Brown Tissue Research Articles

Hepatic SerpinA1 improves energy and glucose metabolism through regulation of preadipocyte proliferation and UCP1 expression.

Lipodystrophy and obesity are associated with insulin resistance and metabolic syndrome accompanied by fat tissue dysregulation. Here, we show that serine protease inhibitor A1 (SerpinA1) expression in the liver is increased during recovery from lipodystrophy caused by the adipocyte-specific loss of insulin signaling in mice. SerpinA1 induces the proliferation of white and brown preadipocytes and increases the expression of uncoupling protein 1 (UCP1) to promote mitochondrial activation in mature white and brown adipocytes. Liver-specific SerpinA1 transgenic mice exhibit increased browning of adipose tissues, leading to increased energy expenditure, reduced adiposity and improved glucose tolerance. Conversely, SerpinA1 knockout mice exhibit decreased adipocyte mitochondrial function, impaired thermogenesis, obesity, and systemic insulin resistance. SerpinA1 forms a complex with the Eph receptor B2 and regulates its downstream signaling in adipocytes. These results demonstrate that SerpinA1 is an important hepatokine that improves obesity, energy expenditure and glucose metabolism by promoting preadipocyte proliferation and activating mitochondrial UCP1 expression in adipocytes.

Gene Therapy Approach for Treatment of Obese Agouti Mice

Obesity is a significant metabolic disorder associated with excessive fat accumulation and insulin resistance. In this study, we explored a gene therapy approach to treat obesity in agouti mice using adeno-associated viruses (AAVs) carrying PRDM16, FoxP4, or Follistatin (FST) genes, which are known to promote the browning of white adipose tissue. Mice treated with AAVs encoding PRDM16, FoxP4, or FST genes showed a reduction in body weight (10–14%) within the first three weeks after administration, compared to the control groups. A lipidomic analysis of the adipose tissue revealed a dramatic reduction in triacylglycerol (TAG) species with low carbon numbers (40–54 acyl carbons) in treated mice.

Phenotypic and functional disparities in perivascular adipose tissue

The adipose tissue surrounding blood vessels is known as perivascular adipose tissue (PVAT), which represents a distinct ectopic fat depot that adheres to the majority of the vasculature. In recent years, owing to its unique location and function, PVAT has been regarded as a new type of adipose tissue distinct from traditional visceral fat. It releases adipokines with vasoconstrictive functions, which regulate vascular function through paracrine and endocrine mechanisms. Interestingly, PVAT can be categorized as white, brown or a mixture of both depending on its anatomical location. Brown adipose tissue (BAT) is located adjacent to the thoracic aorta in rodents, while a mix of brown and white tissue surrounds the abdominal aorta. PVAT exhibits regional phenotypic differences in different parts of the vasculature bed, which may lead to heterogeneity in the secretion profiles and norepinephrine (NE) content in regional PVAT and subsequently affect the regulation of specific adipokine signaling pathways in regional PVAT, resulting in differences in the regulation of vascular function. The aim of this review was to explore the potential factors that influence the anticontractile function of regional PVAT in the vasculature, including the heterogeneity of regional PVAT, the anticontractile function mediated by endothelial nitric oxide synthase (eNOS) in regional PVAT, the activity of the adiponectin-eNOS pathway in regional PVAT adipocytes, and the concentration of the sympathetic neurotransmitter NE in regional PVAT.

Intermittent Fasting Improves Insulin Resistance by Modulating the Gut Microbiota and Bile Acid Metabolism in Diet-Induced Obesity.

