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Brown and beige adipocytes have been widely known for their potential to dissipate excessive energy into heat form, resulting in an alleviation of obesity and other overweight-related conditions. This review highlights the origins, characteristics, and functions of the various kinds of adipocytes, as well as their anatomic distribution inside the human body. This review mainly focuses on various essential transcriptional factors such as PRDM16, FGF21, PPARα, PPARγ and PGC-1α, which exert their effects on the development and activation of thermogenic adipocytes via important pathways such as JAK-STAT, cAMP-PKA and PI3K-AKT signaling pathways. Additionally, this review will underline promising strategies to generate an unexhausted source of thermogenic adipocytes differentiated from human stem cells. These exogenous thermogenic adipocytes offer therapeutic potential for improvement of metabolic disorders via application as single cell or whole tissue transplantation. Graphical abstract Caption is required. Please provide.

Previous studies reported that Stat5 promotes adipogenesis and white adipocyte differentiation. However, the role of Stat5 in brown adipocyte development is poorly understood. We found Stat5a was higher expressed in brown adipocytes than in white adipocytes, and its level was increased during the process of brown adipocyte differentiation. In addition, Stat5a expression was affected by cold stress and high-fat diet-feeding, suggesting a potential role in thermogenesis. Knockdown of Stat5a induced downregulation of brown fat specific genes (UCP1, PGC-1α, Acox-1 and Cidea), while overexpression of Stat5a did the opposite effect. What is more, bioinformatics analysis, ChIP assay and Luciferase activity assay all verified that Stat5a directly bind and transactivate Kdm6a promoter (Lysine-specific demethylase 6A). Further, we found that Stat5a overexpression promoted the expression of Kdm6a and inhibited the trimethylation of H3K27. While inhibiting of Kdm6a reversed the promoting effect of Stat5a overexpression on the expression of brown fat specific genes. Therefore, we conclude that Stat5a participated in brown adipocyte differentiation and thermogenic program through binding and transactivating the Kdm6a promoter. Abbreviations: Stat5: Signal transducers and activators of transcription 5; BAT: brown adipose tissue; WAT; white adipose tissue; eWAT: epididymal white adipose tissue; sWAT: subcutaneous white adipose tissue; SVFs: stromal vascular fractions; UCP1: Uncoupling protein 1; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Acox-1: Peroxisomal acyl-coenzyme A oxidase 1; Cidea: Cell death activator CIDE-A; ChIP: Chromatin Immunoprecipitation; HFD: High fat diet; FBS: Fetal bovine serum; siStat5a: Stat5a siRNA; siKdm6: Kdm6a siRNA; pcDNA-Stat5a: over expression of Stat5a pcDNA3.1 vector; IgG: mouse immunoglobulin G; Kdm6a: Lysine-specific demethylase 6A; H3K27me3: trimethylated H3K27.

Activation of brown adipose tissue (BAT) has been proposed as a promising target against obesity due to its increased capacity for thermogenesis. In this study, we explored the effect of β -Lapachone ( β L), a compound obtained from the bark of the lapacho tree, against obesity. In vivo administration of β L into either high fat diet (HFD)-induced obese C57BL6 mice and genetically obese Lepr - ∕ - mice prevented body weight gain, which was associated with tissue weight loss of white adipose tissue (WAT). In addition, β L elevated thermogenic proteins including uncoupling protein 1 (UCP1) and mitochondrial count in BAT and human adipose tissue-derived mesenchymal stem cells (hAMSCs). β L also induced AMP-activated protein kinase (AMPK) phosphorylation, subsequent upregulation of acetyl-CoA carboxylase (ACC) and UCP1, and these effects were diminished by AMPK inhibitor compound C, suggesting that AMPK underlies the effects of β L. Mitogen-activated protein kinase pathways participated in the thermogenesis of β L, specifically p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) were activated by β L treatment in hAMSCs. Additionally, inhibitors of p38/JNK/ERK1/2 abrogated the activity of β L. Taken together, β L exerts anti-obese effects by inducing thermogenesis mediated by AMPK signaling pathway, suggesting that β L may have a potential therapeutic implication of obesity. Taken together, β L exerts anti-obese effects by not only inducing thermogenesis on brown adipocytes but also inducing the browning of white adipocytes. The anti-obese effect of β L is mediated by AMPK signaling pathway, suggesting that β L may have potential therapeutic implication of obesity.

