Sensing the oxygen and temperature in the adipose tissues - who's sensing what?

Adipose tissues, composed of various cell types, including adipocytes, endothelial cells, neurons, and immune cells, are organs that are exposed to dynamic environmental challenges. During diet-induced obesity, white adipose tissues experience hypoxia due to adipocyte hypertrophy and dysfunctional vasculature. Under these conditions, cells in white adipose tissues activate hypoxia-inducible factor (HIF), a transcription factor that activates signaling pathways involved in metabolism, angiogenesis, and survival/apoptosis to adapt to such an environment. Exposure to cold or activation of the ß-adrenergic receptor (through catecholamines or chemicals) leads to heat generation, mainly in brown adipose tissues through activating uncoupling protein 1 (UCP1), a proton uncoupler in the inner membrane of the mitochondria. White adipose tissues can undergo a similar process under this condition, a phenomenon known as 'browning' of white adipose tissues or 'beige adipocytes'. While UCP1 expression has largely been confined to adipocytes, HIF can be expressed in many types of cells. To dissect the role of HIF in specific types of cells during diet-induced obesity, researchers have generated tissue-specific knockout (KO) mice targeting HIF pathways, and many studies have commonly revealed that intact HIF-1 signaling in adipocytes and adipose tissue macrophages exacerbates tissue inflammation and insulin resistance. In this review, we highlight some of the key findings obtained from these transgenic mice, including Ucp1 KO mice and other models targeting the HIF pathway in adipocytes, macrophages, or endothelial cells, to decipher their roles in diet-induced obesity.

Mulberry leaf flavonoids activate BAT and induce browning of WAT to improve type 2 diabetes via regulating the AMPK/SIRT1/PGC-1α signaling pathway.

Mulberry (Morus alba L.) leaf is a well-established traditional Chinese botanical and culinary resource. It has found widespread application in the management of diabetes. The bioactive constituents of mulberry leaf, specifically mulberry leaf flavonoids (MLFs), exhibit pronounced potential in the amelioration of type 2 diabetes (T2D). This potential is attributed to their ability to safeguard pancreatic ß cells, enhance insulin resistance, and inhibit α-glucosidase activity. Our antecedent research findings underscore the substantial therapeutic efficacy of MLFs in treating T2D. However, the precise mechanistic underpinnings of MLF's anti-T2D effects remain the subject of inquiry. Activation of brown/beige adipocytes is a novel and promising strategy for T2D treatment. In the present study, our primary objective was to elucidate the impact of MLFs on adipose tissue browning in db/db mice and 3T3-L1 cells and elucidate its underlying mechanism. The results manifested that MLFs reduced body weight and food intake, alleviated hepatic steatosis, improved insulin sensitivity, and increased lipolysis and thermogenesis in db/db mice. Moreover, MLFs activated brown adipose tissue (BAT) and induced the browning of inguinal white adipose tissue (IWAT) and 3T3-L1 adipocytes by increasing the expressions of brown adipocyte marker genes and proteins such as uncoupling protein 1 (UCP1) and beige adipocyte marker genes such as transmembrane protein 26 (Tmem26), thereby promoting mitochondrial biogenesis. Mechanistically, MLFs facilitated the activation of BAT and the induction of WAT browning to ameliorate T2D primarily through the activation of AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) signaling pathway. These findings highlight the unique capacity of MLF to counteract T2D by enhancing BAT activation and inducing browning of IWAT, thereby ameliorating glucose and lipid metabolism disorders. As such, MLFs emerge as a prospective and innovative browning agent for the treatment of T2D.

Skeletal muscle-secreted DLPC orchestrates systemic energy homeostasis by enhancing adipose browning.

MyoD is a skeletal muscle-specifically expressed transcription factor and plays a critical role in regulating myogenesis during muscle development and regeneration. However, whether myofibers-expressed MyoD exerts its metabolic function in regulating whole body energy homeostasis in vivo remains largely unknown. Here, we report that genetic deletion of Myod in male mice enhances the oxidative metabolism of muscle and, intriguingly, renders the male mice resistant to high fat diet-induced obesity. By performing lipidomic analysis in muscle-conditioned medium and serum, we identify 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) as a muscle-released lipid that is responsible for MyoD-orchestrated body energy homeostasis in male Myod KO mice. Functionally, the administration of DLPC significantly ameliorates HFD-induced obesity in male mice. Mechanistically, DLPC is found to induce white adipose browning via lipid peroxidation-mediated p38 signaling in male mice. Collectively, our findings not only uncover a novel function of MyoD in controlling systemic energy homeostasis through the muscle-derived lipokine DLPC but also suggest that the DLPC might have clinical potential for treating obesity in humans.