Adipose tissue macrophages (ATMs) are crucial in the pathogenesis of insulin resistance (IR). Intermittent fasting (IF) is an effective intervention for obesity. However, the underlying mechanism by which IF improves IR remains unclear. Male C57BL/6J mice are fed chow-diet and high-fat diet (HFD) for 12 weeks, then is randomized into ad libitum feeding or every other day fasting for 8 weeks. Markers of ATMs and expression of uncoupling protein 1 (UCP-1) are determined. Gut microbiota and bile acids (BAs) are profiled using 16S rRNA sequencing and targeted metabolomics analysis. Results indicate that IF improves IR in HFD-induced obesity. IF decreases ATM infiltration, pro-inflammatory M1 gene expression, and promotes white adipose tissue (WAT) browning by elevating UCP-1 expression. IF restructures microbiota composition, significantly expanding the abundance of Verrucomicrobia particularly Akkermansia muciniphila, with the decrease of that of Firmicutes. IF increases the level of total BAs and alters the composition of BAs with higher proportion of 12α-hydroxylated (12α-OH) BAs. The changes in these BAs are correlated with differential bacteria. The findings indicate that IF improves IR partially mediated by the interplay between restructured gut microbiota and BAs metabolism, which has implications for the dietary management in obesity.

Lactate utilization in Lace1 knockout mice promotes browning of inguinal white adipose tissue.

Recent studies have focused on identifying novel genes involved in the browning process of inguinal white adipose tissue (iWAT). In this context, we propose that the mitochondrial ATPase gene lactation elevated 1 (Lace1) utilizes lactate to regulate the browning capacity of iWAT, specifically in response to challenge with CL-316,243 (CL), a beta3-adrenergic receptor (β3-AR) agonist. The mice were injected with CL over a span of 3 days and exposed to cold temperatures (4-6 °C) for 1 week. The results revealed a significant increase in Lace1 expression levels during beige adipogenesis. Additionally, a strong positive correlation was observed between Lace1 and Ucp1 mRNA expression in iWAT under browning stimulation. To further explore this phenomenon, we subjected engineered Lace1 KO mice to CL and cold challenges to validate their browning potential. Surprisingly, Lace1 KO mice presented increased oxygen consumption and heat generation upon CL challenge and cold exposure, along with increased expression of genes related to brown adipogenesis. Notably, deletion of Lace1 led to increased lactate uptake and browning in iWAT under CL challenge compared with those of the controls. These unique phenomena stem from increased lactate release due to the inactivation of pyruvate dehydrogenase (PDH) in the hearts of Lace1 KO mice.

Preoperative methionine restriction induces perivascular adipose tissue browning and improves vein graft remodeling in male mice

Short-term preoperative methionine restriction (MetR) is a promising translatable strategy to mitigate surgical injury response. However, its application to improve post-interventional vascular remodeling remains underexplored. Here we find that MetR protects from arterial intimal hyperplasia in a focal stenosis model and pathologic vascular remodeling following vein graft surgery in male mice. RNA sequencing reveals that MetR enhances browning in arterial (thoracic aorta) perivascular adipose tissue (PVAT) and induces it in venous (caval vein) PVAT. Specifically, Ppara is highly upregulated in PVAT-adipocytes upon MetR. Furthermore, MetR dampens the postoperative pro-inflammatory response to surgery in PVAT-macrophages in vivo and in vitro. This study shows that the detrimental effects of dysfunctional PVAT on vascular remodeling can be reversed by MetR, and identifies pathways involved in MetR-induced browning of PVAT. Furthermore, we demonstrate the potential of short-term preoperative MetR as a simple intervention to ameliorate vascular remodeling after vascular surgery.

MitoMAMMAL: a genome scale model of mammalian mitochondria predicts cardiac and BAT metabolism

