Studies indicate that the induction and activation of brown and beige adipocytes, which can enhance energy expenditure, may be beneficial for managing obesity and its associated diseases. This study investigated whether a novel lignan (-)-secoisolariciresinol 4-O-methyl ether (S4M) obtained from arctigenin inhibited diet-induced obesity by the browning of white adipose tissue (WAT). S4M treatment inhibited adipogenesis and lipid accumulation in white-induced 3T3-L1 adipocytes and in zebrafish embryonic development. Moreover, S4M treatment promoted browning in white adipocytes by increasing TOM20, UCP1, and PGC1α protein levels and consequently upregulating the mitochondrial content. S4M treatment significantly promoted mitochondrial fission by increasing the expression of DRP1. Furthermore, it enhanced peroxisomal biogenesis and function by inducing PEX13, ACOX1, and catalase. Mdivi-1, a mitochondrial dynamics inhibitor, diminished the browning effect of white adipocytes by the S4M treatment. This study found that S4M treatment inhibited weight gain in high-fat diet-induced obese mice, decreased the weight of WAT, and increased the abundance and function of mitochondria and peroxisomes in inguinal WAT, suggesting that S4M treatment could increase energy expenditure. The results suggest that S4M has potential as a therapeutic agent for combating obesity and its associated metabolic disorders.

With age, our metabolic systems undergo significant alterations, which can lead to a cascade of adverse effects that are implicated in both metabolic disorders, such as diabetes, and in the body's ability to respond to acute stress and trauma. To elucidate the metabolic imbalances arising from aging, we introduce the concept of "metabolaging." This framework encompasses the broad spectrum of metabolic disruptions associated with the hallmarks of aging, including the functional decline of key metabolically active organs, like the adipose tissue. By examining how these organs interact with essential nutrient-sensing pathways, "metabolaging" provides a more comprehensive view of the systemic metabolic imbalances that occur with age. This concept extends to understanding how age-related metabolic disturbances can influence the response to acute stressors, like burn injuries, highlighting the interplay between metabolic dysfunction and the ability to handle severe physiological challenges. Finally, we propose potential interventions that hold promise in mitigating the effects of metabolaging and its downstream consequences.

Type 2 diabetes (T2D) is a persistent illness that has a high incidence rate. Still, there is no conclusive evidence on effectively improving blood sugar levels in patients through physical therapy. This study examined the regulatory effects of different intensities of low-intensity pulsed ultrasound (LIPUS) on T2D by stimulating brown adipose tissue (BAT). Eight-week-old C57BL/6J mice were divided into six groups (n = 10 per group): Control sham (C-Sham), Control-LIPUS (C-LIPUS), T2D-sham (T2D-Sham), T2D groups treated with LIPUS at spatial average-temporal-average intensity (Isata) of 60mW/cm² (T2D-L-60), 80mW/cm² (T2D-L-80), and 100mW/cm² (T2D-L-100). T2D models were induced by intraperitoneal injection of 40 mg/kg streptozotocin (STZ) three times after 12 wks of high-fat diet (HFD). The T2D-LIPUS group received LIPUS stimulation for 20 minutes per day for 6 weeks. The LIPUS stimulation had a duty cycle of 20%, a frequency of 1 MHz, and Isata of 60mW/cm², 80mW/cm², 100mW/cm². Subsequently, glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed, and body fat content in mice was analyzed using nuclear magnetic resonance (NMR). Metabolic changes were monitored using metabolic cages. The results indicated that 80mW/cm² intensity level significantly improved glucose tolerance, insulin sensitivity, and metabolic function after LIPUS exposure. Significant reductions in body fat content and enhanced thermogenesis were observed, highlighting the potential of LIPUS in T2D management. This provides the basis for the dose study of LIPUS in the treatment of T2D.

(+)-Terrein, a low-molecular-weight secondary metabolite from Aspergillus terreus, inhibits adipocyte differentiation in vitro. However, the precise mechanisms underlying the effects of (+)-terrein on adipocytes remain unclear. We hypothesized that (+)-terrein modulates adipogenesis and glucose homeostasis in obesity and diabetes via anti-inflammatory action and regulation of adipocyte differentiation. Hence, in this study, we aimed to investigate the in vivo anti-diabetic and anti-obesity effects of (+)-terrein.

Male C57BL/6 J mice were fed normal chow or high-fat (HF) diet and administered (+)-terrein (180 mg/kg) via intraperitoneal injection. Glucose and insulin tolerance tests, serum biochemical assays, and histological analyses were also performed. Rat brown preadipocytes, mouse brown preadipocytes (T37i cells), and inguinal white adipose tissue (ingWAT) preadipocytes were exposed to (+)-terrein during in vitro adipocyte differentiation. Molecular markers associated with thermogenesis and differentiation were quantified using real-time polymerase chain reaction and western blotting.

