Brown adipose tissue: Updates in cellular and molecular biology

Brown adipose tissue (BAT) is mainly composed of adipocytes, it is highly vascularized and innervated, and can be activated in adult humans. Brown adipocytes are responsible for performing non-shivering thermogenesis, which is exclusively mediated by uncoupling protein (UCP) -1 (a protein found in the inner mitochondrial membrane), the hallmark of BAT, responsible for the uncoupling of the proton leakage from the ATP production, therefore, generating heat (i.e. thermogenesis). Besides UCP1, other compounds are essential not only to thermogenesis, but also to the proliferation and differentiation of BAT, including peroxisome proliferator-activated receptor (PPAR) family, PPARgamma coactivator 1 (PGC1)-alpha, and PRD1-BF-1-RIZ1 homologous domain protein containing protein (PRDM) -16. The sympathetic nervous system centrally regulates thermogenesis through norepinephrine, which acts on the adrenergic receptors of BAT. This bound leads to the initialization of the many pathways that may activate thermogenesis in acute and/or chronic ways. In summary, this mini-review aims to demonstrate the latest advances in the knowledge of BAT.     

MiR-499/PRDM16 axis modulates the adipogenic differentiation of mouse skeletal muscle satellite cells

Obesity is associated with increased risks of diverse diseases; brown adipose tissue (BAT) can increase energy expenditure and protect against obesity by increasing the decomposition of white adipose tissue (WAT) to enhance the non-coupled oxidative phosphorylation of fatty acid in adipocytes and contributes to weight loss. However, BAT is abundant in only small rodents and newborn humans, but not in adults. PRDM16 is a key factor that induces the differentiation of skeletal muscle precursors to brown adipocytes and simultaneously inhibits myogenic differentiation. In the present study, we set insulin-induced skeletal muscle satellite cells (SMSCs) adipogenic differentiation model, as confirmed by the contents of adipogenic markers PRDM16, UCP1 and PGC1α and myogenic markers MyoD1 and MyoG. We selected miR-499 as candidate miRNA, which might regulate PRDM16 to affect SMSCs adipogenic differentiation. Possibly through directly binding to PRDM16 3′-UTR, miR-499 negatively regulated PRDM16 expression and hindered SMSCs adipogenic differentiation by reducing adipogenic markers PRDM16, UCP1 and PGC1α and increasing myogenic markers MyoD1 and MyoG. PRDM16 overexpression could partially reverse the effect of miR-499 on the above markers and SMSCs adipogenic differentiation. Taken together, miR-499/PRDM16 axis can affect the balance between SMSC myogenic and adipogenic differentiation, targeting miR-499 to rescue PRDM16 expression, thus promoting SMSCs adipogenic differentiation may be a promising strategy for obesity treatment.     

Adipose tissue development--impact of the early life environment

Increasing experimental and observational evidence in both animals and humans suggests that early life events are important in setting later fat mass. This includes both the number of adipocytes and the relative distribution of both brown and white adipose tissue. Brown adipose tissue is characterised as possessing a unique uncoupling protein (UCP)1 which enables the rapid generation of large amounts of heat and is most abundant in the newborn. In large mammals such as sheep and humans, brown fat that is located around the major internal organs, is largely lost during the postnatal period. However, it is retained in small and discrete areas into adulthood when it is sensitive to environmental cues such as changes in ambient temperature or day length. The extent to which brown adipose tissue is lost or replaced by white adipose tissue and/or undergoes a process of transdifferentiation remains controversial. Small amounts of UCP1 can also be present in skeletal muscle which now appears to share the same common precursor cell as brown adipose tissue. The functional consequences of UCP1 in muscle remain to be confirmed but it could contribute to dietary induced thermogenesis. Challenges in elucidating the primary mechanisms regulating adipose tissue development include changes in methylation status of key genes during development in different species, strains and adipose depots. A greater understanding of the mechanisms by which early life events regulate adipose tissue distribution in young offspring are likely to provide important insights for novel interventions that may prevent excess adiposity in later life.     

