Role of white adipose tissue browning in cold seasonal acclimation in grazing Mongolian sheep (Ovis aries)
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Centrally administered leptin has been shown to increase insulin-stimulated glucose utilization and to favor the expression of uncoupling proteins (UCPs). To study if leptin also has direct peripherally mediated effects on these processes, this hormone (1 mg/day) or its vehicle was infused iv for 4 days to lean rats and insulin-stimulated glucose utilization in skeletal muscle and adipose tissue as well as the expression of UCP messenger RNAs (mRNAs) in brown adipose tissue were measured. Iv leptin administration resulted in decreases in food intake (31%), body weight gain, and plasma insulin levels (45%), in increases in overall (23%) as well as brown adipose tissue and muscle glucose utilization, and in decreases in white adipose tissue glucose uptake. Most of these changes were mimicked, in control rats, by giving them the same amount of food as that consumed by the leptin-infused group (pair-feeding). Iv leptin infusion also favored the expression of UCPs in brown adipose tissue, either by increasing their expression or preventing the fall occurring during the pair-feeding regimen. Relative UCP expression levels were 100, 104, and 33 for UCP1, 100, 191, and 125 for UCP2 and 100, 107, and 29 for UCP3 in ad libitum fed control rats, in leptin-treated rats and in pair-fed control rats, respectively. These results suggest that the overall effect of leptin on glucose utilization and on the expression of UCPs may be mediated through central mechanism.
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Three types of beta adrenergic receptors (ARβ1-3) mediate the sympathetic activation of brown adipose tissue (BAT), the key thermogenic site for mice which is also present in adult humans. In this study, we evaluated adaptive thermogenesis and metabolic profile of a mouse with Arβ2 knockout (ARβ2KO). At room temperature, ARβ2KO mice have normal core temperature and, upon acute cold exposure (4 °C for 4 h), ARβ2KO mice accelerate energy expenditure normally and attempt to maintain body temperature. ARβ2KO mice also exhibited normal interscapular BAT thermal profiles during a 30-min infusion of norepinephrine or dobutamine, possibly due to marked elevation of interscapular BAT (iBAT) and of Arβ1, and Arβ3 mRNA levels. In addition, ARβ2KO mice exhibit similar body weight, adiposity, fasting plasma glucose, cholesterol, and triglycerides when compared with WT controls, but exhibit marked fasting hyperinsulinemia and elevation in hepatic Pepck (Pck1) mRNA levels. The animals were fed a high-fat diet (40% fat) for 6 weeks, ARβ2KO mice doubled their caloric intake, accelerated energy expenditure, and induced Ucp1 expression in a manner similar to WT controls, exhibiting a similar body weight gain and increase in the size of white adipocytes to the WT controls. However, ARβ2KO mice maintain fasting hyperglycemia as compared with WT controls despite very elevated insulin levels, but similar degrees of liver steatosis and hyperlipidemia. In conclusion, inactivation of the ARβ2KO pathway preserves cold- and diet-induced adaptive thermogenesis but disrupts glucose homeostasis possibly by accelerating hepatic glucose production and insulin secretion. Feeding on a high-fat diet worsens the metabolic imbalance, with significant fasting hyperglycemia but similar liver structure and lipid profile to the WT controls.
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Centrally administered leptin has been shown to increase insulin-stimulated glucose utilization and to favor the expression of uncoupling proteins (UCPs). To study if leptin also has direct peripherally mediated effects on these processes, this hormone (1 mg/day) or its vehicle was infused iv for 4 days to lean rats and insulin-stimulated glucose utilization in skeletal muscle and adipose tissue as well as the expression of UCP messenger RNAs (mRNAs) in brown adipose tissue were measured. Iv leptin administration resulted in decreases in food intake (31%), body weight gain, and plasma insulin levels (45%), in increases in overall (23%) as well as brown adipose tissue and muscle glucose utilization, and in decreases in white adipose tissue glucose uptake. Most of these changes were mimicked, in control rats, by giving them the same amount of food as that consumed by the leptin-infused group (pair-feeding). Iv leptin infusion also favored the expression of UCPs in brown adipose tissue, either by increasing their expression or preventing the fall occurring during the pair-feeding regimen. Relative UCP expression levels were 100, 104, and 33 for UCP1, 100, 191, and 125 for UCP2 and 100, 107, and 29 for UCP3 in ad libitum fed control rats, in leptin-treated rats and in pair-fed control rats, respectively. These results suggest that the overall effect of leptin on glucose utilization and on the expression of UCPs may be mediated through central mechanism.