Obesity is a widespread health problem that brings about various adipose tissue dysfunctions. The balance of energy storage and energy expenditure is critical for normal fat accumulation and lipid metabolism. Therefore, understanding the molecular basis of adipogenesis and thermogenesis is essential to maintain adipose development and lipid homeostasis. Increasing evidence demonstrated that lncRNAs (long non-coding RNAs), a class of non-protein coding RNAs of >200 nucleotides in length, are identified as key regulators in obesity-related biological processes through diverse regulatory mechanisms. In this review, we concentrate on recent and relevant studies on the roles of lncRNAs in regulation of white adipogenesis, brown adipocyte differentiation and lipid metabolism. In addition, the diagnostic and therapeutic potential of lncRNAs is highlighted, and that will make recommendations for the future application of lncRNAs in the treatment of obesity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Much of the fascination of the Wilms tumor protein (WT1) emanates from its unique roles in development and disease. Ubiquitous Wt1 deletion in adult mice causes multiple organ failure including a reduction of body fat. WT1 is expressed in fat cell progenitors in visceral white adipose tissue (WAT) but detected neither in energy storing subcutaneous WAT nor in heat producing brown adipose tissue (BAT). Our recent findings indicate that WT1 represses thermogenic genes and maintains the white adipose identity of visceral fat. Wt1 heterozygosity in mice is associated with molecular and morphological signs of browning including elevated levels of uncoupling protein 1 (UCP1) in epididymal WAT. Compared to their wild-type littermates, Wt1 heterozygous mice exhibit significantly improved whole-body glucose tolerance and alleviated hepatic steatosis under high-fat diet. Partial protection of heterozygous Wt1 knockout mice against metabolic dysfunction is presumably related to browning of their epididymal WAT. In the light of recent advancements, this article reviews the role of WT1 in the development of visceral WAT and its supposed function as a regulator of white adipose identity.

Objective Long noncoding RNAs (lncRNAs) are emerging as important regulators of diverse biological processes. Recent work has demonstrated that the inducible lncRNA Blnc1 stimulates thermogenic gene expression during brown and beige adipocyte differentiation. However, whether Blnc1 is functionally conserved in humans has not been explored. In addition, the molecular basis of the Blnc1 ribonucleoprotein complex in thermogenic gene induction remains incompletely understood. The aims of the current study were to: i) investigate functional conservation of Blnc1 in mice and humans and ii) elucidate the molecular mechanisms by which Blnc1 controls the thermogenic gene program in brown adipocytes. Methods Full-length human Blnc1 was cloned and examined for its ability to stimulate brown adipocyte differentiation. Different truncation mutants of Blnc1 were generated to identify functional RNA domains responsible for thermogenic gene induction. RNA-protein interaction studies were performed to delineate the molecular features of the Blnc1 ribonucleoprotein complex. Results Blnc1 is highly conserved in mice and humans at the sequence and function levels, both capable of stimulating brown adipocyte gene expression. A conserved RNA domain was identified to be required and sufficient for the biological activity of Blnc1. We identified hnRNPU as an RNA-binding protein that facilitates the assembly and augments the transcriptional function of the Blnc1/EBF2 ribonucleoprotein complex. Conclusions Blnc1 is a conserved lncRNA that promotes thermogenic gene expression in brown adipocytes through formation of the Blnc1/hnRNPU/EBF2 ribonucleoprotein complex. [ABSTRACT FROM AUTHOR]