Abstract Motivation Mitochondria perform several essential functions in order to maintain cellular homeostasis and mitochondrial metabolism is inherently flexible to allow correct function in a wide range of tissues. Dysregulated mitochondrial metabolism can therefore affect different tissues in different ways which presents experimental challenges in understanding the pathology of mitochondrial diseases. System-level metabolic modelling is therefore useful in gaining in-depth insights into tissue-specific mitochondrial metabolism, yet despite the mouse being a common model organism used in research, there is currently no mouse specific mitochondrial metabolic model available. Results In this work, building upon the similarity between human and mouse mitochondrial metabolism, we have created mitoMammal, a genome-scale metabolic model that contains human and mouse specific gene-product reaction rules. MitoMammal is therefore able to model mouse and human mitochondrial metabolism. To demonstrate this feature, using an adapted E-Flux algorithm, we first integrated proteomic data extracted from mitochondria of isolated mouse cardiomyocytes and mouse brown adipocyte tissue. We then integrated transcriptomic data from in vitro differentiated human brown adipose cells and modelled the context specific metabolism using flux balance analysis. In all three simulations, mitoMammal made mostly accurate, and some novel predictions relating to energy metabolism in the context of cardiomyocytes and brown adipocytes. This demonstrates its usefulness in research relating to cardiac disease and diabetes in both mouse and human contexts. Availability and implementation MitoMammal is formatted in SBML3. The code required for constraint-based modelling used in this work is implemented in Python 3 and is available as a Jupyter Notebook. The mitoMammal metabolic model, along with Jupyter notebooks and data used in this work are available at: https://gitlab.com/habermann_lab/mitomammal. Supplementary Information Supplementary data are available at Bioinformatics Advances online.

Subcutaneously transplanted xenogeneic protein recruits treg cells and M2 macrophages to induce browning of inguinal white adipose tissue.

To study whether subcutaneously embedding xenogeneic protein threads or synthetic polymer absorbable threads can improve obesity phenotypes and metabolic conditions, and to further explore its underlying mechanism. Thirty-six 8-week-old ob/ob mice were randomly allocated to three groups, respectively, receiving catgut embedding, PGA thread embedding or sham treatment bilaterally to the groin. Individual parameters including weight, food intake, and core temperature are recorded and metabolism assessment, energy expenditure analysis, and PET/CT scanning are also performed at fixed timepoints. After surgical incision, the inguinal white adipose tissue was histologically examined and its expression profile was tested and compared among groups 4 weeks and 12 weeks after operation. Catgut embedding reduced weight gain and improved metabolic status in ob/ob mice. Browning of bilateral inguinal WAT (white adipose tissue) was induced after catgut embedding, with massive infiltration of Treg cells and M2 macrophages in the tissue slices of fat pads. IL-10 and TGF-β released by Treg cells targeted macrophages and the induced M2 macrophages increased the expression of thermogenic and anti-inflammatory genes in fat. The secretion of catecholamines by polarized M2 macrophages led to the activation of β3-AR-related pathways in adipocytes and the browning of adipose tissue. Abdominal subcutaneous catgut embedding has the potential to combat obesity through the induction of WAT browning mediated by infiltrated Treg cells and macrophages.

Evidence of Browning and Inflammation Features in Visceral Adipose Tissue of Women with Endometriosis

Patients with endometriosis tend to have a low body mass index, suggesting an inverse relationship between body fat and risk of disease. This is supported by evidence that miRNAs differentially expressed in endometriosis induce browning of pre-adipocytes in vitro. Thus, we hypothesize that endometriosis may underlie adipose tissue (AT) dysfunction and browning. Identify inflammation and browning processes in AT collected from endometriosis patients. Visceral and subcutaneous AT samples were obtained during endometriosis (n = 32) or uterine myoma (n = 14; controls) surgery. Blood catecholamines were determined by high-performance liquid chromatography while IL-6 and TGF-β levels were quantified by ELISA. Adipocyte cross-sectional areas were analyzed in H&E-stained sections by computer-assisted morphometry. Macrophages (F4/80; Galectin-3) and browning activation (UCP-1; PGC-1α) in tissues were identified by dual label immunofluorescence. Expression of inflammatory (IL-6; MCP-1; Galectin-3; CD206; TIMP1; TGF-β) and browning-related (UCP-1; PGC-1α; DIO2; CITED1; CIDEA; TMEM26; TBX1; PRDM16; PPAR-γ) molecules in AT were assessed by RT-PCR and Western blotting. Compared to controls, patients presented smaller adipocytes, especially in VAT, and lower norepinephrine levels. Serum IL-6, but not TGF-β, was increased in patients. UCP-1, PGC-1α, IL-6, and MCP-1 were upregulated in VAT from endometriosis women, which also evidenced a reduction of CD206, relative to controls. However, no differences were found in mRNA expression of IL-6, TIMP1, and TGF-β nor Galectin-3 protein levels. In SAT, protein expression remained unchanged between patients and controls. Our findings support an endometriosis' role as a pro-catabolic state along with local signals of VAT browning and inflammation.