(+)-Terrein-treated mice exhibited improved insulin sensitivity and reduced serum lipid and glucose levels, irrespective of the diet. Furthermore, (+)-terrein suppressed body weight gain and mitigated fat accumulation by activating brown adipose tissue in HF-fed mice. (+)-Terrein facilitated the in vitro differentiation of rat brown preadipocytes, T37i cells, and ingWAT preadipocytes by upregulating peroxisome proliferator-activated receptor-γ (PPARγ). This effect was synergistic with that of a PPARγ agonist.

This study demonstrated that (+)-terrein effectively induces PPARγ expression and brown adipocyte differentiation, leading to reduced weight gain and improved glucose and lipid profiles in HF-fed mice. Thus, (+)-terrein is a potent novel agent with potential anti-obesity and anti-diabetic properties.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and synaptic dysfunction. The accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau protein leads to neuronal dysfunction, neuroinflammation, and glial cell activation. Emerging evidence suggests that peripheral insulin resistance and chronic inflammation, often associated with type 2 diabetes (T2D) and obesity, promote increased proinflammatory cytokines, oxidative stress, and immune cell infiltration. These conditions further damage the blood-brain barrier (BBB) integrity and promote neurotoxicity and chronic glial cell activation. This induces neuroinflammation and impaired neuronal insulin signaling, reducing glucose metabolism and exacerbating Aβ accumulation and tau hyperphosphorylation. Indeed, epidemiological studies have linked T2D and obesity with an increased risk of developing AD, reinforcing the connection between metabolic disorders and neurodegeneration. This review explores the relationships between peripheral insulin resistance, inflammation, and BBB dysfunction, highlighting their role in glial activation and the exacerbation of AD pathology.

Lipid metabolic disorder (LMD) serves as a systemic driver of osteoporosis (OP), with jawbone osteoporosis (JOP) representing a clinically significant yet underexplored complication. Current clinical treatments for JOP remain suboptimal, highlighting the need for innovative approaches. The use of metabolic regulators represents a promising therapeutic strategy for OP management. While brown adipose tissue-derived extracellular vesicles (BEV) exhibit metabolic regulatory potential, their capacity to mitigate LMD-associated OP remains unclear.

A high-fat diet (HFD)-induced LMD mouse model was established to identify the JOP phenotype through micro-computed tomography (micro-CT) and transcriptomic profiling. BEV isolation was optimized using liberase enzyme-enhanced differential centrifugation, with in vivo tracking confirming biodistribution. In vitro, BEV effects on hepatocytes were assessed with triglyceride (TG) content, free fatty acid (FFA) levels, and mitochondrial function. The additional benefits of BEV on the osteogenic microenvironment were evaluated via AML12/MC3T3-E1 indirect co-culture under high-lipid conditions. Dual therapeutic effects of BEV on LMD and JOP in vivo were validated through metabolic phenotyping, micro-CT and histomorphometry analysis.

Sixteen weeks of HFD successfully induced typical LMD and JOP manifestations in mice. Transcriptomic sequencing revealed downregulation of osteogenic-related genes concomitant with upregulation of lipid metabolism-associated genes in the jawbone of LMD mice. In vivo tracking showed the exogenous BEV predominantly accumulated in the liver rather than the jawbone. BEV treatment significantly reduced intracellular TG and FFA content in hepatocytes, while enhancing osteogenic activity of MC3T3-E1 cells through indirect co-culture. Mitochondrial analyses revealed that BEV effectively increased the proportion of active mitochondria, reduced reactive oxygen species (ROS) generation rate, and enhanced oxygen consumption rate (OCR) in hepatocytes. Biochemical assay and metabolic cage testing showed a lower systemic lipid content level along with improved fat utilization and thermogenesis capacity in BEV-treated mice. Micro-CT and immunofluorescence staining further confirm significant improvements in the jawbone of BEV-treated mice regarding bone volume fraction, trabecular number, trabecular thickness, trabecular separation, and RUNX2 expression.

This study establishes LMD as a crucial driver factor in JOP and identifies BEV-mediated mitochondrial transferring in hepatocytes as a therapeutic strategy for LMD-related JOP.

Beige adipocytes arise from white adipocytes in response to cold or other stimuli, known as browning of white adipose. Beige adipocytes play a role similar to that of brown adipocytes, express high levels of uncoupling protein 1 (UCP1), and are responsible for energy consumption via heat production, thus aiding in fat loss. Although histidine (His) and soy isoflavones (Iso) co-ingestion reportedly reduces food intake, body weight, and fat accumulation in female rats, the underlying mechanism remains unclear. Therefore, this study aimed to elucidate the mechanisms whereby histidine and soy isoflavones (His-Iso) co-ingestion suppresses fat accumulation. Female rats were fed a control diet or diet containing Iso, His, or His-Iso for 2 weeks, followed by sampling of periovarian white adipose tissue (poWAT) and retroperitoneal white adipose tissue (rWAT) and adipocyte morphology analysis. Additionally, the expression of browning- and lipid metabolism-related genes was examined. Histochemical analysis revealed the presence of multilocular lipid droplets, representative of beige adipocytes, in the poWAT and rWAT of rats in the His-Iso co-ingestion group. Quantitative PCR analysis showed that His-Iso co-ingestion upregulated brown adipocyte and beige adipocyte markers, including UCP1, indicating that His-Iso intake induces beige adipocytes. Moreover, His-Iso co-ingestion upregulated genes related to fatty acid oxidation (carnitine palmitoyl transferase 1A) and lipolysis (adipose triglyceride lipase) in WATs. In conclusion, His-Iso co-ingestion increases UCP1 expression and morphological changes to beige adipocytes, and suppresses fat accumulation by promotion of lipolysis and fatty acid oxidation in WAT.

