Next-generation live biotherapeutics are promising to aid the treatment of obesity and metabolic diseases. Here, we reported a novel anti-obesity probiotic candidate, Roseburia hominis, that was depleted in stool samples of obese subjects compared with lean controls, and its abundance was negatively correlated with body mass index and serum triglycerides. Supplementation of R. hominis prevented body weight gain and disorders of glucose and lipid metabolism, prevented fatty liver, inhibited white adipose tissue expansion and brown adipose tissue whitening in mice fed with high-fat diet, and boosted the abundance of lean-related species. The effects of R. hominis could be partially attributed to the production of nicotinamide riboside and upregulation of the Sirtuin1/mTOR signaling pathway. These results indicated that R. hominis is a promising candidate for the development of next-generation live biotherapeutics for the prevention of obesity and metabolic diseases.

Objective: This review examines the evolution of obesity evaluation methods, from traditional anthropometric indices to advanced imaging techniques, focusing on their clinical utility, limitations, and potential for personalized assessment of visceral adiposity and associated metabolic risks.

Methods: A comprehensive analysis of existing literature was conducted, encompassing anthropometric indices (BMI, WC, WHR, WHtR, NC), lipid-related metrics (LAP, VAI, CVAI, mBMI), and imaging technologies (3D scanning, BIA, ultrasound, DXA, CT, MRI). The study highlights the biological roles of white, brown, and beige adipocytes, emphasizing visceral adipose tissue (VAT) as a critical mediator of metabolic diseases.

Conclusion: Although BMI and other anthropometric measurements are still included in the guidelines, indicators that incorporate lipid metabolism information can more accurately reflect the relationship between metabolic diseases and visceral obesity. At the same time, the use of more modern medical equipment, such as ultrasound, X-rays, and CT scans, allows for a more intuitive assessment of the extent of visceral obesity.

Knee osteoarthritis (OA), a degenerative joint disease, causes pain and reduced activity levels, with prevalence increasing with age. Knee OA is recognized as a "joint organ disease," where interactions between the articular cartilage, meniscus, synovium, and infrapatellar fat pad (IFP) are critical. Obesity contributes to OA not only through mechanical stress but also via systemic and local inflammation mediated by adipose tissue. Adiponectin, an adipokine with anti-inflammatory and chondroprotective effects, shows levels negatively correlated with obesity and positively correlated with OA severity. This study explored the role of IFP in OA progression using a rat model of monoiodoacetic acid-induced IFP fibrosis. In vivo, IFP and cartilage degeneration were assessed via histological analysis, real-time PCR, and RNA sequencing. Ex vivo, the effects of conditioned media from synovial cells and IFP on chondrocytes were evaluated. Findings revealed that fibrosis reduced adiponectin expression and accelerated OA progression. Gene sequencing showed significant metabolic pathway changes, particularly in fatty acid β-oxidation, indicating impaired IFP function. Conditioned media from inflamed IFP negatively affected chondrocytes by reducing anabolic factors and increasing cartilage-degrading enzymes. These results suggest that IFP degeneration contributes to OA by promoting inflammation and cartilage degradation. Targeting IFP fibrosis and fatty acid metabolism may offer therapeutic potential to mitigate OA progression.

The incidence of overweight and obesity continues to grow at alarming rates around the world. The search for foods with potential benefits in the prevention/treatment of overweight/obesity and related disorders has great relevance. The aim of this study was to evaluate the effect of astaxanthin (ASTX) from freshwater crustaceans (crabs) upon visceral adiposity, adipose tissue lipid metabolism disorders and dyslipidemia present in a Metabolic Syndrome rodent model. Male Wistar rats were fed for 90 days with 1 of 4 experimental diets: a-Reference group (RD) received a standard commercial rodent diet, b- High-sucrose diet (HSD) group received a HSD, c- RD+ASTX group received a standard commercial rodent diet plus ASTX, d- HSD+ASTX group received a HSD plus ASTX. The rats were given orally either ASTX (10 mg/kg body weight/day in sunflower oil) or only sunflower oil. Compared with HSD-fed rats, HSD+ASTX group had lower body weight gain (19%) and both reduced abdominal circumference (5%) and visceral adiposity index (5%). Energy intake was 24% lower at the middle of the experimental period. Epididymal adipocytes size and triglyceride (TG) content was reduced by 14%. Besides, fatty acid synthase, malic enzyme and glucose-6-phosphate dehydrogenase activities in epididymal adipose tissue were 43%, 28% and 38% lower respectively. These changes were accompanied by lower TG (25%) and cholesterol (27%) serum levels, atherogenic index (31%) and reduced Systolic (12%) and Diastolic (15%) blood pressure. The results show that ASTX could be a potential strategy to prevent/attenuate the incidence of metabolic risk factors such as overweight/adiposity and dyslipidemia.