A PPARγ/long noncoding RNA axis regulates adipose thermoneutral remodeling in mice.

Interplay between energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of specialized niche, adipocytes require the activity of the nuclear receptor PPARγ for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ; however, the molecular mechanisms by which PPARγ licenses white adipose tissue to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ/long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity. Pharmacologic inhibition or genetic deletion of the lncRNA Lexis enhances uncoupling protein 1-dependent (UCP1-dependent) and -independent thermogenesis. Adipose-specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT that preserves white adipose tissue plasticity.

CXCL13 promotes thermogenesis in mice via recruitment of M2 macrophage and inhibition of inflammation in brown adipose tissue.

Introduction: Brown adipose tissue (BAT) is mainly responsible for mammalian non-shivering thermogenesis and promotes energy expenditure. Meanwhile, similar to white adipose tissue (WAT), BAT also secretes a variety of adipokines to regulate metabolism through paracrine, autocrine, or endocrine ways. The chemokine C-X-C motif chemokine ligand-13 (CXCL13), a canonical B cell chemokine, functions in inflammation and tumor-related diseases. However, the role of CXCL13 in the adipose tissues is unclear. Methods: The expression of CXCL13 in BAT and subcutaneous white adipose tissue (SWAT) of mice under cold stimulation were detected. Local injection of CXCL13 into BAT of normal-diet and high-fat-diet induced obese mice was used to detect thermogenesis and determine cold tolerance. The brown adipocytes were treated with CXCL13 alone or in the presence of macrophages to determine the effects of CXCL13 on thermogenic and inflammation related genes expression in vitro. Results: In this study, we discovered that the expression of CXCL13 in the stromal cells of brown adipose tissue significantly elevated under cold stimulation. Overexpression of CXCL13 in the BAT via local injection could increase energy expenditure and promote thermogenesis in obese mice. Mechanically, CXCL13 could promote thermogenesis via recruiting M2 macrophages in the BAT and, in the meantime, inhibiting pro-inflammatory factor TNFα level. Discussion: This study revealed the novel role of adipose chemokine CXCL13 in the regulation of BAT activity and thermogenesis.

The Enhancement of Acylcarnitine Metabolism by 5-Heptadecylresorcinol in Brown Adipose Tissue Contributes to Improving Glucose and Lipid Levels in Aging Male Mice.

5-Heptadecylresorcinol (AR-C17), a primary biomarker of whole grain (WG) consumption, has been demonstrated to improve the thermogenic activity of aging mice. However, the intricate regulatory mechanism is not fully understood. This study conducted metabolomics analysis on young and aging mice with or without AR-C17 administration after cold exposure. The results showed that the aging mice displayed lower levels of acylcarnitine (ACar) in their plasma compared with the young mice during cold exposure, and 150 mg/kg/day of AR-C17 administration for 8 weeks could increase the plasma ACar levels of aging mice. ACar has been reported to be an essential metabolic fuel for the thermogenesis of brown adipose tissue (BAT). AR-C17 had similar effects on the ACar levels in the BAT as on the plasma of the aging mice during cold exposure. Furthermore, the aging mice had reduced ACar metabolism in the BAT, and AR-C17 could improve the ACar metabolism in the BAT of aging mice, thereby promoting the metabolic utilization of ACar by BAT. Moreover, the glucose and lipid levels of aging mice could be improved by AR-C17. This study revealed a deeper metabolic mechanism involved in the AR-C17-mediated thermogenic regulation of BAT, providing a new theoretical basis for the nutrition and health benefits of WG.

Time-restricted feeding alleviates metabolic implications of circadian disruption by regulating gut hormone release and brown fat activation.

Individuals with rotating and night shift work are highly susceptible to developing metabolic disorders such as obesity and diabetes. This is primarily attributed to disruptions in the circadian rhythms caused by activities and irregular eating habits. Time-restricted feeding (tRF) limits the daily eating schedules and has been demonstrated to markedly improve several metabolic disorders. Although an intricate relationship exists between tRF and circadian rhythms, the underlying specific mechanism remains elusive. We used a sleep disruption device for activity interference and established a model of circadian rhythm disorder in mice with different genetic backgrounds. We found that circadian rhythm disruption led to abnormal hormone secretion in the gut and elevated insulin resistance. tRF improved metabolic abnormalities caused by circadian rhythm disruption, primarily by restoring the gut hormone secretion rhythm and activating brown fat thermogenesis. The crucial function of brown fat in tRF was confirmed using a mouse model with brown fat removal. We demonstrated that chenodeoxycholic acid (CDCA) effectively improved circadian rhythm disruption-induced metabolic disorders by restoring brown fat activation. Our findings demonstrate the potential benefits of CDCA in reversing metabolic disadvantages associated with irregular circadian rhythms.