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Leptin is a hormone mainly synthesized and secreted by white adipose tissue (WAT), which regulates various physiological processes. To investigate the role of leptin in energy balance and thermoregulation in Eothenomys miletus , voles were randomly divided into leptin-injected and PBS-injected groups and placed at 25°C ± 1°C with a photoperiod of 12 L:12 D. They were housed under laboratory conditions for 28 days and compared in terms of body mass, food intake, water intake, core body temperature, interscapular skin temperature, resting metabolic rate (RMR), nonshivering thermogenesis (NST), liver and brown adipose tissue (BAT) thermogenic activity, and serum hormone levels. The results showed that leptin injection decreased body mass, body fat, food intake, and water intake. But it had no significant effect on carcass protein. Leptin injection increased core body temperature, interscapular skin temperature, resting metabolic rate, non-shivering thermogenesis, mitochondrial protein content and cytochrome C oxidase (COX) activity in liver and brown adipose tissue, uncoupling protein 1 (UCP1) content and thyroxin 5′-deiodinase (T 4 5′-DII) activity in brown adipose tissue significantly. Serum leptin, triiodothyronine (T 3 ), thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone (CRH) concentrations were also increased significantly. Correlation analysis showed that serum leptin levels were positively correlated with core body temperature, body mass loss, uncoupling protein 1 content, thyroxin 5′-deiodinase activity, nonshivering thermogenesis, and negatively correlated with food intake; thyroxin 5′-deiodinase and triiodothyronine levels were positively correlated, suggesting that thyroxin 5′-deiodinase may play an important role in leptin-induced thermogenesis in brown adipose tissue. In conclusion, our study shows that exogenous leptin is involved in the regulation of energy metabolism and thermoregulation in E. miletus , and thyroid hormone may play an important role in the process of leptin regulating energy balance in E. miletus .
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The relation between gut microbiota and the host has been suggested to benefit metabolic homeostasis. Brown adipose tissue (BAT) and beige adipocytes facilitate thermogenesis to maintain host core body temperature during cold exposure. However, the potential impact of gut microbiota on the thermogenic process is confused. Here, we evaluated how BAT and white adipose tissue (WAT) responded to temperature challenges in mice lacking gut microbiota. We found that microbiota depletion via treatment with different cocktails of antibiotics (ABX) or in germ-free (GF) mice impaired the thermogenic capacity of BAT by blunting the increase in the expression of uncoupling protein 1 (UCP1) and reducing the browning process of WAT. Gavage of the bacterial metabolite butyrate increased the thermogenic capacity of ABX-treated mice, reversing the deficit. Our results indicate that gut microbiota contributes to upregulated thermogenesis in the cold environment and that this may be partially mediated via butyrate.
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Abstract The anti-obesity and anti-diabetic effects of a highly specific β 3 -adrenoceptor agonist, CL316.243 (CL; β 1 :β 2 :β 3 =0:1:100 000), were investigated in Otsuka Long-Evans Tokushima Fatty (fatty) and LongEvans Tokushima Otsuka (control) rats. Daily injection of CL (0·1 mg/kg, s.c.) to these rats (10 weeks old) for 14 weeks caused a significant reduction in body weight (fatty, 27% control, 15%), associated with a marked decrease in fat pad weight (inguinal: fatty, 60%; control, 36%; retroperitoneal: fatty, 75%; control, 77%) without affecting food intake. The levels of uncoupling protein mRNA and protein levels of uncoupling protein (UCP), as well as guanosine 5′-diphosphate-binding (a reliable index of thermogenesis) in brown adipose tissue, were lower in the fatty than in the control rats. However, after CL treatment, these parameters in brown adipose tissue increased significantly 2- to 3-fold in both groups. Furthermore, uncoupling protein was induced in white adipose tissue as well as in brown adipose tissue. The fatty rats showed hyperglycemia and hyperinsulinemia during the glucose tolerance test, but CL ameliorated these parameters. These findings suggest that decreased thermogenesis in brown adipose tissue may be one of the causes of obesity in the fatty rats and that administration of CL prevents obesity by decreasing white fat mass, by activating brown adipose tissue thermogenesis, and by inducing uncoupling protein in white adipose tissue. Furthermore, CL treatment may inhibit diabetes mellitus by ameliorating obesity and by activating glucose transporter 4 in white adipose tissue and brown adipose tissue. European Journal of Endocrinology 136 429–437
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PRDM16
