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BackgroundThe global obesity epidemic is a significant public health issue, often leading to metabolic disorders such as diabetes and cardiovascular diseases. Collagen peptides (CP) and their bioactive component, Prolyl-hydroxyproline (Pro-Hyp), have shown potential in reducing adipocyte size, with unclear mechanisms concerning brown adipocyte differentiation.MethodsWe investigated the effects of Pro-Hyp on the differentiation of brown adipocytes in C3H10T1/2 mesenchymal stem cells, focusing on its impact on adipocyte size, gene expression related to brown fat function, and mitochondrial activity.ResultsPro-Hyp treatment decreased adipocyte size and upregulated brown fat-specific genes, including C/EBPα, PGC-1α, and UCP-1. Remarkably, it did not alter PPARγ expression. Pro-Hyp also elevated mitochondrial activity, suggesting enhanced brown adipocyte functionality. A Pro-Hyp responsive element was identified in the PGC-1α gene promoter, which facilitated the binding of the Foxg1 transcription factor, indicating a novel regulatory mechanism.ConclusionPro-Hyp promotes brown adipocyte differentiation, potentially offering a therapeutic strategy for obesity management. This study provides a molecular basis for the anti-obesity effects of CP, although further in vivo studies are needed to confirm these findings and to investigate the potential impact on beige adipocyte differentiation.

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.

Background: The global obesity epidemic is a significant public health issue, often leading to metabolic disorders such as diabetes and cardiovascular diseases. Collagen peptides (CP) and their bioactive component, Prolyl-hydroxyproline (Pro-Hyp), have shown potential in reducing adipocyte size, with unclear mechanisms concerning brown adipocyte differentiation., Methods: We investigated the effects of Pro-Hyp on the differentiation of brown adipocytes in C3H10T1/2 mesenchymal stem cells, focusing on its impact on adipocyte size, gene expression related to brown fat function, and mitochondrial activity., Results: Pro-Hyp treatment decreased adipocyte size and upregulated brown fat-specific genes, including C/EBPα, PGC-1α, and UCP-1. Remarkably, it did not alter PPARγ expression. Pro-Hyp also elevated mitochondrial activity, suggesting enhanced brown adipocyte functionality. A Pro-Hyp responsive element was identified in the PGC-1α gene promoter, which facilitated the binding of the Foxg1 transcription factor, indicating a novel regulatory mechanism., Conclusion: Pro-Hyp promotes brown adipocyte differentiation, potentially offering a therapeutic strategy for obesity management. This study provides a molecular basis for the anti-obesity effects of CP, although further in vivo studies are needed to confirm these findings and to investigate the potential impact on beige adipocyte differentiation., Competing Interests: AK-M was employed by Nitta Gelatin Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nomura, Kimira, Kobayashi, Shiobara, Osawa, Kataoka-Matsushita, Shimizu, Wada and Mano.)

Aging-associated chronic inflammation is a key contributing factor to a cluster of chronic metabolic disorders, such as cardiovascular disease, obesity, and type 2 diabetes. Immune cells particularly T cells accumulate in adipose tissue with advancing age, and there exists a cross talk between T cell and preadipocyte, contributing to age-related adipose tissue remodeling. Here, we compared the difference in morphology and function of adipose tissue between young (3-month-old) and old (18-month-old) mice and showed the phenomenon of brown adipose tissue (BAT) “whitening” in old mice. Flow cytometry analysis suggested an increased proportion of T cells in BAT of old mice comparing with the young and exhibited senescent characteristics. We take advantage of coculture system to demonstrate directly that senescent T cells inhibited brown adipocyte differentiation of preadipocytes in adipose tissue. Mechanistically, both in vitro and in vivo studies suggested that senescent T cells produced and released a higher level of IFN-γ, which plays a critical role in inhibition of preadipocyte-to-brown adipocyte differentiation. Taken together, the data indicate that senescent T cell-derived IFN-γ is a key regulator in brown adipocyte differentiation.

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. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

In recent years, brown adipose tissue (BAT), which has a high heat-producing capacity, has been confirmed to exist even in adults, and it has become a focal point for the prevention and the improvement of obesity and lifestyle-related diseases. However, the influences of obesity and physical activity (PA) on the fluid factors secreted from BAT (brown adipokines) are not well understood. In this study, therefore, we focused on brown adipokines and investigated the effects of obesity and PA. The abnormal expressions of gene fluid factors such as galectin-3 (Lgals3) and Lgals3 binding protein (Lgals3bp), whose proteins are secreted from HB2 brown adipocytes, were observed in the interscapular BAT of obese mice fed a high-fat diet for 4 months. PA attenuated the abnormalities in the expressions of these genes. Furthermore, although the gene expressions of factors related to brown adipocyte differentiation such as peroxisome proliferator-activated receptor gamma coactivator 1-α were also down-regulated in the BAT of the obese mice, PA suppressed the down-regulation of these factors. On the other hand, lipogenesis was increased more in HB2 cells overexpressing Lgals3 compared with that in control cells, and the overexpression of Lgals3bp decreased the mitochondrial mass. These results indicate that PA attenuates the obesity-induced dysregulated expression of brown adipokines and suggests that Lgals3 and Lgals3bp are involved in brown adipocyte differentiation.