The increasing prevalence of obesity and its related diseases, including diabetes mellitus and metabolic dysfunction-associated fatty liver disease, has become a significant social problem. These diseases are believed to be preventable through healthy diet and exercise habits, and the investigation of food ingredients that are useful for prevention of these diseases is actively ongoing. Carotenoids are the major lipophilic pigments responsible for yellow-to-red colors in our diet, and the ingestion of certain carotenoids has been reported to prevent obesity. For example, β-carotene suppresses adipogenic differentiation of mouse preadipocyte line 3T3-L1 through its provitamin A activity. Fucoxanthin, a carotenoid found in brown algae, also has the similar effect via a different mechanism and is used as an active ingredient in foods with functional claims in Japan. In contrast, siphonaxanthin, a carotenoid found in some green algae such as Caulerpa lentillifera (commonly known as sea grape), exhibited stronger biological activities than other carotenoids in cell-based studies; it significantly suppressed adipogenic differentiation of 3T3-L1 cells even at low concentrations where β-carotene and fucoxanthin did not show inhibitory effects. However, its practical applications have not yet been realized. This review summarizes the studies on the anti-obesity effects of carotenoids and discusses the potential of siphonaxanthin as a novel functional food ingredient.

Whether and how regulatory events at the translation stage shape the cellular and metabolic features of thermogenic adipocytes is hardly understood. In this study, we report two hitherto unidentified cross-talk pathways between metabolic and translational regulation in beige adipocytes. By analysing temporal profiles of translation activity and protein level changes during precursor-to-beige differentiation, we found selective translational down-regulation of OXPHOS component-coding mRNAs. The down-regulation restricted to Complexes I, III, IV, and V, is coordinated with enhanced translation of TCA cycle genes, engendering distinct stoichiometry of OXPHOS and TCA cycle components and altering the related metabolic activities in mitochondria of thermogenic adipocytes. Our high-resolution description of ribosome positioning unveiled potentiated ribosome pausing at glutamate codons. The increased stalling is attributable to remodelled glutamate metabolism that decreases glutamates for tRNA charging during pan-adipocyte differentiation. The ribosome pauses decrease protein synthesis and mRNA stability of glutamate codon-rich genes, such as actin cytoskeleton-associated genes.

Systemic administration of β-aminopropionitrile to inhibit lysyl oxidase (Lox) activity improves metabolism, but it exhibits a broad spectrum of effects. Clarification of the role of Lox in adipose tissue metabolism under high-fat diet (HFD) conditions is needed.

Mice with adipose tissue knockout of Lox (LoxAKO) and wild-type mice were subjected to a 16-week HFD regimen. A detailed evaluation encompassing adipose tissue, hepatic function, and systemic metabolism was conducted. RNA sequencing analysis was used to unravel the intricate mechanisms behind the metabolic enhancements in LoxAKO mice.

Compared with the control, although there was no difference in body weight, LoxAKO mice exhibited an improved metabolic phenotype, including enhanced insulin sensitivity, improved glucose tolerance, and reduced liver steatosis, along with reduced adipose tissue inflammation and fibrosis. LoxAKO mice showed increased thermogenic activity in brown adipose tissue with increased uncoupling protein 1 (UCP1) expression and oxygen consumption rate. Additionally, RNA sequencing analysis revealed that adipose deletion of Lox might facilitate the metabolic processing of glucose, branched-chain amino acids, and fatty acids in brown adipose tissue.

These findings indicate that adipocyte Lox deletion improves metabolic adaptability under an HFD, highlighting Lox as a promising therapeutic target for obesity-associated metabolic disorders.

Chronic stress in daily life is a well-known trigger for various health issues. Despite advancements in obesity research, the mechanisms governing lipid metabolism in adipose tissue during cachexia remain poorly understood.

A chronic restraint stress (CRS) model was used to induce significant physiological and psychological stress in mice. Mice were subjected to 6 h of restraint daily in 50 mL plastic tubes for seven consecutive days. A fasting control group was included for comparison. Post-stress assessments included behavioural tests, glucose and insulin tolerance tests and indirect calorimetry. Blood and adipose tissue samples were collected for mRNA and protein analyses.

CRS induced significant psychological and physiological changes in mice, including depression-like behaviours, weight loss and reduced insulin sensitivity. Notably, CRS caused extensive adipose tissue remodelling. White adipose tissue (WAT) underwent significant 'browning' accompanied by an increase in the expression of thermogenic proteins. This counteracted the stress-induced 'whitening' of brown adipose tissue (BAT), which exhibited impaired thermogenesis and functionality, thereby maintaining energy balance systematically. The glucocorticoid receptor (GR) plays a crucial role in lipid metabolism regulation during these changes. GR expression levels were inversely correlated in BAT and WAT, but aligned with the expression patterns of thermogenic proteins across adipose tissues. These findings suggest that under chronic metabolic stress, GR mediates tissue-specific responses in adipose tissues, driving functional and phenotypic transitions in BAT and WAT to maintain energy homeostasis.

