Brown adipose tissue volume in healthy lean south Asian adults compared with white Caucasians: a prospective, case-controlled observational study
Leontine E. H. BakkerMariëtte R. BoonRianne A. D. van der LindenLenka M. Pereira Arias‐BoudaJan B. van KlinkenFrits SmitHein J. VerberneJ. Wouter JukemaJouke T. TamsmaLouis M. HavekesWouter D. van Marken LichtenbeltIngrid M. JazetPatrick C.N. Rensen
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Resting energy expenditure
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 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 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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Energy expenditure for thermogenesis in brown adipose tissue (BAT) serves either to maintain body temperature in the cold or to waste food energy. It has roles in thermal balance and energy balance, and when defective, is usually associated with obesity. BAT can grow or atrophy; it is usually atrophied in obese animals. Control of BAT thermogenesis and growth is by the sympathetic nervous system, with integration of signals in the hypothalamus. Sensory nerves may also be involved. Understanding the control of growth and differentiation of BAT is important for discovering how to reactivate it in obesity. Studies on control of gene expression in BAT are concentrating on thermogenically important components such as the uncoupling protein (which allows BAT mitochondria to operate in a thermogenic uncoupled mode), lipoprotein lipase (which allows BAT to compete with white adipose tissue for dietary lipid), and thyroxine 5'-deiodinase (which allows endogenous triiodothyronine generation, part of the control of differentiation and growth of BAT). Differentiation of BAT cell precursors in culture has recently been achieved. BAT is present in adult humans and some anti-obesity drugs are targeted to stimulation of BAT thermogenesis. However, extrapolation to humans of results of studies of BAT requires the development of novel approaches to the noninvasive assessment of amount and function of human BAT.— Himms-Hagen, J. Brown adipose tissue thermogenesis: interdisciplinary studies. FASEB J. 4: 2890-2898; 1990.
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Sympathetic nervous system (SNS) innervation into brown adipose tissue (BAT) has been viewed as an impetus for brown fat thermogenesis. However, we surprisingly discovered that BAT SNS innervation is dispensable for mice to maintain proper body temperature during a prolonged cold exposure. Here we aimed to uncover the physiological factors compensating for maintaining brown fat thermogenesis in the absence of BAT innervation. After an initial decline of body temperature during cold exposure, mice with SNS surgical denervation in interscapular BAT gradually recovered their temperature comparable to that of sham-operated mice. The surgically denervated BAT also maintained a sizable uncoupling protein 1 (UCP1) protein along with basal norepinephrine (NE) at a similar level to that of sham controls, which were associated with increased circulating NE. Furthermore, the denervated mice exhibited increased free fatty acid levels in circulation. Indeed, surgical denervation of mice with CGI-58 deletion in adipocytes, a model lacking lipolytic capacity to release fatty acids from WAT, dramatically reduced BAT UCP1 protein and rendered the mice susceptible to cold. We conclude that circulating fatty acids and NE may serve as key factors for maintaining BAT thermogenic function and body temperature in the absence of BAT sympathetic innervation.
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Increasing whole-body energy expenditure via the pharmacological activation of uncoupling protein 1 (UCP1)-dependent brown adipose tissue (BAT) thermogenesis is a promising weight management strategy, yet most therapeutics studied in rodents to date either induce compensatory increases in energy intake, have thermogenic effects that are confounded by sub-thermoneutral housing temperatures or are not well tolerated in humans. Here, we sought to determine whether the non-invasive topical application of the pharmacological cold mimetic and transient receptor potential (TRP) cation channel subfamily M member 8 (TRPM8) agonist L-menthol (MNTH), could be used to stimulate BAT thermogenesis and attenuate weight gain in mice housed at thermoneutrality. Using three different strains of mice and multiple complimentary approaches to quantify thermogenesis in vivo, coupled with ex vivo models to quantify direct thermogenic effects, we were able to convincingly demonstrate the following: (1) acute topical MNTH application induces BAT thermogenesis in a TRPM8- and UCP1-dependent manner; (2) MNTH-induced BAT thermogenesis is sufficient to attenuate weight gain over time without affecting energy intake in lean and obese mice; (3) the ability of topical MNTH application to stimulate BAT thermogenesis is mediated, in part, by a central mechanism involving the release of norepinephrine. These data collectively suggest that topical application of MNTH may be a promising weight management strategy.
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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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The role of the sympathetic nervous system in 10-min cold (5°C)- or 2-min immobilization-induced thermogenesis in brown adipose tissue (BAT) was studied in warm(25°C)-acclimated rats. Both cold- and immobilization-stresses increased heat production (M), interscapular brown adipose tissue temperature (Tbat), and colonic temperature (Tcol). Resulting from both stresses, the increase in Tbat was greater than that in Tcol, the differences (ΔTbat) becoming approximately 0.48 and 0.46°C by the cold exposure and the immobilization, respectively. After sympathectomy, Tbat and ΔTbat did not change on immobilization but increased significantly on the cold exposure. ΔTbat was 0.31°C in the sympathectomized rats at the end of the cold exposure period. Immobilization-induced BAT thermogenesis may be mainly controlled by the sympathetic nervous system. On the other hand cold-induced BAT thermogenesis seems to be controlled by certain hormonal factors as well as the sympathetic nervous system.
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Individual variation in cold adaptive thermogenesis can potentially be attributed to sympathetic nervous innervation of brown adipose tissue (BAT). In humans BAT was thought to be present only in infants. Recent results from PET‐CT scans indicate that adults may have significant amounts of active BAT. The objective is to study the relation between presence and activity of BAT and the level of cold induced thermogenesis in humans. Male volunteers (age: 24.3±3.5 y; length: 181±5.5 cm; weight: 75±4.3) were examined for presence and/or activity (standardized uptake value) of BAT during cold exposure by means of 18F‐FDG PET‐CT. In a climate chamber thermoneutral (1 h; 22 °C) condition is compared to mild cold (2 h; 16 °C). Increase in resting metabolic rate (RMR) as measured by indirect calorimetry is compared to the BAT data. Six subjects have currently been measured. RMR (mean 4.07±0.42 kJ/min) increased between 1.5 and 25 %, depending on the subject. Five subjects showed significant amounts of BAT, especially in the supra‐clavicular region. One showed no sign of BAT. This study shows high prevalence of BAT in young adult human males and will relate cold induced thermogenesis to BAT activity.
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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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