Thermogenic capacity of human and mouse BAT can be measured by positron emission tomography-computed tomography quantifying the uptake of 18F-fluodeoxyglucose or lipid tracers. BAT activation is typically studied in response to cold exposure or treatment with β-3-adrenergic receptor agonists such as CL316,243 (CL). Currently, it is unknown whether cold-stimulated uptake of glucose or lipid tracers is a good surrogate marker of UCP1-mediated thermogenesis. In metabolic studies using radiolabeled tracers, we found that glucose uptake is increased in mildly cold-activated BAT of Ucp1-/- versus WT mice kept at subthermoneutral temperature. Conversely, lower glucose disposal was detected after full thermogenic activation achieved by sustained cold exposure or CL treatment. In contrast, uptake of lipoprotein-derived fatty acids into chronically activated thermogenic adipose tissues was substantially increased in UCP1-deficient mice. This effect is linked to higher sympathetic tone in adipose tissues of Ucp1-/- mice, as indicated by elevated levels of thermogenic genes in BAT and WAT. Thus, glucose and lipoprotein handling does not necessarily reflect UCP1-dependent thermogenic activity, but especially lipid uptake rather mirrors sympathetic activation of adipose tissues.
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ABSTRACT: Brown adipose tissue (BAT) produces heat by oxidation of fatty acids. This takes place when the tissue is stimulated by norepinephrine; the molecular background for the ability of BAT to produce heat is the tissue‐specific mitochondrial protein UCP1. In the classic view of BAT with respect to fever, BAT is an effector organ, producing heat especially during the onset phase of the fever. There is good evidence that BAT thermogenesis is stimulated via a lipopolysaccharide (LPS), interleukin (IL)‐1β, IL‐6, prostaglandin E cascade. Under physiologic conditions of constantly stimulated activity, BAT is expected to be recruited, but in fevers this is only evident in thyroxine fever. However, BAT may be more than merely an effector. There are indications of a correlation between the amount of BAT and the intensity of fevers, and brown adipocytes can indeed produce IL‐1α and IL‐6. Furthermore, brown adipocytes are directly sensitive to LPS; this LPS sensitivity is augmented in brown adipocytes from IL‐1β‐deficient mice. Thus, BAT may also have a controlling role in thermoregulation. The existence of transgenic mice with ablations of proteins central in fever and in BAT thermogenesis opens up possibilities for identification and elucidation of this putative new role for brown adipose tissue as an endocrine organ involved in the control of fever.
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