This study provides novel insights into the contrasting thermogenic phenotypes of BAT and WAT under emaciation and highlights the critical role of GRs in adipose tissue remodelling during CRS and its potential as a therapeutic target. Addressing GR-mediated changes in adipose tissues may help alleviate BAT dysfunction in cachexia and promote WAT browning, enhancing metabolic stress resistance.

Obesity and hypertension are prevalent comorbidities in heart failure with preserved ejection fraction (HFpEF). Increased adiposity is implicated in its pathophysiology. We investigated changes in white adipose tissue (WAT) in obesity-associated HFpEF utilizing patient samples and a murine model of obesity-associated HFpEF. WAT analysis revealed "browning", characterized by smaller adipocytes and increased UCP1 expression, alongside fibrosis and reduced vascular markers during acute HF decompensation. During chronic, stable HFpEF, "browning" markers declined. There is a dynamic process in WAT, where acute HF exacerbations trigger transient "browning", fibrosis, and vascular deterioration, which partially reverse but fibrosis persists. WAT dysfunction worsens during acute HF, highlighting a potential therapeutic target for obesity-related HFpEF.

This review aimed to highlight the known role of histone deacetylases (HDACs) and lysine acetyltransferases (KATs) in individuals with obesity, better understand the role of HDACs and KATs enzymes in obesity and related metabolic disorders.

Numerous cellular activities, including DNA replication, DNA repair, cell cycle regulation, RNA splicing, signal transmission, metabolic function, protein stability, transportation, and transcriptional regulation, are influenced by lysine acetylation. Protein lysine acetylation serves several purposes, which not only contribute to the development of metabolic disorders linked to obesity but also hold promise for therapeutic approaches. The current study demonstrates that HDACs and KATs control lysine acetylation. This review details the advancements made in the study of obesity, related metabolic diseases, and protein lysine acetylation. It contributes to our understanding of the function and mechanism of protein lysine acetylation in obesity and MS and offers a fresh method for treating these diseases.

The ongoing increase in the prevalence of obesity and its comorbidities such as cardiovascular disease, type 2 diabetes (T2D) and dyslipidemia warrants discovery of novel therapeutic options for these metabolic diseases. Obesity is characterized by white adipose tissue expansion due to chronic positive energy balance as a result of excessive energy intake and/or reduced energy expenditure. Despite various efforts to prevent or reduce obesity including lifestyle and behavioral interventions, surgical weight reduction approaches and pharmacological methods, there has been limited success in significantly reducing obesity prevalence. Recent research has shown that thermogenic adipocyte (brown and beige) activation or formation, respectively, could potentially act as a therapeutic strategy to ameliorate obesity and its related disorders. This can be achieved through the ability of these thermogenic cells to enhance energy expenditure and regulate circulating levels of glucose and lipids. Thus, unraveling the molecular mechanisms behind the formation and activation of brown and beige adipocytes holds the potential for probable therapeutic paths to combat obesity. In this review, we provide a comprehensive update on the development and regulation of different adipose tissue types. We also emphasize recent interventions in harnessing therapeutic potential of thermogenic adipocytes by bioactive compounds and new pharmacological anti-obesity agents.

Sirtuins (SIRTs) are NAD+-dependent deacetylases that mediate post-translational modifications of proteins. Seven members of the SIRT family have been identified in mammals. Importantly, SIRTs interact with numerous metabolic and inflammatory pathways. Thus, researchers have investigated their role in metabolic and inflammatory disorders.

In this review, we comprehensively discuss the involvement of SIRTs in the processes of pancreatic β-cell dysfunction, glucose tolerance, insulin secretion, lipid metabolism, and adipocyte functions. In addition, we describe the current evidence regarding modulation of the expression and activity of SIRTs in diabetes, diabetic complications, and obesity.

The development of specific SIRT activators and inhibitors that exhibit high selectivity toward specific SIRT isoforms remains a major challenge. This involves the need to elucidate the physiological pathways involving SIRTs, as well as their important role in the development of metabolic disorders. Molecular modeling techniques will be helpful to develop new compounds that modulate the activity of SIRTs, which may contribute to the preparation of new drugs that selectively target specific SIRTs. SIRTs hold promise as potential targets in metabolic disease, but there is much to learn about specific modulators and the final answers will await clinical trials.