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. [ABSTRACT FROM AUTHOR]

Abstract 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. Highlights • The transcriptional and regulatory mechanisms of lncRNAs are illustrated by figure. • Roles of lncRNAs in regulation of white/brown adipogenesis and lipid metabolism are summarized. • The potential lncRNAs involved in adipogenesis and lipid metabolism are represented. • The diagnostic and therapeutic potential of lncRNAs is highlighted. [ABSTRACT FROM AUTHOR]

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]

Brown adipose tissue (BAT) holds promise to combat obesity through energy-spending, non-shivering thermogenesis. Understanding of regulation of BAT development can lead to novel strategies to increase BAT mass and function for obesity treatment and prevention. Here, we report the effects of chronic activation of PRR on brown adipogenesis of multipotent mesodermal stem C3H10T1/2 cells and immortalized brown pre-adipocytes from the classical interscapular BAT of mice. Activation of NOD1, TLR4, or TLR2 by their respective synthetic ligand suppressed brown marker gene expression and lipid accumulation during differentiation of brown-like adipocytes of C3H10T1/2. Activation of the PRR only during the commitment was sufficient to suppress the differentiation. PRR activation suppressed PGC-1α mRNA, but induced PRDM16 mRNA at the commitment. Consistently, PRR activation suppressed the differentiation of immortalized brown pre-adipocytes. Activation of PRR induced NF-κB activation in both cells, which correlated with their abilities to suppress PPARγ transactivation, a critical event for brown adipogenesis. Taken together, our results demonstrate that chronic PRR activation suppressed brown adipogenesis of multipotent mesodermal stem cells and brown pre-adipocytes, possibly through suppression of PPARγ transactivation. The results suggest that anti- inflammatory therapies targeting PRRs may be beneficial for the BAT development. [ABSTRACT FROM AUTHOR]

The molecular clock is intimately linked to metabolic regulation, and brown adipose tissue plays a key role in energy homeostasis. However, whether the cell-intrinsic clock machinery participates in brown adipocyte development is unknown. Here, we show that Bmal1 (also known as ARNTL), the essential clock transcription activator, inhibits brown adipogenesis to adversely affect brown fat formation and thermogenic capacity. Global ablation of Bmall in mice increases brown fat mass and cold tolerance, and adipocyte-selective inactivation of Bmall recapitulates these effects and demonstrates its cell-autonomous role in brown adipocyte formation. Further loss-and gain-of-function studies in mesenchymal precursors and committed brown progenitors reveal that Bmall inhibits brown adipocyte lineage commitment and terminal differentiation. Mechanistically, Bmall inhibits brown adipogenesis through direct transcriptional control of key components of the TGF-b pathway together with reciprocally altered BMP signaling; activation of TGF-b or blockade of BMP pathways suppresses enhanced differentiation in Bmall-deficient brown adipocytes. Collectively, our study demonstrates a novel temporal regulatory mechanism in fine-tuning brown adipocyte lineage progression to affect brown fat formation and thermogenic regulation, which could be targeted therapeutically to combat obesity. [ABSTRACT FROM AUTHOR]

In recent years, brown adipose tissue (BAT), which has a high heat-producing capacity, has been confirmed to exist even in adults, and it has become a focal point for the prevention and the improvement of obesity and lifestyle-related diseases. However, the influences of obesity and physical activity (PA) on the fluid factors secreted from BAT (brown adipokines) are not well understood. In this study, therefore, we focused on brown adipokines and investigated the effects of obesity and PA. The abnormal expressions of gene fluid factors such as galectin-3 (Lgals3) and Lgals3 binding protein (Lgals3bp), whose proteins are secreted from HB2 brown adipocytes, were observed in the interscapular BAT of obese mice fed a high-fat diet for 4 months. PA attenuated the abnormalities in the expressions of these genes. Furthermore, although the gene expressions of factors related to brown adipocyte differentiation such as peroxisome proliferator-activated receptor gamma coactivator 1-α were also down-regulated in the BAT of the obese mice, PA suppressed the down-regulation of these factors. On the other hand, lipogenesis was increased more in HB2 cells overexpressing Lgals3 compared with that in control cells, and the overexpression of Lgals3bp decreased the mitochondrial mass. These results indicate that PA attenuates the obesity-induced dysregulated expression of brown adipokines and suggests that Lgals3 and Lgals3bp are involved in brown adipocyte differentiation. [ABSTRACT FROM AUTHOR]

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kirschner and Scholz.)

