Uncoupling Protein 1 Expression In Brown Adipose Tissue Research Articles

Adaptive character of metabolism in Eothenomys miletus in Hengduan Mountains region during cold acclimation

Environmental factors play an important role in the seasonal adaptation of body mass and thermogenesis in small, wild mammals. The purpose of the present study was to test the hypothesis that ambient temperature was a cue to trigger the seasonal adjustments in body mass, energy intake, uncoupling protein 1 (UCP1) in brown adipose tissue (BAT), and other biochemical characteristics of Eothenomys miletus during 49 days of cold exposure. Our data demonstrated that cold acclimation induced a remarkable decrease in body mass, a significant increase in energy intake and metabolic rate, and high expression of UCP1 in BAT of E. miletus. Biochemical characteristics of BAT and liver respiration were also increased following cold acclimation. These data suggest that E. miletus reduced the body mass and increased energy intake and expenditure under cold acclimation. Increased expression of UCP1 was potentially involved in the regulation of energy metabolism and thermogenic capacity following cold acclimation.

Brain-derived neurotrophic factor (BDNF) in the hypothalamic ventromedial nucleus increases energy expenditure

Brain-derived neurotrophic factor (BDNF) decreases food intake and body weight, but few central sites of action have been identified for its effect on energy expenditure. The hypothalamic ventromedial nucleus (VMH) is important in regulating energy metabolism. Our previous work indicated that BDNF in the VMH reduced food intake. The purposes of the study were to determine: 1) if BDNF in the VMH increases energy expenditure (EE); 2) if BDNF-enhanced thermogenesis results from increased spontaneous physical activity (SPA) and resting metabolic rate (RMR); and 3) if VMH BDNF thermogenic effects are mediated by uncoupling protein 1 (UCP1) in brown adipose tissue (BAT). BDNF (0.5 μg) was injected into the VMH of male Sprague–Dawley rats and oxygen consumption, carbon dioxide production, food intake and SPA were measured for 24 h in an indirect calorimeter. Animals were sacrificed 4 h after BDNF injection, and BAT UCP1 gene expression was measured with quantitative real-time polymerase chain reaction. BDNF significantly decreased food and water intake, and body weight gain. Heat production and RMR were significantly elevated for 9 h immediately after BDNF injection. BDNF increased SPA and EE during SPA (aEE) within 9 h after injection although BDNF had no effect on 0–24 h SPA and aEE. BDNF did not induce a significant increase in BAT UCP1 expression. In conclusion, VMH BDNF reduces body weight by decreasing food intake and increasing EE consequent to increased SPA and RMR, suggesting that the VMH is an important site of BDNF action to influence energy balance.

Basal adrenergic tone is required for maximal stimulation of rat brown adipose tissue UCP1 expression by chronic PPAR-γ activation

We investigated the involvement of basal sympathetic tone in brown adipose tissue (BAT) recruitment and gene expression profile induced by peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation. Innervated and surgically denervated BAT pads of rats treated or not with rosiglitazone (15 mg.kg(-1).day(-1), 7 days) were evaluated for weight, triacylglycerol (TAG) and DNA content, mitochondrial mass, and gene expression. Rosiglitazone induced BAT recruitment (increased mass, TAG and DNA content) and mRNA levels of lipolytic (adipose tissue triglyceride lipase and CGI58) and lipogenic (lipoprotein lipase, phosphoenolpyruvate carboxykinase, fatty acid binding protein 4, and diacylglycerol acyltransferase 1) proteins independently of tissue innervation status. Mitochondrial mass and mRNA levels of its regulators peroxisome proliferator-activated receptor coactivator-alpha and CCAAT/enhancer binding protein-beta were not affected by rosiglitazone, while being significantly reduced by denervation. By contrast, maximal stimulation of uncoupling protein 1 (UCP1) (thermogenesis), cell death-inducing DNA fragmentation factor-45-like effector A (inhibitor of UCP1 activity), monoacylglycerol lipase (lipolysis), small heterodimer partner (transcription), and glycerokinase (TAG synthesis) by rosiglitazone depended on the presence of intact BAT innervation. Cold exposure (5 degrees C, 24 h) significantly increased UCP1 mRNA levels in innervated BAT pads of untreated rats, without affecting the already high BAT UCP1 levels of rosiglitazone-treated animals. A similar pattern of response was found in denervated pads, but with markedly lower UCP1 expression than that in innervated BAT. In conclusion, whereas the mass (hyperplasia and hypertrophy), lipogenic, and lipolytic components of BAT recruitment induced by rosiglitazone occur independently of tissue sympathetic innervation, maximal UCP1 expression induced by PPAR-gamma in vivo depends on the presence of basal BAT adrenergic tone. The residual sympathetic tone found under rosiglitazone treatment is, therefore, involved in the modulation of a subset of major components of PPAR-gamma-mediated BAT recruitment.