Mirabegron displays anticancer effects by globally browning adipose tissues.

Metabolic reprogramming in malignant cells is a hallmark of cancer that relies on augmented glycolytic metabolism to support their growth, invasion, and metastasis. However, the impact of global adipose metabolism on tumor growth and the drug development by targeting adipose metabolism remain largely unexplored. Here we show that a therapeutic paradigm of drugs is effective for treating various cancer types by browning adipose tissues. Mirabegron, a clinically available drug for overactive bladders, displays potent anticancer effects in various animal cancer models, including untreatable cancers such as pancreatic ductal adenocarcinoma and hepatocellular carcinoma, via the browning of adipose tissues. Genetic deletion of the uncoupling protein 1, a key thermogenic protein in adipose tissues, ablates the anticancer effect. Similarly, the removal of brown adipose tissue, which is responsible for non-shivering thermogenesis, attenuates the anticancer activity of mirabegron. These findings demonstrate that mirabegron represents a paradigm of anticancer drugs with a distinct mechanism for the effective treatment of multiple cancers.

SLC35D3 promotes white adipose tissue browning to ameliorate obesity by NOTCH signaling.

White adipose tissue browning can promote lipid burning to increase energy expenditure and improve adiposity. Here, we show that Slc35d3 expression is significantly lower in adipose tissues of obese mice. While adipocyte-specific Slc35d3 knockin is protected against diet-induced obesity, adipocyte-specific Slc35d3 knockout inhibits white adipose tissue browning and causes decreased energy expenditure and impaired insulin sensitivity in mice. Mechanistically, we confirm that SLC35D3 interacts with the NOTCH1 extracellular domain, which leads to the accumulation of NOTCH1 in the endoplasmic reticulum and thus inhibits the NOTCH1 signaling pathway. In addition, knockdown of Notch1 in mouse inguinal white adipose tissue mediated by orthotopic injection of AAV8-adiponectin-shNotch1 shows considerable improvement in obesity and glucolipid metabolism, which is more pronounced in adipocyte-specific Slc35d3 knockout mice than in knockin mice. Overall, in this study, we reveal that SLC35D3 is involved in obesity via NOTCH1 signaling, and low adipose SLC35D3 expression in obesity might be a therapeutic target for obesity and associated metabolic disorders.

The secreted peptide BATSP1 promotes thermogenesis in adipocytes.

Although brown adipose tissue (BAT) has historically been viewed as a major site for energy dissipation through thermogenesis, its endocrine function has been increasingly recognized. However, the circulating factors in BAT that play a key role in controlling systemic energy homeostasis remain largely unexplored. Here, we performed a peptidomic analysis to profile the extracellular peptides released from human brown adipocytes upon exposure to thermogenic stimuli. Specifically, we identified a secreted peptide that modulates adipocyte thermogenesis in a cell-autonomous manner, and we named it BATSP1. BATSP1 promoted BAT thermogenesis and induced browning of white adipose tissue in vivo, leading to increased energy expenditure under cold stress. BATSP1 treatment in mice prevented high-fat diet-induced obesity and improved glucose tolerance and insulin resistance. Mechanistically, BATSP1 facilitated the nucleocytoplasmic shuttling of forkhead transcription factor 1 (FOXO1) and released its transcriptional inhibition of uncoupling protein 1 (UCP1). Overall, we provide a comprehensive analysis of the human brown adipocyte extracellular peptidome following acute forskolin (FSK) stimulation and identify BATSP1 as a novel regulator of thermogenesis that may offer a potential approach for obesity treatment.

Roles of Protein Post-Translational Modifications During Adipocyte Senescence.