The development of hepatic steatosis depends on the presence of liver-innervating parasympathetic cholinergic neurons in mice fed a high-fat diet.

Hepatic lipid metabolism is regulated by the autonomic nervous system of the liver, with the sympathetic innervation being extensively studied, while the parasympathetic efferent innervation is less understood despite its potential importance. In this study, we investigate the consequences of disrupted brain-liver communication on hepatic lipid metabolism in mice exposed to obesogenic conditions. We found that a subset of hepatocytes and cholangiocytes are innervated by parasympathetic nerve terminals originating from the dorsal motor nucleus of the vagus. The elimination of the brain-liver axis by deleting parasympathetic cholinergic neurons innervating the liver prevents hepatic steatosis and promotes browning of inguinal white adipose tissue (ingWAT). The loss of liver-innervating cholinergic neurons increases hepatic Cyp7b1 expression and fasting serum bile acid levels. Furthermore, knockdown of the G protein-coupled bile acid receptor 1 gene in ingWAT reverses the beneficial effects of the loss of liver-innervating cholinergic neurons, leading to the reappearance of hepatic steatosis. Deleting liver-innervating cholinergic neurons has a small but significant effect on body weight, which is accompanied by an increase in energy expenditure. Taken together, these data suggest that targeting the parasympathetic cholinergic innervation of the liver is a potential therapeutic approach for enhancing hepatic lipid metabolism in obesity and diabetes.

Molecular characterization of Fusarium isolates from Upland cotton roots in Uzbekistan and whole-genome comparison with isolates from the USA.

Fusarium oxysporum f. sp. vasinfectum (FOV) is a significant cotton (Gossypium spp.) pathogen causing vascular wilt, browning of the vascular tissues, and plant death in the most severe cases. This global disease is responsible for sizeable crop losses annually and is found in many cotton producing regions, including the Republic of Uzbekistan and the USA. Specifically, FOV race 4 (FOV4) has been disrupting production for years. This study aimed to genetically characterize FOV4 isolates causing disease in the main cotton producing region of Uzbekistan and compare with FOV4 isolates from the USA. A field study conducted in the Bukhara region of the Republic of Uzbekistan in the spring of 2022 identified both FOV4 and new Fusarium isolates from Upland cotton exhibiting typical Fusarium wilt symptoms. Molecular markers were initially used to identify isolates of interest, and a phylogenetic analysis was performed using partial EF1-α sequences, followed by a comparative genomic analysis. We also report for the first time the isolation of F. solani and F. commune causing Fusarium wilt in Uzbekistan. Furthermore, we show that the FOV4 population within our sampling region of Uzbekistan may be dominated by a single biotype with an effector profile similar to that of FOV race 7 (FOV7). One of these effector proteins is also present in the F. commune isolate showing virulence to cotton. Whole genome comparisons between FOV races can identify unique genetic markers for FOV4 and aid in the development of tools for breeding FOV resistant cotton varieties.

Hederagenin from Hedera helix Promotes Fat Browning in 3T3-L1 Adipocytes.