Fucoxanthin from edible seaweed, Undaria pinnatifida, shows antiobesity effect through UCP1 expression in white adipose tissues

Mitochondrial uncoupling protein 1 (UCP1) is usually expressed only in brown adipose tissue (BAT) and a key molecule for metabolic thermogenesis to avoid an excess of fat accumulation. However, there is little BAT in adult humans. Therefore, UCP1 expression in tissues other than BAT is expected to reduce abdominal fat. Here, we show reduction of abdominal white adipose tissue (WAT) weights in rats and mice by feeding lipids from edible seaweed, Undaria pinnatifida. Clear signals of UCP1 protein and mRNA were detected in WAT of mice fed the Undaria lipids, although there is little expression of UCP1 in WAT of mice fed control diet. The Undaria lipids mainly consisted of glycolipids and seaweed carotenoid, fucoxanthin. In the fucoxanthin-fed mice, WAT weight significantly decreased and UCP1 was clearly expressed in the WAT, while there was no difference in WAT weight and little expression of UCP1 in the glycolipids-fed mice. This result indicates that fucoxanthin upregulates the expression of UCP1 in WAT, which may contribute to reducing WAT weight.     

Shc depletion stimulates brown fat activity in vivo and in vitro

Adipose tissue is an important metabolic organ that integrates a wide array of homeostatic processes and is crucial for whole‐body insulin sensitivity and energy metabolism. Brown adipose tissue (BAT) is a key thermogenic tissue with a well‐established role in energy expenditure. BAT dissipates energy and protects against both hypothermia and obesity. Thus, BAT stimulation therapy is a rational strategy for the looming pandemic of obesity, whose consequences and comorbidities have a huge impact on the aged. Shc‐deficient mice (ShcKO) were previously shown to be lean, insulin sensitive, and resistant to high‐fat diet and obesity. We investigated the contribution of BAT to this phenotype. Insulin‐dependent BAT glucose uptake was higher in ShcKO mice. Primary ShcKO BAT cells exhibited increased mitochondrial respiration; increased expression of several mitochondrial and lipid‐oxidative enzymes was observed in ShcKO BAT. Levels of brown fat‐specific markers of differentiation, UCP1, PRDM16, ELOVL3, and Cox8b, were higher in ShcKO BAT. In vitro, Shc knockdown in BAT cell line increased insulin sensitivity and metabolic activity. In vivo, pharmacological stimulation of ShcKO BAT resulted in higher energy expenditure. Conversely, pharmacological inhibition of BAT abolished the improved metabolic parameters, that is the increased insulin sensitivity and glucose tolerance of ShcKO mice. Similarly, in vitro Shc knockdown in BAT cell lines increased their expression of UCP1 and metabolic activity. These data suggest increased BAT activity significantly contributes to the improved metabolic phenotype of ShcKO mice.     

Pharmacological and nutritional agents promoting browning of white adipose tissue

The role of brown adipose tissue in the regulation of energy balance and maintenance of body weight is well known in rodents. Recently, interest in this tissue has re-emerged due to the realization of active brown-like adipose tissue in adult humans and inducible brown-like adipocytes in white adipose tissue depots in response to appropriate stimuli (“browning process”). Brown-like adipocytes that appear in white fat depots have been called “brite” (from brown-in-white) or “beige” adipocytes and have characteristics similar to brown adipocytes, in particular the capacity for uncoupled respiration. There is controversy as to the origin of these brite/beige adipocytes, but regardless of this, induction of the browning of white fat represents an attractive potential strategy for the management and treatment of obesity and related complications. Here, the different physiological, pharmacological and dietary determinants that have been linked to white-to-brown fat remodeling and the molecular mechanisms involved are reviewed in detail. In the light of available data, interesting therapeutic perspectives can be expected from the use of specific drugs or food compounds able to induce a program of brown fat differentiation including uncoupling protein 1 expression and enhancing oxidative metabolism in white adipose cells. However, additional research is needed, mainly focused on the physiological relevance of browning and its dietary control, where the use of ferrets and other non-rodent animal models with a more similar adipose tissue organization and metabolism to humans could be of much help. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease.     