Obesity is characterized by an enlargement of white adipose tissue caused by caloric excess. The depot-specific adaptation of white adipose tissue in individuals resistant to obesity despite a high-calorie diet is crucial for understanding the pathogenesis of obesity and related metabolic disorders. Our aim was to characterize the metabolic and morphological state of obesity resistance and to investigate depot-specific changes in signaling pathways in epididymal visceral (eVAT) and inguinal subcutaneous (iSAT) white adipose tissue of C57BL/6J male mice on a high-fat diet (60 kcal% fats). After 14 weeks, the mice were categorized as obese (at least 30% higher body mass compared to the control group) or obesity-resistant (weight gain below 30%). Biochemical and morphological parameters, as well as histology, and signaling pathways involved in lipid metabolism, inflammation, and insulin sensitivity were investigated in eVAT and iSAT. The results showed unaltered body, total VAT and iSAT mass in obesity-resistant mice despite increased caloric intake. Leptin levels and glucose homeostasis were improved in these animals compared to the obese mice. In both eVAT and iSAT of the obesity-resistant mice, adipocyte size and lipolytic capacity were retained at control levels, while compared to the obese mice, preserved capacity for adipogenesis, improved local insulin sensitivity and the absence of inflammation were observed only in the eVAT. In conclusion, metabolic adaptation of eVAT rather than iSAT may have a substantial impact on the maintenance of the obesity-resistant phenotype with fewer metabolic complications, which could contribute to the improvement of existing obesity therapies.

The population with cardiovascular-kidney-metabolic (CKM) syndrome has a higher risk of cardiovascular events. Chinese visceral adiposity index (CVAI), an index of both visceral obesity and surrogate insulin resistance, has been linked to cardiovascular events. However, the nature of this relationship remains unclear in individuals with CKM syndrome.

All data came from the China Health and Retirement Longitudinal Study (CHARLS). The association between CVAI and cardiovascular events risk was explored using Cox regression models, restricted cubic spline (RCS) curves, and multiple sensitivity analyses. To compare the predictive abilities of various indices, receiver operating characteristic (ROC) analyses were employed.

7744 participants were in final analysis. During 9 year follow-up, 1679 cases of cardiovascular disease (CVD), 1,255 cases of heart disease, and 604 cases of stroke were recorded. Cox regression analyses revealed that per-SD (standard deviation) increase in CVAI, the risk of CVD, heart disease, and stroke increased by 22% (95% CI 1.13-1.32), 22% (95% CI 1.13-1.32), and 32% (95% CI 1.19-1.47). In participants at CKM stage 3 with CVD, a J-shaped curve was observed in the RCS analyses (P non-linearity = 0.036). Subgroup analysis revealed an interaction between age and each 10-unit increase in CVAI in CVD (P interaction = 0.0173) and stroke risk (P interaction = 0.028). The AUC (area under curve) value for CVAI was highest compared to other indicators (all DeLong Test P values < 0.05).

This research demonstrates a higher CVAI was linked to increased cardiovascular risk in individuals with CKM syndrome stage 0-3. Monitoring CVAI can help identify high-risk individuals early and improve the effectiveness of disease management.