Adipocytes are adipose tissues that supply energy to the body through lipids. The two main types of adipocytes comprise white adipocytes (WAT) that store energy, and brown adipocytes (BAT), which generate heat by burning stored fat (thermogenesis). Emerging evidence indicates that dysregulated adipocyte senescence may disrupt metabolic homeostasis, leading to various diseases and aging. Adipocytes undergo senescence via irreversible cell-cycle arrest in response to DNA damage, oxidative stress, telomere dysfunction, or adipocyte over-expansion upon chronic lipid accumulation. The amount of detectable BAT decreases with age. Activation of cell cycle regulators and dysregulation of adipogenesis-regulating factors may constitute a molecular mechanism that accelerates adipocyte senescence. To better understand the regulation of adipocyte senescence, the effects of post-translational modifications (PTMs), is essential for clarifying the activity and stability of these proteins. PTMs are covalent enzymatic protein modifications introduced following protein biosynthesis, such as phosphorylation, acetylation, ubiquitination, or glycosylation. Determining the contribution of PTMs to adipocyte senescence may identify new therapeutic targets for the regulation of adipocyte senescence. In this review, we discuss a conceptual case in which PTMs regulate adipocyte senescence and explain the mechanisms underlying protein regulation, which may lead to the development of effective strategies to combat metabolic diseases.

Dietary Ferulic Acid-Mediated Suppression of Fat Deposits Is Associated with Induction of Beige Adipocyte Formation and Thermogenesis in Inguinal White Adipose Tissue in Mice.

Ferulic acid (FA) is the most abundant phenolic acid in wheat grains. Recent studies have reported that FA intake significantly suppresses body weight gain and accumulation of fat deposits in mice. However, the mechanism by which FA intake affects body fat accumulation remains unclear. We hypothesized that dietary FA induces the formation of beige adipocytes and contributes to the suppression of body fat accumulation. In this study, we investigated whether dietary FA significantly induces beige adipocyte formation and thermogenesis in mice. We found that intake of dietary FA (control diet supplemented with 10 g of FA/kg diet) for 4 wk significantly decreased white adipose tissue (WAT) deposits and body weight gain and significantly induced beige adipocyte formation in inguinal WAT (iWAT) in mice. Furthermore, dietary FA specifically induced thermogenesis in iWAT, dependent upon the significant induction of uncoupling protein 1 expression. These findings suggest that the dietary FA-mediated reduction of WAT accumulation and body weight gain is associated with the induction of beige adipocyte formation and thermogenesis in iWAT, which increases energy expenditure. Our study presents a novel example of dietary FA intake-mediated bioactivity as a functional food-derived factor.

Transcriptional repression of beige fat innervation via a YAP/TAZ-S100B axis.

Sympathetic innervation is essential for the development of functional beige fat that maintains body temperature and metabolic homeostasis, yet the molecular mechanisms controlling this innervation remain largely unknown. Here, we show that adipocyte YAP/TAZ inhibit sympathetic innervation of beige fat by transcriptional repression of neurotropic factor S100B. Adipocyte-specific loss of Yap/Taz induces S100b expression to stimulate sympathetic innervation and biogenesis of functional beige fat both in subcutaneous white adipose tissue (WAT) and browning-resistant visceral WAT. Mechanistically, YAP/TAZ compete with C/EBPß for binding to the zinc finger-2 domain of PRDM16 to suppress S100b transcription, which is released by adrenergic-stimulated YAP/TAZ phosphorylation and inactivation. Importantly, Yap/Taz loss in adipocytes or AAV-S100B overexpression in visceral WAT restricts both age-associated and diet-induced obesity, and improves metabolic homeostasis by enhancing energy expenditure of mice. Together, our data reveal that YAP/TAZ act as a brake on the beige fat innervation by blocking PRDM16-C/EBPß-mediated S100b expression.

Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning

Hepatocellular carcinoma (HCC) markedly enhances liver secretion of fibroblast growth factor 21 (FGF-21), a hepatokine that increases brown and subcutaneous inguinal white adipose tissues (BAT and iWAT, respectively) uncoupling protein 1 (UCP-1) content, thermogenesis and energy expenditure. Herein, we tested the hypothesis that an enhanced BAT and iWAT UCP-1-mediated thermogenesis induced by high levels of FGF-21 is involved in HCC-associated catabolic state and fat mass reduction. For this, we evaluated body weight and composition, liver mass and morphology, serum and tissue levels of FGF-21, BAT and iWAT UCP-1 content, and thermogenic capacity in mice with Pten deletion in hepatocytes that display a well-defined progression from steatosis to steatohepatitis (NASH) and HCC upon aging. Hepatocyte Pten deficiency promoted a progressive increase in liver lipid deposition, mass, and inflammation, culminating with NASH at 24 weeks and hepatomegaly and HCC at 48 weeks of age. NASH and HCC were associated with elevated liver and serum FGF-21 content and iWAT UCP-1 expression (browning), but reduced serum insulin, leptin, and adiponectin levels and BAT UCP-1 content and expression of sympathetically regulated gene glycerol kinase (GyK), lipoprotein lipase (LPL), and fatty acid transporter protein 1 (FATP-1), which altogether resulted in an impaired whole-body thermogenic capacity in response to CL-316,243. In conclusion, FGF-21 pro-thermogenic actions in BAT are context-dependent, not occurring in NASH and HCC, and UCP-1-mediated thermogenesis is not a major energy-expending process involved in the catabolic state associated with HCC induced by Pten deletion in hepatocytes. (AU)

18F-FDG PET/CT technology for the assessment of brown adipose tissue: an updated review.