Retinol-binding protein 4 (RBP4), the sole specific carrier for retinol (vitamin A) in circulation, is highly expressed in liver and adipose tissues. Previous studies have demonstrated that RBP4 plays a role in cold-mediated adipose tissue browning and thermogenesis. However, the role of RBP4 in brown adipose tissue and its metabolic significance remain unclear. Here we generated and studied transgenic mice that express human RBP4 (hRBP4), specifically in brown adipocytes (UCP1-RBP4 mice), to better understand these uncertainties. When fed a chow diet, these mice presented significantly lower body weights and fat mass than their littermate controls. The UCP1-RBP4 mice also showed significant improvements in glucose clearance, enhanced energy expenditure and increased thermogenesis in response to a cold challenge. This was associated with increased lipolysis and fatty acid oxidation in brown adipose tissue, which was attributed to the activation of canonical adrenergic signaling pathways. In addition, high-performance liquid chromatography analysis revealed that plasma RBP4 and retinol levels were elevated in the UCP1-RBP4 mice, whereas their hepatic retinol levels decreased in parallel with a chow diet. Steady-state brown fat levels of total retinol were significantly elevated in the UCP1-RBP4 mice, suggesting that their retinol uptake was increased in RBP4-expressing brown adipocytes when fed a chow diet. These findings reveal a critical role for RBP4 in canonical adrenergic signaling that promotes lipid mobilization and oxidation in brown adipocytes, where the harnessed energy is dissipated as heat by adaptive thermogenesis.

Inflammatory bowel disease (IBD) represents a group of chronic inflammatory disorders of the gastrointestinal tract. Despite substantial advances in our understanding of IBD pathogenesis, the currently available therapeutic options remain limited in their efficacy and often come with significant side effects. Therefore, there is an urgent need to explore novel approaches for the management of IBD. One promising avenue of investigation revolves around the use of histone deacetylase (HDAC) inhibitors, which have garnered considerable attention for their potential in modulating gene expression and curbing inflammatory responses. This review emphasizes the pressing need for innovative drugs in the treatment of IBD, and drawing from a wealth of preclinical studies and clinical trials, we underscore the multifaceted roles and the therapeutic effects of HDAC inhibitors in IBD models and patients. This review aims to contribute significantly to the understanding of HDAC inhibitors' importance and prospects in the management of IBD, ultimately paving the way for improved therapeutic strategies in this challenging clinical landscape.

Thermogenic adipose tissue, both beige and brown, experiences whitening as animals are exposed to warmth and age, but the potential mechanisms are not fully understood. In this study, we employed single-nucleus RNA-seq to construct a cell atlas during whitening progression and identified the characteristics of thermogenic adipocytes.

Our histological studies and bulk transcriptome gene expression analysis confirmed that both perirenal and omental adipose tissues (pAT and oAT) exhibited progressive whitening in goats. Compared to the classic brown adipocytes in mice, goat thermogenic adipocytes were more closely related in gene expression patterns to human beige adipocytes, which was also confirmed by adipocyte type- and lineage-specific marker expression analysis. Furthermore, trajectory analysis revealed beige- and white-like adipocytes deriving from a common origin, coexisting and undergoing the transdifferentiation. In addition, differences in gene expression profiles and cell communication patterns (e.g., FGF and CALCR signaling) between oAT and pAT suggested a lower thermogenic capacity of oAT than that of pAT.

We constructed a cell atlas of goat pAT and oAT and descripted the characteristics of thermogenic adipocytes during whitening progression. Altogether, our results make a significant contribution to the molecular and cellular mechanisms behind the whitening of thermogenic adipocytes, and providing new insights into obesity prevention in humans and cold adaptation in animals.

Thermogenic fat, including brown and beige fat, dissipates heat via thermogenesis and enhances energy expenditure. Thus, its activation represents a therapeutic strategy to combat obesity. Here, we demonstrate that levels of F-box and WD repeat domain-containing 7 (FBXW7), an E3 ubiquitin protein ligase, negatively correlate with thermogenic fat functionality. FBXW7 overexpression in fat suppresses energy expenditure and thermogenesis, thus aggravates obesity and metabolic dysfunctions in mice. Conversely, FBXW7 depletion in fat leads to brown fat expansion and browning of white fat, and protects mice from diet induced obesity, hepatic steatosis, and hyperlipidemia. Mechanistically, FBXW7 binds to S6K1 and promotes its ubiquitination and proteasomal degradation, which in turn impacts glycolysis and brown preadipocyte proliferation via lactate. Besides, the beneficial metabolic effects of FBXW7 depletion in fat are attenuated by fat-specific knockdown of S6K1 in vivo. In summary, we provide evidence that adipose FBXW7 acts as a major regulator for thermogenic fat biology and energy homeostasis and serves as potential therapeutic target for obesity and metabolic diseases.

The escalating obesity epidemic poses serious public health challenges, requiring the development of effective therapeutic strategies. In this study, we aimed to determine if recombinant glycoprotein hormone β5 (GPHB5) protein, particularly in the hybrid form with glycoprotein hormone α2 (GPHA2) (recombinant corticotroph-derived glycoprotein hormone, rCGH), can alleviate obesity in the genetically obese mice, ob/ob. Six-week-old male ob/ob mice were intraperitoneally injected for four weeks with rCGH (10 mg/kg) treatment. Body weight, fat mass and lean mass as well as energy expenditure were evaluated. Blood samples were collected to assess circulating concentrations of triiodothyronine (T3) and thyroxine (T4). Glucose and insulin tolerance tests were also conducted. rCGH significantly decreased body weight and fat mass, stimulated energy expenditure without alterations in food consumption, induced lipolysis and browning of white adipose tissue (WAT) by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway. The treatment with the recombinant protein also led to marked reduction in hepatic steatosis, improved glucose tolerance and insulin sensitivity, and reduced triglycerides (TG), and total cholesterol (T-CHO) levels in ob/ob mice. In conclusion, rCGH attenuated obesity and alleviated metabolic syndromes in ob/ob mice, and it may represent a promising polypeptide-based drug candidate in treating obesity and obesity-related complications without interfering energy intake.