KD025(belumosudil), a selective ROCK2 inhibitor, exhibits unique anti-adipogenic activity through inhibition of casein kinase 2 (CK2). This study investigated the dual inhibitory effects of KD025 on metabolism in a diet-induced obese model. C57BL/6 mice on a high fat diet (HFD) were treated with KD025 for 4 weeks, while fasudil (a pan-ROCK inhibitor) and CX-4945 (a CK2-specific inhibitor) served as comparison treatments. KD025 significantly reduced body weight gain without affecting food intake, serum insulin, or fasting blood glucose levels. In contrast, while both CX-4945 and fasudil treatments showed a trend toward weight reduction, these results were not statistically significant. KD025 improved lipid metabolism by significantly lowering LDL cholesterol and triglyceride, although it slightly impaired glucose metabolism, as observed in insulin and glucose tolerance tests. Weight reduction in the KD025- and CX-4945-treated groups was attributed to decreased adipose tissue mass, particularly in inguinal (ingWAT) and epididymal (epiWAT) fat depots. Hematoxylin and eosin (H&E) staining confirmed smaller adipocyte size in these groups. KD025 had no significant effect on serum levels of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), or monocyte chemoattractant protein-1 (MCP-1) with varied inflammatory responses. Furthermore, KD025 and CX-4945 upregulated adipogenic and browning markers, such as Cebpa, Cidea, and Pparg in the epiWAT, though without significant UCP1 expression. Overall, KD025 effectively reduced weight gain in HFD-fed mice through dual inhibition of CK2 and ROCK2, highlighting its potential as a therapeutic agent for obesity-related conditions.

Epithelial V-like antigen 1 (Eva1) is a highly specific marker for brown adipose tissue (BAT) in both mice and humans, but its metabolic function remains unclear. We investigated the impact of Eva1 deletion on the development of obesity.

To assess the metabolic role of Eva1, we generated whole-body and adipocyte-specific Eva1knockout (KO) mice, which were subjected to a high-fat diet (HFD) for 12 weeks and characterized metabolic phenotypes. To further elucidate the depot-dependent impact of Eva1 deficiency, we performed histological analysis and 3' mRNA-seq of BAT and epididymal visceral white adipose tissue (eWAT). To investigate the role of macrophage-derived Eva1 in obesity development, we transplanted wild-type (WT) or Eva1KO macrophages into Eva1KO mice fed an HFD.

We found that whole-body Eva1KO mice are resistant to HFD-induced obesity, insulin resistance and visceral adipose inflammation. However, Eva1 deletion in adipocytes, both brown and white, did not phenocopy these protective effects. Notably, whole-body Eva1 deficiency triggers functional changes in eWAT, but not in BAT. These results led us to investigate a possible involvement of macrophages in Eva1-mediated obesity regulation. We found that Eva1 is expressed in macrophages and plays a role in lipopolysaccharide (LPS)-induced inflammatory responses, possibly through the direct interaction with toll-like receptor 4 (TLR4). Moreover, Eva1KO mice exhibited improved survival rates in the face of severe sepsis induced by LPS. Importantly, transplantation of WT macrophages to Eva1KO mice abolished the beneficial effects of whole-body Eva1 deletion against obesity and visceral adipose inflammation.

Our findings highlight macrophage-derived Eva1 as an important mediator in obesity-induced eWAT remodeling, suggesting that targeting Eva1 could offer a novel therapeutic strategy for obesity-related metabolic disorders.

The treatment of chronic disease (CKD) is a great challenge in healthcare that requires an innovative approach to address its complex nature. RNA nanotechnology has emerged rapidly and received attention in the last few years because of its significant aptitude for therapies. Hence, the present study aimed to design, construct, and characterize a multifunctional (anti-miR-34a DNA aptamer-kidney targeted) RNA nanoparticle (RNPs) based on bacteriophage phi29 packaging RNA three-way junction (pRNA-3WJ), and then explore their in vivo toxicity and therapeutic potentials in mice model of CKD. After confirming the safety and specific targeting capability of the prepared core 3WJ (3WJ) and the therapeutic 3WJ (3WJ-Kapt/anti-miR-34a) RNPs to renal tissue using healthy mice, CKD was induced in C57BL/6 mice using adenine. CKD mice were treated with a single intravenous injection of 3WJ or 3WJ-Kapt/anti-miR-34a. Every week, 5 mice of each group were selected randomly for sample collection for 4 weeks post-treatment. The anti-miR-34a 3WJ-RNPs have shown stability, safety, and efficacy in renal targeting using DNA aptamer, by targeting miR-34a in renal tissue, 3WJ-Kapt/anti-miR-34a suppressed profibrotic gene expression and induced anti-fibrotic pathways' expression. Our present study provides preliminary and pioneering evidence for the promising treatment of renal fibrosis and CKD through targeting miR-34a in the renal tissue by 3WJ-RNPs. The CKD mice showed marked time-dependent up-regulation of the renal profibrotic pathways, including TGF-β, FGF2, and WNT/β-catenin pathways. The same mice showed suppressed renal expression of the antifibrotic pathways, including α and β Klotho, SMAD7, and SIRT1. The prepared anti-miR-34a 3WJ-RNPs have shown stability, safety, and efficacy in renal targeting using DNA aptamer. By targeting miR-34a in renal tissue, 3WJ-Kapt/anti-miR-34a suppressed profibrotic gene expression and induced anti-fibrotic pathways' expression. Our present study provides preliminary and pioneer evidence for the promising treatment of renal fibrosis and CKD through targeting miR-34a in the renal tissue by 3WJ-RNPs.