INTRODUCTION: This review provides an update of 18 F-fluorodeoxyglucose ([18F] FDG) for Brown adipose tissue (BAT) activity quantification, whose role is not completely understood. AREAS COVERED: We conducted an unstructured search of the literature for any studies employing the [18F] FDG PET in BAT assessment. We explored BAT quantification both in healthy individuals and in different pathologies, after cold exposure and as a metabolic biomarker. The assessment of possible BAT modulators by using [18F] FDG PET is shown. Further PET tracers and novel developments for BAT assessments are also described. EXPERT OPINION: Further PET tracers and imaging modalities are under investigation, but the [18F] FDG PET is currently the method of choice for the evaluation of BAT and further multicentric trials are needed for a better understanding of the BAT physiopathology, also after cold stimuli. The modulation of BAT activity, assessed by [18F] FDG PET imaging, seems a promising tool for the management of conditions such as obesity and type 2 diabetes. Moreover, an interesting possible correlation of BAT activation with prognostic [18F] FDG PET indices in cancer patients should be assessed with further multicentric trials.

Brown adipose tissue transplantation improves skin fibrosis in localized scleroderma.

Adipose tissue transplantation shows great therapeutic potential in reversing localized scleroderma-associated skin fibrosis. Brown adipose tissue (BAT) can specifically secrete various cytokines against fibrosis, but its therapeutic potential in improving skin fibrosis has not yet been demonstrated. In this study, we have demonstrated the superior therapeutic efficacy of BAT transplantation for sclerotic skin by transplanting two distinct types of adipose tissue. In comparison to the white adipose tissue (WAT) group, mice treated with BAT transplantation exhibited a significant reduction in dermal thickness. BAT transplantation effectively reverses skin sclerosis through mechanisms involving inflammation reduction, promotion of angiogenesis, inhibition of myofibroblast accumulation, and collagen deposition. This therapeutic effect can be attributed to its unique paracrine effects. Furthermore, transcriptome sequencing (RNA-Seq) revealed upregulation of pathways associated with lipogenesis and fatty acid metabolism in BAT while downregulating pathways are related to transforming growth factor ß(TGF-ß), epithelial-mesenchymal transition (EMT), and inflammatory response. These findings suggest that BAT transplantation holds great promise as a novel approach for localized scleroderma treatment.

White adipose tissue-derived small extracellular vesicles: A new potential therapeutic reagent for accelerating diabetic wound healing.

Small extracellular vesicles (sEVs) from adipose-derived stem cells (ADSCs) have gained great attention and have been widely used in cell-free therapies for treating diabetic non-healing wounds in recent years. However, further clinical application of ADSC-sEVs have been limited due to their unsolvable defects, including cumbersome extraction procedure, high cost, low yield, etc. Thus, we urgently need to find one therapeutic reagent that could not only accelerate diabetic wound healing as ADSC-sEVs but also overcome these shortcomings. As the extraction process of adipose tissue-derived sEVs (AT-sEVs) is quite simple and labor saving, we put our focus on the efficiencies of white adipose tissue-derived sEVs (WAT-sEVs) and brown adipose tissue-derived sEVs (BAT-sEVs) in diabetic wound repair. After successfully isolating WAT-sEVs and BAT-sEVs by ultracentrifugation, we thoroughly characterized them and compared their diabetic wound healing capabilities both in vitro and in vivo. According to our study, AT-sEVs possess similar competence in diabetic wound healing as compared with ADSC-sEVs. While the effect of BAT-sEVs is not as stable as WAT-sEVs and ADSC-sEVs, the repair efficiency is also slightly lower than the other two sEVs in some cases. In summary, we are the first to discover that WAT-sEVs show great potential in diabetic wound repair. With advantages that are specific to tissue-derived sEVs (Ti-sEVs) such as time- and cost-saving, high-yield, and simple isolation procedure, we believe WAT-sEVs could serve as a novel reliable cell-free therapy for clinical diabetic wound treatment.