Beige adipocytes have physiological functions similar to brown adipocytes, which are available to increase energy expenditure through uncoupling protein 1 (UCP1) within mitochondria. Recently, many studies showed white adipocytes can undergo remodeling into beige adipocytes, called "browning", by increasing fusion and fission events referred to as mitochondrial dynamics.

In this study, we aimed to investigate the browning effects of 4-hydroxybenzoic acid (4-HA), one of the major compounds of black raspberries.

We examined the mechanism underlying the browning properties of 4-HA focusing on UCP1-dependent non-shivering thermogenesis in 3T3-L1 white adipocytes, high-fat diet (HFD)-induced obese male C57BL/6J mice, and cold-exposed male C57BL/6J mice.

4-HA treatment elevates browning markers such as UCP1, T-Box transcription factor 1, and PR domain containing 16, mitochondrial function factors like oxidative phosphorylation complex as well as mitochondrial dynamic-related factors like phosphorylated dynamin-related protein 1 (p-DRP1), DRP1, and mitofusin 1 in 3T3-L1 white adipocytes, which were also confirmed in inguinal white adipose tissue (iWAT) of HFD-induced obese mice. Mdivi-1 blocked the increased DRP1-mediated mitochondrial fission by 4-HA, and even the browning effect of 4-HA was abolished. Furthermore, 4-HA increased AMP-activated protein kinase (AMPK) in both the 3T3-L1 white adipocytes and iWAT of HFD-induced obese mice. Inhibition of AMPK with Compound C also blocked the 4-HA-induced mitochondrial fission and browning effect.

4-HA induces the browning of white adipocytes into beige adipocytes by regulating the DRP1-mediated mitochondrial dynamics through AMPK. These findings suggest that 4-HA could serve as a therapeutic candidate for obesity and related metabolic disorders.

Commensal bacteria affect host health by producing various metabolites from dietary carbohydrates via bacterial glycometabolism; however, the underlying mechanism of action remains unclear. Here, we identified Streptococcus salivarius as a unique anti-obesity commensal bacterium. We found that S. salivarius may prevent host obesity caused by excess sucrose intake via the exopolysaccharide (EPS) -short-chain fatty acid (SCFA) -carbohydrate metabolic axis in male mice. Healthy human donor-derived S. salivarius produced high EPS levels from sucrose but not from other sugars. S. salivarius abundance was significantly decreased in human donors with obesity compared with that in healthy donors, and the EPS-SCFA bacterial carbohydrate metabolic process was attenuated. Our findings reveal an important mechanism by which host-commensal interactions in glycometabolism affect energy regulation, suggesting an approach for preventing lifestyle-related diseases via prebiotics and probiotics by targeting bacteria and EPS metabolites.

Diabetes mellitus (DM), a global disease that significantly impacts public health, has become increasingly common over time. In this review, we aim to determine the potential benefits of St. John's Wort (SJW) as an adjunct therapy for DM. We gathered information from studies conducted in vitro, in vivo, and in humans. In vitro studies investigated the concentrations of SJW extracts capable of inhibiting certain enzymes or factors involved in the inflammatory pathway, such as the β-signal transducer and activator of transcription 1, nuclear factor κB, methylglyoxal, and oxidative stress (OS). The extract was found to have positive effects on OS and anti-inflammatory properties in DM, suggesting it could serve as a protective agent against diabetic vascular complications, cell damage, and apoptosis. According to in vivo research, the essential components of the extract can stimulate thermogenesis in adipose tissue, inhibit several key inflammatory signaling pathways, and delay the early death of pancreatic β cells, all of which contribute to combating obesity. The extract may also help treat prediabetes and significantly reduce neuropathic pain. Human studies have also confirmed some of these results. However, some of the plant's side effects need further investigation through clinical research before it can be used to treat DM.

AMP-activated protein kinase (AMPK) is a ubiquitous sensor of cellular energy and nutrient status in eukaryotic cells. It serves an essential function in the modulation of energy balance and metabolism homeostasis through its regulation of carbohydrate metabolism, lipid metabolism and protein metabolism. The dysregulation of AMPK is closely related to a series of systemic diseases, affecting multiple organs and tissues. Baicalin is a natural compound derived from the dry raw root of Scutellaria baicalensis, and it has been found to exhibit several potential pharmacological actions. These include hepatoprotective effects, anti-inflammation effects and anti-tumor effects. These biological activities are related to the regulatory effect of baicalin on the host metabolism, which is closely associated with AMPK modulation. In this review, we provide an overview of the regulatory effect of baicalin on AMPK and its upstream and downstream signaling pathways. The pharmacological properties and underlying mechanism of baicalin for regulating AMPK were summarized with regards to four aspects: regulatory effect of baicalin on AMPK in lipid metabolism and glucose metabolism, regulatory effect of baicalin on AMPK in its pharmacological effect of anti-tumor and anti-inflammation. As a natural compound, baicalin has the potential for the management of certain AMPK-related diseases.