京尼平对小鼠棕色和白色脂肪组织UCP1表达的影响

目的:棕色脂肪组织活化和白色脂肪组织棕化是改善减肥的良好策略。本研究利用冷刺激作为阳性对照,观察京尼平对小鼠脂肪组织活化与棕化的作用。方法:8周龄雄性C57BL/6J小鼠30只,随机分为正常对照组、京尼平组、冷刺激组, 每组10只。京尼平组小鼠腹腔注射给予京尼平处理(15 mg/(kg·d),连续9 d),对照组用生理盐水处理,冷刺激组小鼠在室温(22℃±2℃)下处理4 d后,置于4℃环境中进行冷刺激处理5 d(24 h/d)。检测各组小鼠每天摄食量、体重和体温变化,取肩胛下区、腹股沟区及附睾周围部分脂肪组织观察形态学的变化,测定棕色脂肪组织、皮下白色脂肪组织以及内脏白色脂肪组织解偶联蛋白1(UCP1)的表达。结果:与正常对照组相比,京尼平组小鼠白色脂肪湿重下降16%,冷刺激组下降28%,均有明显差异(P＜0.05);京尼平组和冷刺激组白色脂肪组织颜色变深,HE染色显示脂肪细胞内的脂滴变小,数量增加;京尼平组小鼠的皮下、内脏白色脂肪组织和棕色3种脂肪组织中的UCP1表达量均明显增加(P＜0.05)。结论:京尼平通过上调UCP1的表达促进棕色脂肪组织活化和白色脂肪组织棕化,此效应是京尼平降脂减轻体重的作用机制之一。     

N-butylidenephthalide ameliorates high-fat diet-induced obesity in mice and promotes browning through adrenergic response/AMPK activation in mouse beige adipocytes

Thermogenesis (non-exercise activity) in brown adipose tissue (BAT) promotes energy expenditure because of its higher number of mitochondria than white adipose tissue (WAT). The main function of thermogenesis in BAT can counteract obesity through the dissipation of calories as heat. N-butylidenephthalide (BP) is a natural derivative from Angelica sinensis, a Chinese herb that has been used for thousands of years. In this report, we demonstrated that BP improved the metabolic profiles of mice with high fat diet-induced obesity (DIO) by preventing weight gain, improving serum blood parameters, enhancing energy expenditure, stimulating white fat browning, and reversing hepatic steatosis. Further investigations demonstrated that BP administration upregulated the mRNA expression of beige (CD137, TMEM26) and brown fat selected genes (UCP1, PRDM16, PGC-1α, PPARγ) in white adipose tissues. In vitro studies, BP treatment increased multilocular lipid droplet levels, induced β-adrenergic receptor (cAMP/PKA) and AMP-activated protein kinase (AMPK) signaling (AMPK/acetyl-CoA carboxylase/SIRT1), and increased oxygen consumption in murine differentiated beige adipocytes, and the effects of BP were blocked by an AMPK inhibitor. BP promoted the interaction of AMPK with PGC-1α in beige adipocytes. Our findings provide novel insights into the application of BP in regulating energy metabolism and suggest its utility for clinical use in the treatment of obesity and related diseases.     

Expression of Class III facilitative glucose transporter genes (GLUT-10 and GLUT-12) in mouse and human adipose tissues

We have examined whether GLUT-10 and GLUT-12, members of the Class III group of the recently expanded family of facilitative glucose transporters, are expressed in adipose tissues. The mouse GLUT-12 gene, located on chromosome 10, comprises at least five exons and encodes a 622 amino acid protein exhibiting 83% sequence identity and 91% sequence similarity to human GLUT-12. Expression of the GLUT-12 gene was evident in all the major mouse adipose tissue depots (epididymal, perirenal, mesenteric, omental, and subcutaneous white; interscapular brown). The GLUT-10 gene is also expressed in mouse adipose tissues and as with GLUT-12 expression occurred in the mature adipocytes as well as the stromal vascular cells. 3T3-L1 adipocytes express GLUT-10, but not GLUT-12, and expression of GLUT-12 was not induced by insulin or glucose. Both GLUT-10 and GLUT-12 expression was also found in human adipose tissue (subcutaneous and omental) and SGBS adipocytes. It is concluded that white fat expresses a wide range of facilitative glucose transporters.