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Deposition of excess body fat occurs when energy intake chronically exceeds energy expenditure. In ob/ob mice, the absence of leptin affects both components of the energy balance equation, and the mice become morbidly obese after weaning. Treatment of ob/ob mice with exogenous leptin reduces body weight by decreasing food intake and stimulating energy utilization, but even when saline- and leptin-injected ob/ob mice are pair-fed, mice receiving leptin lose significantly more weight. Therefore, the purpose of the present study was to test the hypotheses that uncoupling protein-1 (UCP1) expression is reduced in adipose tissue from ob/ob mice and is restored by treatment with exogenous leptin. Lean and ob/ob mice (5–6 weeks old) were housed at 23 C and treated with leptin (20 μg/g BW·day) for 3 days before they were killed. Compared with levels in lean littermates, UCP1 messenger RNA (mRNA) and protein levels were lower in brown adipose tissue (BAT) and retroperitoneal white adipose tissue (WAT) from ob/ob mice. Treatment of ob/ob mice with leptin reduced body weight and produced a 4- to 5-fold increase in UCP1 mRNA levels in both interscapular BAT and retroperitoneal WAT. The increases in UCP1 mRNA were accompanied by comparable increases in UCP1 protein in mitochondrial preparations from each tissue. Given that the sole known function of UCP1 is to uncouple oxidative phosphorylation, the present results are consistent with the conclusion that leptin stimulates energy utilization in ob/ob mice by increasing thermogenic activity and capacity (UCP1). In addition, the present results suggest that decreased UCP1 expression in BAT and WAT of ob/ob mice is in part responsible for their increased metabolic efficiency and propensity to become obese.
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Aging is associated with increased adiposity in white adipose tissues and impaired thermogenesis in brown adipose tissues; both contribute to increased incidences of obesity and type 2 diabetes. Ghrelin is the only known circulating orexigenic hormone that promotes adiposity. In this study, we show that ablation of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) improves insulin sensitivity during aging. Compared to wild-type (WT) mice, old Ghsr(-/-) mice have reduced fat and preserve a healthier lipid profile. Old Ghsr(-/-) mice also exhibit elevated energy expenditure and resting metabolic rate, yet have similar food intake and locomotor activity. While GHS-R expression in white and brown adipose tissues was below the detectable level in the young mice, GHS-R expression was readily detectable in visceral white fat and interscapular brown fat of the old mice. Gene expression profiles reveal that Ghsr ablation reduced glucose/lipid uptake and lipogenesis in white adipose tissues but increased thermogenic capacity in brown adipose tissues. Ghsr ablation prevents age-associated decline in thermogenic gene expression of uncoupling protein 1 (UCP1). Cell culture studies in brown adipocytes further demonstrate that ghrelin suppresses the expression of adipogenic and thermogenic genes, while GHS-R antagonist abolishes ghrelin's effects and increases UCP1 expression. Hence, GHS-R plays an important role in thermogenic impairment during aging. Ghsr ablation improves aging-associated obesity and insulin resistance by reducing adiposity and increasing thermogenesis. Growth hormone secretagogue receptor antagonists may be a new means of combating obesity by shifting the energy balance from obesogenesis to thermogenesis.
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The brown adipose tissue (BAT) mediates adaptive changes in metabolic rate by responding to the sympathetic nervous system through β-adrenergic receptors (AR). Here, we wished to define the role played by the ARβ3 isoform in this process. This study focused on the ARβ3 knockout mice (ARβ3KO), including responsiveness to cold exposure, diet-induced obesity, intolerance to glucose, dyslipidaemia and lipolysis in white adipose tissue (WAT). ARβ3KO mice defend core temperature during cold exposure (4°C for 5 h), with faster BAT thermal response to norepinephrine (NE) infusion when compared with wild-type (WT) mice. Despite normal BAT thermogenesis, ARβ3KO mice kept on a high-fat diet (HFD; 40% fat) for 8 weeks exhibited greater susceptibility to diet-induced obesity, markedly increased epididymal adipocyte area with clear signs of inflammation. The HFD-induced glucose intolerance was similar in both groups but serum hypertriglyceridemia and hypercholesterolemia were less intense in ARβ3KO animals when compared with WT controls. Isoproterenol-induced lipolysis in isolated white adipocytes as assessed by glycerol release was significantly impaired in ARβ3KO animals despite normal expression of key proteins involved in lipid metabolism. In conclusion, ARβ3 inactivation does not affect BAT thermogenesis but increases susceptibility to diet-induced obesity by dampening WAT lipolytic response to adrenergic stimulation.
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