UCP1 Expression In Brown Adipocytes Research Articles

Gab2 deficiency suppresses high-fat diet-induced obesity by reducing adipose tissue inflammation and increasing brown adipose function in mice

Obesity is caused by a long-term imbalance between energy intake and consumption and is regulated by multiple signals. This study investigated the effect of signaling scaffolding protein Gab2 on obesity and its relevant regulation mechanism. Gab2 knockout (KO) and wild-type (WT) mice were fed with a standard diet (SD) or high-fat diet (HFD) for 12 weeks. The results showed that the a high-fat diet-induced Gab2 expression in adipose tissues, but deletion of Gab2 attenuated weight gain and improved glucose tolerance in mice fed with a high-fat diet. White adipose tissue and systemic inflammations were reduced in HFD-fed Gab2 deficiency mice. Gab2 deficiency increased the expression of Ucp1 and other thermogenic genes in brown adipose tissue. Furthermore, the regulation of Gab2 on the mature differentiation and function of adipocytes was investigated in vitro using primary or immortalized brown preadipocytes. The expression of brown fat-selective genes was found to be elevated in differentiated adipocytes without Gab2. The mechanism of Gab2 regulating Ucp1 expression in brown adipocytes involved with its downstream PI3K (p85)-Akt-FoxO1 signaling pathway. Our research suggests that deletion of Gab2 suppresses diet-induced obesity by multiple pathways and Gab2 may be a novel therapeutic target for the treatment of obesity and associated complications.

Indirubin, a small molecular deriving from connectivity map (CMAP) screening, ameliorates obesity-induced metabolic dysfunction by enhancing brown adipose thermogenesis and white adipose browning

BackgroundObesity occurs when the body’s energy intake is constantly greater than its energy consumption and the pharmacological enhancing the activity of brown adipose tissue (BAT) and (or) browning of white adipose tissue (WAT) has been considered promising strategies to treat obesity.MethodsIn this study, we took a multi-pronged approach to screen UCP1 activators, including in silico predictions, in vitro assays, as well as in vivo experiments.ResultsBase on Connectivity MAP (CMAP) screening, we obtained multiple drugs that possess a remarkably correlating gene expression pattern to that of enhancing activity in BAT and (or) sWAT signature. Particularly, we focused on a previously unreported drug-indirubin, a compound obtained from the Indigo plant, which is now mainly used for the treatment of chronic myelogenous leukemia (CML). In the current study, our results shown that indirubin could enhance the BAT activity, as evidenced by up-regulated Ucp1 expression and enhanced mitochondrial respiratory function in vitro cellular model. Furthermore, indirubin treatment restrained high-fat diet (HFD)-induced body weight gain, improved glucose homeostasis and ameliorated hepatic steatosis which were associated with the increase of energy expenditure in the mice model. Moreover, we revealed that indirubin treatment increased BAT activity by promoting thermogenesis and mitochondrial biogenesis in BAT and induced browning of subcutaneous inguinal white adipose tissue (sWAT) of mice under HFD. Besides, our results indicated that indirubin induced UCP1 expression in brown adipocytes, at least in part, via activation of PKA and p38MAPK signaling pathways.ConclusionsOur results clearly show that as an effective BAT (as well as beige cells) activator, indirubin may have a protective effect on the prevention and treatment of obesity and its complications.

Role of estradiol and testosterone in Ucp1 expression in brown/beige adipocytes.

Activity of brown/beige adipocytes is higher in women than in men. The expression level of uncoupling protein 1 (UCP1) is largely consistent with the thermogenic activity in brown/beige adipocytes. The present study examined the direct effects of sex hormones on Ucp1 expression in brown adipocytes and beige adipocytes, which were differentiated from HB2 brown preadipocytes and 3T3-L1 white preadipocytes, respectively; treatment with estradiol or testosterone was used during the early (days 0-8) or late stage (days 8-12) of brown adipogenesis and beige adipogenesis. On day 8 or day 12, cells were treated with or without isoproterenol (Iso), an agonist for the β-adrenergic receptor, for 4hours. Furthermore, the sex of cells was examined; the sex-determining region y gene, which is located on the y chromosome, was present in HB2 cells, but not in 3T3-L1 cells, suggesting that HB2 cells and 3T3-L1 cells are male and female cells, respectively. Treatment with 17β-estradiol during the early stage of brown adipogenesis enhanced the responsiveness to Iso on Ucp1 induction, whereas treatment during the late stage of brown adipogenesis decreased Ucp1 expression in unstimulated brown adipocytes. Estradiol decreased Iso-induced Ucp1 expression during the early stage of beige adipogenesis. Treatment with testosterone during the early stage of brown adipogenesis did not affect Ucp1 expression but increased the responsiveness to Iso on Ucp1 induction by the treatment during the late stage of brown adipogenesis. The present results suggest that sex hormones modulate the expression level of Ucp1 in brown/beige adipocytes in a stage-dependent manner. Direct effects of sex hormones in brown/beige adipogenesis were evaluated. Treatment with 17β-estradiol during the early stage of brown adipogenesis enhanced the responsiveness to isoproterenol (Iso), an agonist for the β-adrenergic receptor, on Ucp1 induction, whereas treatment during the late stage of brown adipogenesis decreased Ucp1 expression in unstimulated brown adipocytes. Estradiol decreased Iso-induced Ucp1 expression during the early stage of beige adipogenesis. Testosterone during the late stage of brown adipogenesis increased the responsiveness to Iso on Ucp1 induction. Sex hormones modulate the expression level of Ucp1 in brown/beige adipocytes in a stage-dependent manner.