The prevalence of obesity is increasing globally, with approximately 700 million obese people worldwide. Currently, regulating energy homeostasis by increasing energy expenditure is attracting attention as a strategy for treating obesity. White adipose tissue is known to play a role in accumulating energy by storing excess energy, while brown adipose tissue expends energy and maintains body temperature. Thus, the browning of white adipose tissue has been shown to be effective in controlling obesity. Hedera helix (H. helix) has been widely used as a traditional medicine for various diseases. In several previous studies, hederagenin (HDG) from H. helix has demonstrated many biological activities. In this study, we investigated the antiobesity effect of HDG on fat browning in 3T3-L1 adipocytes. Consequent to HDG treatment, a reduction in lipid accumulation was measured through oil red O staining. In addition, this study investigated that HDG increases energy expenditure by upregulating the expression of several targets related to thermogenesis, including uncoupling protein 1 (UCP1). This process involves inhibiting lipogenesis via the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and promoting lipolysis through the protein kinase A (PKA) pathway. HDG is expected to be effective in promoting fat browning, indicating its potential as a natural antiobesity candidate.

Early Chilling Injury Symptom Development and Recovery of Mature Green Banana: Involvement of Ethylene under Different Severities of Chilling Stress

The involvement of stress ethylene in early chilling injury (CI) symptom development of mature-green (MG) banana fruit was examined using the ethylene action inhibitor, 1-methyclopropene (1-MCP). MG banana fruit pretreated with 0 or 50 μg L−1 1-MCP were stored at two chilling temperatures, 5 °C or 10 °C, for 0, 1, 12, or 72 h (different CI stresses), then transferred to 20 °C (rewarming) for 2 d. Irreversible CI symptoms that developed during 72 h storage at 5 or 10 °C included vascular browning and epidermal color parameters (L*, chroma, and hue angle). Some CI symptoms drastically intensified during exposure to 5 or 10 °C for 72 h, even being exacerbated after rewarming. Fruit in the other treatments suffered milder CI, and the recovery response progressed from slight and reversible to severe and irreversible with longer durations of exposure to lower temperatures. The effect of 1-MCP pretreatment was to attenuate the effect of chilling in terms of the CI symptom development (i.e., the browning of sub-epidermal tissues and the increasing of electrolyte efflux) and to promote recovery after rewarming, especially for the fruit stored at 5 °C, indicating the potential involvement of ethylene in membrane structural alterations under CI stress.

Simvastatin-Loaded Polymeric Nanoparticles: Targeting Inflammatory Macrophages for Local Adipose Tissue Browning in Obesity Treatment.

Obesity is defined as chronic, low-grade inflammation within specific tissues. Given the escalating prevalence of obesity among individuals of all ages, obesity has reached epidemic proportions, posing an important public health challenge. Despite significant advancements in treating obesity, conventional approaches remain largely ineffective or involve severe side effects, thus underscoring the pressing need to explore and develop treatment approaches. Targeted and local immunomodulation using nanoparticles (NPs) can influence fat production and utilization processes. Statins, known for their anti-inflammatory properties, show the potential for mitigating obesity-related inflammation. A localized delivery option offers several advantages over oral and parenteral delivery methods. Here, we developed simvastatin (Sim) encapsulated within PLGA NPs (Sim-NP) for localized delivery of Sim to adipose tissues (ATs) for immunomodulation to treat obesity. In vitro experiments revealed the strong anti-inflammatory effects of Sim-NPs, which resulted in enhanced modulation of macrophage (MΦ) polarization and induction of AT browning. We then extended our investigation to an in vivo mouse model of high-fat-diet (HFD)-induced obesity. Sim-NP administration led to the controlled release of Sim within AT, directly impacting MΦ activity and inducing AT browning while inducing weight loss. Our findings demonstrated that Sim-NP administration effectively inhibited the progression of obesity-related inflammation, controlled white fat production, and enhanced AT modulation. These results highlight the potential of Sim-NP as a potent nanotherapy for treating obesity by modulating the immune system.

The SIRT5-Mediated Upregulation of C/EBPβ Promotes White Adipose Tissue Browning by Enhancing UCP1 Signaling.