Tea catechins enhance the mRNA expression of uncoupling protein 1 in rat brown adipose tissue

The aim of the present study was to determine whether the antiobesity effects of tea catechins (TCs) are associated with the expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT). Male Sprague–Dawley rats were fed a high-fat (HF; 35% fat) diet for 5 weeks, then divided into four groups and fed an HF, HF with 0.5% TC (HFTC), normal-fat (NF; 5% fat) or NF with 0.5% TC (NFTC) diet for 8 weeks. At the end of the experimental period, perirenal and epididymal white adipose tissues (WATs) and interscapular BAT were isolated. The NFTC group had significantly lower perirenal WAT weights than the NF group (NF: 12.7±0.53 g; NFTC: 10.2±0.43 g; P<.01), but the HF and HFTC groups did not differ significantly. TC intake had no effects on epididymal WAT weights. The NFTC and HFTC groups had significantly lower BAT weights than the NF and HF groups, respectively. The NFTC group had significantly higher UCP1 mRNA levels in BAT than the NF group (NF: 0.35±0.02; NFTC: 0.60±0.11; P<.05), but the HF and HFTC groups did not differ significantly. Thus, TC intake in the context of the NF diet reduced perirenal WAT weight and up-regulated UCP1 mRNA expression in BAT. These results suggest that the suppressive effect of TC on body fat accumulation is associated with UCP1 expression in BAT.

Increased Uncoupling Protein 1 mRNA Expression in Mice Brown Adipose Tissue After Burn Injury

Brown adipose tissue (BAT) contains numerous mitochondria and is characterized by the presence of uncoupling protein 1 (UCP1). UCP1 is the main mediator of thermogenesis that plays an important role in the modulation of energy balance. The authors hypothesize that alterations in the expression of UCP1 might be involved in the major metabolic disorders occurring during burn trauma. The present study is designed to explore the potential role of the UCP1 in metabolic disorders after burn injury. The authors have used the real-time reverse transcription-polymerase chain reaction to quantify UCP1 mRNA expression in the mice BAT and white adipose tissue (WAT). UCP1 mRNA expression was up-regulated in BAT, especially at 24 hours after burn. UCP1 mRNA expression was detectable and also up-regulated by burn injury in WAT. The authors provide evidence that one of the mechanisms mediating hypermetabolism and increased energy expenditure in burn injury is a pronounced increase in thermogenic capacity, as illustrated by robust gene expression of UCP1 in BAT and WAT.

Tea catechins enhance the mRNA expression of uncoupling protein 1

The aim of the present study was to determine whether the anti‐obesity effects of tea catechins (TCs) are associated with the expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT). Male Sprague Dawley rats were fed for five weeks with a high‐fat (HF; 35% fat) diet, then divided into four groups and fed for eight weeks with a HF, HF with 0.5% TC (HFTC), normal fat (NF; 5% fat), or NF with 0.5% TC (NFTC) diet. At the end of the experimental period, perirenal and epididymal white adipose tissues (WATs) and interscapular BAT were isolated. The NFTC group had significantly lower perirenal WAT weights than the NF group (NF: 12.7 ± 0.53 g; NFTC: 10.2 ± 0.43 g, p &lt; 0.01) but the HF and HFTC groups did not differ significantly. TC intake had no effects on epididymal WAT weights. The NFTC and HFTC groups had significantly lower BAT weights than the NF and HF groups, respectively. The NFTC group had significantly higher UCP1 mRNA levels in BAT than the NF group (NF: 0.35 ± 0.02; NFTC: 0.60 ± 0.11, p &lt; 0.05) but the HF and HFTC groups did not differ significantly. Thus, TC intake in the context of the NF diet reduced perirenal WAT weight and up‐regulated UCP1 mRNA expression in BAT. These results suggest that the suppressive effect of TC on body fat accumulation is associated with UCP1 expression in BAT.