Inhabiting some of the world's most inhospitable climatic regions, the Sunite Mongolian sheep generates average temperatures as low as 4.3 °C and a minimum temperature of -38.8 °C; in these environments, they make essential cold adaptations. In this regard, scapular fat tissues from Mongolian sheep were collected both in winter and summer for transcriptomic and proteomic analyses to identify genes related to adaptive thermogenesis. In the transcriptome analysis, 588 differentially expressed genes were identified to participate in smooth muscle activity and fat metabolism, as well as in nutrient regulation. There were 343 upregulated and 245 downregulated genes. GO and KEGG pathway analyses on these genes revealed their participation in regulating smooth muscle activity, metabolism of fats, and nutrients. Proteomic analysis showed the differential expression of 925 proteins: among them, there are 432 up- and 493 down-expressed proteins. These proteins are mainly involved in oxidative phosphorylation, respiratory chain complex assembly, and ATP production by electron transport. Furthermore, using both sets at a more detailed level of analysis revealed over-representation in gene ontology categories related to hormone signaling, metabolism of lipids, the pentose phosphate pathway, the TCA cycle, and especially the process of oxidative phosphorylation. The identified essential genes and proteins were further validated by quantitative real-time polymerase chain reaction and Western blotting, respectively; key metabolic network constriction was constructed. The present study emphasized the critical role of lipid turnover in scapular fat for thermogenic adaptation in Sunite sheep.

Subcutaneous adipose tissue (SAT) is the deepest component of the three-layered cutaneous integument. While mesenteric adipose tissue-based immune processes have gained recognition in the context of the metabolic syndrome, SAT has been traditionally considered primarily for energy storage, with less attention to its immune functions. SAT harbors a reservoir of immune and stromal cells that significantly impact metabolic and immunologic processes not only in the skin, but even on a systemic level. These processes include wound healing, cutaneous and systemic infections, immunometabolic, and autoimmune diseases, inflammatory skin diseases, as well as neoplastic conditions. A better understanding of SAT immune functions in different processes, could open avenues for novel therapeutic interventions. Targeting SAT may not only address SAT-specific diseases but also offer potential treatments for cutaneous or even systemic conditions. This review aims to provide a comprehensive overview on SAT's structure and functions, highlight recent advancements in understanding its role in both homeostatic and pathological conditions within and beyond the skin, and discuss the main questions for future research in the field.

In mammals, brown adipose tissue (BAT) and beige adipocytes in white adipose tissue (WAT) play pivotal roles in maintaining body temperature and energy metabolism. In mice, BAT quickly stimulates thermogenesis by activating brown adipocytes upon cold exposure. In the presence of chronic cold stimuli, beige adipocytes are recruited in inguinal WAT to support heat generation. Accumulated evidence has shown that thermogenic execution of brown and beige adipocytes is regulated in a fat depot-specific manner. Recently, we have demonstrated that ubiquitin ligase ring finger protein 20 (RNF20) regulates brown and beige adipocyte thermogenesis through fat-depot-specific modulation. In BAT, RNF20 regulates transcription factor GA-binding protein alpha (GABPα), whereas in inguinal WAT, RNF20 potentiates transcriptional activity of peroxisome proliferator-activated receptor-gamma (PPARγ) through the degradation of nuclear corepressor 1 (NCoR1). This study proposes the molecular mechanisms by which co-regulator(s) selectively and temporally control transcription factors to coordinate adipose thermogenesis in a fat-depot-specific manner. In this Commentary, we provide molecular features of brown and beige adipocyte thermogenesis and discuss the underlying mechanisms of distinct thermogenic processes in two fat depots.

To reveal the differences in the properties of visceral adipose tissue in healthy unstimulated mice, we performed transcriptome analysis using RNA sequencing. Among visceral adipose tissues, perinephric adipose tissue was found to exclusively express beige adipocyte markers while expressing white adipocyte markers. These results imply potential specific roles of perinephric adipose tissue in both physiological and pathological conditions.

Brown/beige adipose tissue has attracted much attention in previous studies because it can improve metabolism and combat obesity through non-shivering thermogenesis. However, recent studies have also indicated that especially in critical illness, overactivated brown adipose tissue or extensive browning of white adipose tissue may bring damage to individuals mainly by exacerbating hypermetabolism. In this review, the phenomenon of fat browning in critical illness will be discussed, along with the potential harm, possible regulatory mechanism and corresponding clinical treatment options of the induction of fat browning. The current research on fat browning in critical illness will offer more comprehensive understanding of its biological characteristics, and inspire researchers to develop new complementary treatments for the hypermetabolic state that occurs in critically ill patients.