Sirtuin 5 (SIRT5) plays an important role in the maintenance of lipid metabolism and in white adipose tissue browning. In this study, we established a mouse model for diet-induced obesity and the browning of white fat; combined with gene expression intervention, transcriptome sequencing, and cell molecular biology methods, the regulation and molecular mechanisms of SIRT5 on fat deposition and beige fat formation were studied. The results showed that the loss of SIRT5 in obese mice exacerbated white adipose tissue deposition and metabolic inflexibility. Furthermore, the deletion of SIRT5 in a white-fat-browning mouse increased the succinylation of uncoupling protein 1 (UCP1), resulting in a loss of the beiging capacity of the subcutaneous white adipose tissue and impaired cold tolerance. Mechanistically, the inhibition of SIRT5 results in impaired CCAAT/enhancer binding protein beta (C/EBPβ) expression in brown adipocytes, which in turn reduces the UCP1 transcriptional pathway. Thus, the transcription of UCP1 mediated by the SIRT5-C/EBPβ axis is critical in regulating energy balance and obesity-related metabolism.

Mesenchymal Stem Cell-Derived Exosomes Attenuate Hepatic Steatosis and Insulin Resistance in Diet-Induced Obese Mice by Activating the FGF21-Adiponectin Axis.

Exosomes derived from mesenchymal stem cells have shown promise in treating metabolic disorders, yet their specific mechanisms remain largely unclear. This study investigates the protective effects of exosomes from human umbilical cord Wharton's jelly mesenchymal stem cells (hWJMSCs) against adiposity and insulin resistance in high-fat diet (HFD)-induced obese mice. HFD-fed mice treated with hWJMSC-derived exosomes demonstrated improved gut barrier integrity, which restored immune balance in the liver and adipose tissues by reducing macrophage infiltration and pro-inflammatory cytokine expression. Furthermore, these exosomes normalized lipid metabolism including lipid oxidation and lipogenesis, which alleviate lipotoxicity-induced endoplasmic reticulum (ER) stress, thereby decreasing fat accumulation and chronic tissue inflammation in hepatic and adipose tissues. Notably, hWJMSC-derived exosomes also promoted browning and thermogenic capacity of adipose tissues, which was linked to reduced fibroblast growth factor 21 (FGF21) resistance and increased adiponectin production. This process activated the AMPK-SIRT1-PGC-1α pathway, highlighting the role of the FGF21-adiponectin axis. Our findings elucidate the molecular mechanisms through which hWJMSC-derived exosomes counteract HFD-induced metabolic dysfunctions, supporting their potential as therapeutic agents for metabolic disorders.

Irisin in Reproduction: Its Roles and Therapeutic Potential in Male and Female Fertility Disorders.

The current study focused on identifying the potential of irisin in mammalian reproduction. The established role of irisin, a proteolytic product of FNDC5, in adipose tissue browning, energy metabolism, and thermogenesis suggests its role in reproductive health, often disturbed by metabolic imbalances. Various studies on mice demonstrated irisin's role in improving spermatogenesis, sperm count, and testosterone levels by influencing the hypothalamus-pituitary-gonadal axis. Moreover, in females, there is a fluctuation in levels of irisin during critical reproductive stages, including menstrual cycles, puberty, and pregnancy. Conditions like pregnancy complications, precocious puberty, and polycystic ovary syndrome (PCOS) are found to have an association with abnormal irisin levels. The potential role of irisin in endometrial receptivity and preventing endometritis is also discussed in this review. Overall, the influence of irisin on female and male reproduction is evident from various studies. However, further research is needed to elucidate irisin mechanism in reproduction and its potential as a therapeutic or diagnostic tool for reproductive dysfunctions and infertility.

The development of hepatic steatosis depends on the presence of liver-innervating parasympathetic cholinergic neurons in mice fed a high-fat diet.