Defective Lipid Delivery Modulates Glucose Tolerance and Metabolic Response to Diet in Apolipoprotein E–Deficient Mice

Apolipoprotein E (ApoE) regulates plasma lipid levels via modulation of lipolysis and serving as ligand for receptor-mediated clearance of triglyceride (TG)-rich lipoproteins. This study tested the impact of modulating lipid delivery to tissues on insulin responsiveness and diet-induced obesity. ApoE(+/+) and apoE(-/-) mice were placed on high-fat-high-sucrose diabetogenic diet or control diet for 24 weeks. Plasma TG clearance, glucose tolerance, and tissue uptake of dietary fat and glucose were assessed. Plasma TG clearance and lipid uptake by adipose tissue were impaired, whereas glucose tolerance was improved in control diet-fed apoE(-/-) mice compared with apoE(+/+) mice after an oral lipid load. Fat mass was reduced in apoE(-/-) mice compared with apoE(+/+) mice under both dietary conditions. The apoE(-/-) mice exhibited lower body weight and insulin levels than apoE(+/+) mice when fed the diabetogenic diet. Glucose tolerance and uptake by muscle and brown adipose tissue (BAT) was also improved in mice lacking apoE when fed the diabetogenic diet. Indirect calorimetry studies detected no difference in energy expenditure and respiratory quotient between apoE(+/+) and apoE(-/-) mice on control diet. Energy expenditure and uncoupling protein-1 expression in BAT were slightly but not significantly increased in apoE(-/-) mice on diabetogenic diet. These results demonstrated that decreased lipid delivery to insulin-sensitive tissues improves insulin sensitivity and ameliorates diet-induced obesity.

Uncoupling protein 1 contributes to fat-reducing effect of leptin

Leptin is proposed to reduce body fat by increasing energy expenditure, in addition to decreasing food intake, through the activation of brown adipose tissue (BAT) thermogenesis. To confirm this, we investigated the effects of leptin on whole body energy expenditure, BAT functions and adiposity in wild-type (WT) mice, and compared with those in mice deficient in uncoupling protein 1 (UCP1), a key molecule for BAT thermogenesis. Chronic hyperleptinemia induced by adenovirus gene transfer reduced food intake in both WT and UCP1-KO mice. WT mice with hyperleptinemia, compared to pair-fed controls, showed increased oxygen consumption, elevated UCP1 expression in BAT, ectopic UCP1 induction in white adipose tissue (WAT), and reduced body fat content. These effects of chronic hyperleptinemia were not observed in UCP1-KO mice. It was concluded that the fat-reducing effect of leptin is due to not only decreased food intake, but also increased UCP1-dependent energy expenditure.:

Chronic REM-sleep deprivation of rats elevates metabolic rate and increases UCP1 gene expression in brown adipose tissue

A cluster of unique pathologies progressively develops during chronic total- or rapid eye movement-sleep deprivation (REM-SD) of rats. Two prominent and readily observed symptoms are hyperphagia and decline in body weight. For body weight to be lost despite a severalfold increase in food consumption suggests that SD elevates metabolism as the subject enters a state of negative energy balance. To test the hypothesis that mediation of this hypermetabolism involves increased gene expression of uncoupling protein-1 (UCP1), which dissipates the thermodynamic energy of the mitochondrial proton-motive force as heat instead of ATP formation in brown adipose tissue (BAT), we 1) established the time course and magnitude of change in metabolism by measuring oxygen consumption, 2) estimated change in UCP1 gene expression in BAT by RT-PCR and Western blot, and 3) assayed serum leptin because of its role in regulating energy balance and food intake. REM-SD of male Sprague-Dawley rats was enforced for 20 days with the platform (flowerpot) method, wherein muscle atonia during REM sleep causes contact with surrounding water and awakens it. By day 20, rats more than doubled food consumption while losing approximately 11% of body weight; metabolism rose to 166% of baseline with substantial increases in UCP1 mRNA and immunoreactive UCP1 over controls; serum leptin decreased and remained suppressed. The decline in leptin is consistent with the hyperphagic response, and we conclude that one of the mediators of elevated metabolism during prolonged REM-SD is increased gene expression of UCP1 in BAT.

Metallothionein is expressed in adipocytes of brown fat and is induced by catecholamines and zinc.