Brown and beige adipocytes can be activated by β-adrenergic agonist via cAMP-dependent signaling. Performing RNA-sequencing analysis in human cervical area-derived adipocytes, we found that dibutyryl-cAMP, which can mimic in vivo stimulation of browning and thermogenesis, enhanced the expression of browning and batokine genes and upregulated several signaling pathway genes linked to thermogenesis. We observed that the expression of inhibitor of DNA binding and cell differentiation (ID) 1 and particularly ID3 was strongly induced by the adrenergic stimulation. The degradation of ID1 and ID3 elicited by the ID antagonist AGX51 during thermogenic activation prevented the induction of proton leak respiration that reflects thermogenesis and abrogated cAMP analogue-stimulated upregulation of thermogenic genes and mitochondrial complex I, II, and IV subunits, independently of the proximal cAMP-PKA signaling pathway. The presented data suggests that ID proteins contribute to efficient thermogenic response of adipocytes during adrenergic stimulation.

Platelet Derived Growth Factor Receptor Beta (Pdgfrβ) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if deleting Pdgfrβ in aged mice could rejuvenate metabolically active beige adipocytes by activating group 2 innate lymphoid cells (ILC2), and whether this effect could counteract diet-induced obesity-associated beige fat decline.

We employed Pdgfrβ gain-of-function and loss-of-function mouse models targeting beige adipocyte progenitor cells (APCs). Our approach included cold exposure, metabolic cage analysis, and age and diet-induced obesity models to examine beige fat development and metabolic function under varied Pdgfrβ activity.

Acute cold exposure alone enhanced metabolic benefits in aged mice, irrespective of beige fat generation. However, Pdgfrβ deletion in aged mice reestablished the formation of metabolically functional beige adipocytes, enhancing metabolism. Conversely, constitutive Pdgfrβ activation in young mice stymied beige fat development. Mechanistically, Pdgfrβ deletion upregulated IL-33, promoting ILC2 recruitment and activation, whereas Pdgfrβ activation reduced IL-33 levels and suppressed ILC2 activity. Notably, diet-induced obesity markedly increased Pdgfrβ expression and Stat1 signaling, which inhibited IL-33 induction and ILC2 activation. Genetic deletion of Pdgfrβ restored beige fat formation in obese mice, improving whole-body metabolism.

This study reveals that cold temperature exposure alone can trigger metabolic activation in aged mammals. However, reversing Pdgfrβ signaling in aged and obese mice not only restores beige fat formation but also renews metabolic function and enhances the immunological environment of white adipose tissue (WAT). These findings highlight Pdgfrβ as a crucial target for therapeutic strategies aimed at combating age- and obesity-related metabolic decline.

The overdevelopment of adipose tissues, accompanied by excess lipid accumulation and energy storage, leads to adipose deposition and obesity. With the increasing incidence of obesity in recent years, obesity is becoming a major risk factor for human health, causing various relevant diseases (including hypertension, diabetes, osteoarthritis and cancers). Therefore, it is of significance to antagonize obesity to reduce the risk of obesity-related diseases. Excess lipid accumulation in adipose tissues is mediated by adipocyte hypertrophy (expansion of pre-existing adipocytes) or hyperplasia (increase of newly-formed adipocytes). It is necessary to prevent excessive accumulation of adipose tissues by controlling adipose development. Adipogenesis is exquisitely regulated by many factors in vivo and in vitro, including hormones, cytokines, gender and dietary components. The present review has concluded a comprehensive understanding of adipose development including its origin, classification, distribution, function, differentiation and molecular mechanisms underlying adipogenesis, which may provide potential therapeutic strategies for harnessing obesity without impairing adipose tissue function.

Adipose tissue can recruit catabolic adipocytes that utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-adipocytes and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-adipocyte subpopulation is highly metabolically active and utilizes FCs to dissipate energy, thus contributing to thermogenesis independent of Ucp1. Furthermore, FC-adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals.

Extracellular vesicles (EVs) are nanovesicles containing bioactive molecules including proteins, nucleic acids and lipids that mediate intercellular and inter-organ communications, holding promise as potential therapeutics for multiple diseases. Adipose tissue (AT) serves as a dynamically distributed energy storage organ throughout the body, whose accumulation leads to obesity, a condition characterized by infiltration with abundant immune cells. Emerging evidence has illustrated that EVs secreted by AT are the novel class of adipokines that regulate the homeostasis between AT and peripheral organs. However, most of the studies focused on the investigations of EVs derived from adipocytes or adipose-derived stem cells (ADSCs), the summarization of functions in cellular and inter-organ crosstalk of EVs directly derived from adipose tissue (AT-EVs) are still limited. Here, we provide a systemic summary on the key components and functions of EVs derived from healthy adipose tissue, showing their significance on the tissue recovery and metabolic homeostasis regulation. Also, we discuss the harmful influences of EVs derived from obese adipose tissue on the distal organs. Furthermore, we elucidate the potential applications and constraints of EVs from healthy patients lipoaspirates as therapeutic agents, highlighting the potential of AT-EVs as a valuable biological material with broad prospects for future clinical use.