Hepatic lipid metabolism is regulated by the autonomic nervous system of the liver, with the sympathetic innervation being extensively studied, while the parasympathetic efferent innervation is less understood despite its potential importance. In this study, we investigate the consequences of disrupted brain-liver communication on hepatic lipid metabolism in mice exposed to obesogenic conditions. We found that a subset of hepatocytes and cholangiocytes are innervated by parasympathetic nerve terminals originating from the dorsal motor nucleus of the vagus. The elimination of the brain-liver axis by deleting parasympathetic cholinergic neurons innervating the liver prevents hepatic steatosis and promotes browning of inguinal white adipose tissue (ingWAT). The loss of liver-innervating cholinergic neurons increases hepatic Cyp7b1 expression and fasting serum bile acid levels. Furthermore, knockdown of the G protein-coupled bile acid receptor 1 gene in ingWAT reverses the beneficial effects of the loss of liver-innervating cholinergic neurons, leading to the reappearance of hepatic steatosis. Deleting liver-innervating cholinergic neurons has a small but significant effect on body weight, which is accompanied by an increase in energy expenditure. Taken together, these data suggest that targeting the parasympathetic cholinergic innervation of the liver is a potential therapeutic approach for enhancing hepatic lipid metabolism in obesity and diabetes.

Differential mitochondrial adaptation and FNDC5 production in brown and white adipose tissue in response to cold and obesity.

Fibronectin type III domain-containing protein 5 (FNDC5) modulates adipocyte metabolism by increasing white and brown adipose tissue (WAT and BAT) browning and activity, respectively. We investigated whether FNDC5 can regulate visceral WAT and BAT adaptive thermogenesis by improving mitochondrial homeostasis in response to cold and obesity. Adipose tissue expression of FNDC5 and factors involved in mitochondrial homeostasis were determined in patients with normal weight and obesity (n = 159) and in rats with diet-induced obesity after 1 week of cold exposure (n = 61). The effect of different FNDC5 concentrations on mitochondrial biogenesis, dynamics, and mitophagy was evaluated in vitro in human adipocytes. In human visceral adipocytes, FNDC5/irisin triggered mitochondrial biogenesis (TFAM) and fusion (MFN1, MFN2, and OPA1) while inhibiting peripheral fission (DNM1L and FIS1) and mitophagy (PINK1 and PRKN). Circulating and visceral WAT expression of FNDC5 wasdecreased in patients and experimental animals with obesity, whereas its receptor, integrin αV, was upregulated. Obesity increased mitochondrial fusion while decreasing mitophagy in visceral WAT from patients and rats. By contrast, in rat BAT, an upregulation of Fndc5 and genes involved in mitochondrial biogenesis and fission was observed. Cold exposure promoted mitochondrial biogenesis and healthy peripheral fission while repressing Fndc5 expression and mitophagy in BAT from rats. Depot differences in FNDC5 production and mitochondrial adaptations in response to obesity and cold might indicate a self-regulatory mechanism to control thermogenesis in response to energy needs.

GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia

Cachexia, which affects 50–80% of cancer patients, is a debilitating syndrome that leads to 20% of cancer-related deaths. A key feature of cachexia is adipose tissue atrophy, but how it contributes to the development of cachexia is poorly understood. Here, we demonstrate in mouse models of cancer cachexia that white adipose tissue browning, which can be a characteristic early-onset manifestation, occurs prior to the loss of body weight and skeletal muscle wasting. By analysing the proteins differentially expressed in extracellular vesicles derived from cachexia-inducing tumours, we identified a molecular chaperone, Glucose-regulated protein 75 (GRP75), as a critical mediator of adipocyte browning. Mechanistically, GRP75 binds adenine nucleotide translocase 2 (ANT2) to form a GRP75–ANT2 complex. Strikingly, stabilized ANT2 enhances its interaction with uncoupling protein 1, leading to elevated expression of the latter, which, in turn, promotes adipocyte browning. Treatment with withanone, a GRP75 inhibitor, can reverse this browning and alleviate cachectic phenotypes in vivo. Overall, our findings reveal a novel mechanism by which tumour-derived GRP75 regulates white adipose tissue browning during cachexia development and suggest a potential white adipose tissue-centred targeting approach for early cachexia intervention.