UCP1 transrepression in Brown Fat in vivo and mineralocorticoid receptor anti-thermogenic effects

ObjectivesThe mineralocorticoid receptor (MR), a hormone-activated transcription factor, besides its role in controlling hydroelectrolytic homeostasis, exerts pro-adipogenic and anti-thermogenic effects, inhibiting mitochondrial-uncoupling protein UCP1 expression in brown adipocytes. The aim of this study was to gain insight into the molecular mechanisms by which MR participates in such metabolic regulation. MethodsWe evaluated in vivo MR effects on cold-induced UCP1 expression in MR-overexpressing mice. Expression profiles of several transcriptional coregulators were analyzed during differentiation of the brown adipocyte T37i cell line. Given that UCP1 expression is inversely controlled by catecholamines/retinoic acid and corticosteroids, we investigated the mechanisms of MR's inhibitory effect on UCP1 transcription in T37i cells. Chromatin immunoprecipitation (ChIP) experiments enabled us to explore MR interaction with UCP1 promoter regions. ResultsCold-induced UCP1 expression was blunted in the brown fat of MR-overexpressing mice. Along with induction of increasing mRNA levels for specific adipocyte markers during T37i differentiation, MR coactivator transcript levels significantly increased in intermediate states of differentiation, whereas expression of MR corepressors transiently increased approximately 2-fold. Such a simultaneous transient peak in coregulator expression is consistent with physiologically relevant cooperation occurring during brown adipogenesis. ChIP demonstrated that, after retinoic acid stimulation and aldosterone exposure, MR and PPARγ concomitantly bind to specific UCP1 promoter motifs. ConclusionOur studies demonstrate that MR exerts a pivotal metabolic role by controlling energy expenditure, and provide novel information on how MR participates in the regulation of brown adipocyte function.

The steroid RU486 induces UCP1 expression in brown adipocytes.

RU486 (mifepristone), a potent antagonist at progesterone and glucocorticoid receptors (PR and GR), is well known for its use in the termination of unwanted pregnancies, the potential development of oral contraceptives, treatment of certain cancers and other activities. Potentially, it could also play a role in obesity control, although the few studies that have addressed this aspect have focused mainly on its central and anti-glucocorticoid effects. We have shown previously that it could have a direct effect on brown adipocytes in culture when administered together with progesterone. The aim of the present work was to analyse the effects of RU486 on the expression of uncoupling proteins (UCPs) in brown adipocytes. In culture-grown, differentiated brown adipocytes, placed in a serum-free medium to exclude the presence of progesterone or glucocorticoids, RU486 stimulated UCP1 expression at both the mRNA and protein levels. These effects could be mediated by PR, GR or other unknown mechanisms but do not seem to be due to its anti-progestin or anti-glucocorticoid actions. The results suggest that the steroid RU486 has a direct action on adipocytes which could be useful for stimulating non-shivering BAT thermogenesis and therefore is of interest in obesity studies.

Uncoupling proteins: gender dependence and their relation to body weight control.

Members of the uncoupling protein (UCP) family have different purported functions, which can be either directly or indirectly related to the control of body weight. In this sense, most studies on this topic have been carried out using male subjects, although different works with males and females have shown important sex-associated differences in the regulation of these proteins; for instance, sex differences have been shown in the cold-, diet- and overweight-induced expression of brown adipose tissue UCP1 and also in the correlation of muscle UCP3 with overweight. In these kinds of studies, models of obesity such as cafeteria diet feeding and postcafeteria have been very useful. Moreover, sex hormones have been shown to modulate UCP1 expression in brown adipocytes in vitro. All these sex-dependent differences, as well as sex differences in body weight gain under a hypercaloric diet, could be related to the different respective biological functions of males and females, taking into account the fact that the gender effect in future studies on obesity could be of interest.

Uncoupling proteins: gender-dependence and their relation to body weight control.

The members of the uncoupling protein family have different purported functions, which can be either directly or indirectly related to the control of body weight. In this sense, a great part of the studies carried out on this topic have been made using male subjects, although different works with male and female subjects have shown important sex-associated differences in the regulation of these proteins; for instance, sex differences have been shown in the cold-, diet- and overweight-induced expression of brown adipose tissue UCP1 and also in the correlation of muscle UCP3 with overweight. In these kinds of studies, models of obesity such as the cafeteria diet feeding and postcafeteria have been very useful. Moreover, sex hormones have been shown to modulate UCP1 expression in brown adipocytes in vitro. All of these sex-dependent differences, as well as sex differences in body weight gain under a hypercaloric diet, could be related to the different respective biological functions of male and female subjects and taking into account the gender effect in future studies on obesity could be of interest.