Metallothionein (MT) is thought to have an antioxidant function and is strongly expressed during activation of thermogenesis and increased oxidative stress in brown adipose tissue (BAT). Localization and regulation of MT expression in BAT was therefore investigated in rats and mice. Immunohistochemical analysis of BAT from rats exposed to 4 degrees C for 24 h showed that MT and uncoupling protein 1 (UCP1) were coexpressed in differentiated adipocytes, and both cytoplasmic and nuclear localization of MT was observed. Cold induction of MT-1 expression in BAT was also observed in mice. Administration of norepinephrine to rats and isoproterenol to mice stimulated MT and UCP1 expression in BAT, implying a sympathetically mediated pathway for MT induction. In mice, zinc, and particularly dexamethasone, induced MT-2 expression in BAT and liver. Surprisingly, zinc also induced UCP1 in BAT, suggesting that elevated zinc may induce thermogenesis. We conclude that expression of MT in mature brown adipocytes upon beta-adrenoceptor activation is consistent with a role in protecting against physiological oxidative stress or in facilitating the mobilization or utilization of energy reserves.

Norepinephrine Is Required for Leptin Effects on Gene Expression in Brown and White Adipose Tissue

Exogenous leptin enhances energy utilization in ob/ob mice by binding its hypothalamic receptor and selectively increasing peripheral fat oxidation. Leptin also increases uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), but the neurotransmitter that mediates this effect has not been established. The present experiments sought to determine whether leptin regulates UCP1 expression in BAT and its own expression in white adipose tissue (WAT) through the long or short forms of leptin receptor and modulation of norepinephrine release. Mice lacking dopamineβ -hydroxylase (Dbh−/−), the enzyme responsible for synthesizing norepinephrine and epinephrine from dopamine, were treated with leptin (20 μg/g body weight/day) for 3 days before they were euthanized. UCP1 messenger RNA (mRNA) and protein expression were 5-fold higher in BAT from control (Dbh+/−) compared with Dbh−/− mice. Leptin produced a 4-fold increase in UCP1 mRNA levels in Dbh+/− mice but had no effect on UCP1 expression in Dbh−/−. Theβ3-adrenergic agonist, CL-316,243 increased UCP1 expression and established that BAT from both groups of mice was capable of responding to β-adrenergic stimulation. Similarly, exogenous leptin reduced leptin mRNA in WAT from Dbh+/− but not Dbh−/− mice. In separate experiments, leptin produced comparable reductions in food intake in both Dbh+/− and Dbh−/− mice, illustrating that norepinephrine is not required for leptin’s effect on food intake. Lastly, db/db mice lacking the long form of the leptin receptor failed to increase UCP1 mRNA in response to exogenous leptin but increased UCP1 mRNA in response to CL-316,243. These studies establish that norepinephrine is required for leptin to regulate its own expression in WAT and UCP1 expression in BAT and indicate that these effects are likely mediated through the centrally expressed long form of the leptin receptor.

Norepinephrine is required for leptin effects on gene expression in brown and white adipose tissue.

Exogenous leptin enhances energy utilization in ob/ob mice by binding its hypothalamic receptor and selectively increasing peripheral fat oxidation. Leptin also increases uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), but the neurotransmitter that mediates this effect has not been established. The present experiments sought to determine whether leptin regulates UCP1 expression in BAT and its own expression in white adipose tissue (WAT) through the long or short forms of leptin receptor and modulation of norepinephrine release. Mice lacking dopamine beta-hydroxylase (Dbh-/-), the enzyme responsible for synthesizing norepinephrine and epinephrine from dopamine, were treated with leptin (20 microg/g body weight/day) for 3 days before they were euthanized. UCP1 messenger RNA (mRNA) and protein expression were 5-fold higher in BAT from control (Dbh+/-) compared with Dbh-/- mice. Leptin produced a 4-fold increase in UCP1 mRNA levels in Dbh+/- mice but had no effect on UCP1 expression in Dbh-/-. The beta3-adrenergic agonist, CL-316,243 increased UCP1 expression and established that BAT from both groups of mice was capable of responding to beta-adrenergic stimulation. Similarly, exogenous leptin reduced leptin mRNA in WAT from Dbh+/- but not Dbh-/- mice. In separate experiments, leptin produced comparable reductions in food intake in both Dbh+/- and Dbh-/- mice, illustrating that norepinephrine is not required for leptin's effect on food intake. Lastly, db/db mice lacking the long form of the leptin receptor failed to increase UCP1 mRNA in response to exogenous leptin but increased UCP1 mRNA in response to CL-316,243. These studies establish that norepinephrine is required for leptin to regulate its own expression in WAT and UCP1 expression in BAT and indicate that these effects are likely mediated through the centrally expressed long form of the leptin receptor.

Induction of uncoupling protein expression in brown and white adipose tissue by leptin.

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 microg/g BW x 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.