Brown adipocytes play important roles in the regulation of energy homeostasis by uncoupling protein 1-mediated non-shivering thermogenesis. Recent studies suggest that brown adipocytes as novel therapeutic targets for combating obesity and associated diseases, such as type II diabetes. However, the molecular mechanisms underlying brown adipocyte differentiation and function are not fully understood. We employed previous findings obtained through proteomic studies performed to assess proteins displaying altered levels during brown adipocyte differentiation. Here, we performed assays to determine the functional significance of their altered levels during brown adipogenesis and development. We identified isocitrate dehydrogenase 1 (IDH1) as upregulated during brown adipocyte differentiation, with subsequent investigations revealing that ectopic expression of IDH1 inhibited brown adipogenesis, whereas suppression of IDH1 levels promoted differentiation of brown adipocytes. Additionally, Idh1 overexpression resulted in increased levels of intracellular α-ketoglutarate (α-KG) and inhibited the expression of genes involved in brown adipogenesis. Exogenous treatment with α-KG reduced brown adipogenesis during the early phase of differentiation, and ChIP analysis revealed that IDH1-mediated α-KG reduced trimethylation of histone H3 lysine 4 in the promoters of genes associated with brown adipogenesis. Furthermore, administration of α-KG decreased adipogenic gene expression by modulating histone methylation in brown adipose tissues of mice. These results suggested that the IDH1–α-KG axis plays an important role in regulating brown adipocyte differentiation and might represent a therapeutic target for treating metabolic diseases. Unlabelled Image • IDH1 inhibits brown adipogenesis in a α-KG-dependent manner. • Administration of α-KG suppresses brown fat gene expression both in vitro and in vivo. • α-KG reduces H3K4me3 levels in the promoters of brown fat genes, which was accompanied by their transcriptional repression. • IDH1–α-KG axis negatively regulates brown fat differentiation and function via histone demethylation. [ABSTRACT FROM AUTHOR]

Aging-associated chronic inflammation is a key contributing factor to a cluster of chronic metabolic disorders, such as cardiovascular disease, obesity, and type 2 diabetes. Immune cells particularly T cells accumulate in adipose tissue with advancing age, and there exists a cross talk between T cell and preadipocyte, contributing to age-related adipose tissue remodeling. Here, we compared the difference in morphology and function of adipose tissue between young (3-month-old) and old (18-month-old) mice and showed the phenomenon of brown adipose tissue (BAT) "whitening" in old mice. Flow cytometry analysis suggested an increased proportion of T cells in BAT of old mice comparing with the young and exhibited senescent characteristics. We take advantage of coculture system to demonstrate directly that senescent T cells inhibited brown adipocyte differentiation of preadipocytes in adipose tissue. Mechanistically, both in vitro and in vivo studies suggested that senescent T cells produced and released a higher level of IFN-γ, which plays a critical role in inhibition of preadipocyte-to-brown adipocyte differentiation. Taken together, the data indicate that senescent T cell-derived IFN-γ is a key regulator in brown adipocyte differentiation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pan, Yao, Yang, Ge, Zhang, Gao, Ruan and Wu.)

Scope: Brown adipose tissue (BAT) is the main regulator of thermogenesis by increasing energy expenditure through the uncoupling of oxidative metabolism from ATP synthesis. There is a growing body of evidence for BAT being the key responsible organ in combating obesity and its related disorders. Herein we propose the fungal protein ostreolysin (Oly), which has been previously shown to bind to cholesterol-enriched raft-like membrane domains (lipid rafts) of mammalian cells, as a suitable candidate for interaction with brown preadipocytes. The aim of the present study was therefore to characterize the mechanism by which a recombinant version of ostreolysin (rOly) induces brown adipocyte differentiation., Methods and Results: Primary isolated brown preadipocytes or HIB-1B brown preadipocyte cells were treated with rOly and the effects on morphology, lipid accumulation, respiration rate, and associated gene and protein expression were measured. rOly upregulated mRNA and protein levels of factors related to brown adipocyte differentiation, induced lipid droplet formation, and increased cellular respiration rate due to expression of uncoupling protein 1. rOly also upregulated β-tubulin expression, and therefore microtubules might be involved in its mechanism of action., Conclusion: rOly promotes brown adipocyte differentiation, suggesting a new mechanism for rOly's contribution to the battle against obesity., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.