Obesity is characterized by a significant imbalance in adipose tissue macrophages (ATMs), shifting from anti-inflammatory M2 to pro-inflammatory M1 phenotypes, contributing to chronic low-grade inflammation and metabolic dysfunction. This study explores the potential of nanoparticle (NP)-mediated immunomodulation to address obesity-related inflammation, adipocyte browning, and metabolic dysfunction. Apigenin (Api), a natural compound with notable anti-inflammatory properties, was encapsulated within poly(lactic-co-glycolic acid) (PLGA) NPs (Api-NPs) for localized delivery to adipose tissues (ATs). Api-NPs demonstrated favorable physicochemical properties and sustained release profiles. In vitro, Api-NPs, increased M2 macrophage (MΦ) polarization, reduced inflammatory markers, and promoted adipocyte browning. In a high-fat diet (HFD)-induced obesity mouse model, Api-NP administration effectively modulated MΦ polarization and enhanced AT browning, leading to marked reductions in body weight and AT mass. Our findings indicate that Api-NP treatment mitigates obesity-related inflammation and promotes beneficial changes in AT composition and function. Importantly, histological evaluations confirmed the absence of toxicity in major organs, reinforcing the safety profile of this approach. These results position Api-NPs as a promising novel therapeutic strategy for obesity management, integrating immune modulation and localized drug delivery to address the complexities of obesity and its associated inflammatory processes.

The gut microbiome has been identified as a significant factor in host metabolism, playing a key role in the etiology of obesity, type 2 diabetes and cardiometabolic risk. Butyrate, produced by the gut microbiome from indigestible carbohydrates, has been shown to have beneficial effects on body weight control, inflammation, and insulin resistance, primarily evidenced by animal studies and in vitro experiments. However, translating these benefits to humans remains challenging due to variability in mode of butyrate administration or production upon fermentation of dietary fibers, as well as in butyrate absorption, and its metabolism. For instance, oral butyrate supplementation can directly increase circulating butyrate levels, thereby targeting peripheral tissues. In contrast, butyrate produced by the gut microbiome may also influence metabolism through local signaling mechanisms affecting peripheral tissues. Additionally, there may be large heterogeneity in the response of the individuals to butyrate interventions. Future research should aim to better understand butyrate kinetics and dynamics and its mechanisms in regulating intestinal and metabolic health. In human studies, longer-term, placebo-controlled trials are needed to establish the efficacy of either targeting butyrate production or supplementation in individuals with obesity and/or metabolic disturbances. Personalized dietary interventions based on individual microbiota composition and/or function and metabolic profiles may optimize butyrate production and its metabolic benefits. This could pave the way for effective butyrate-based interventions to improve metabolic health and prevent obesity-related complications.

Obesity is considered the most important risk factor for the development of osteoarthritis (ОА) - progressive inflammatory disease of the joints, that is one of the causes of disability and long-term immobilization. Excessively developed adipose tissue not only increases the mechanical load on the joints, but also participates in the maintenance of chronic low-grade inflammation through the production of adipokines, cytokines, hemokines, complement factors and hormones. Adipokines influence cells of synovial tissue, cartilage and bone, which in turn produce some adipokines locally, maintaining an inflammatory microenvironment intraarticularly. Adipokines, including leptin, adiponectin, chemerin, and resistin, regulate inflammatory immune responses in cartilage, also affecting synovial tissue cells and bone. In turn, chondrocytes, osteoblasts and osteoclasts produce some adipokines locally, maintaining an inflammatory microenvironment intra-articularly. Weight loss in OA can improve the patient's quality of life, physical function, lead to reduce pain, and slow or halt the progression of structural degenerative changes. The purpose of this article is to clearly describe the pathogenetic ways between obesity and inflammation, to reveal the mechanisms of the pathological state of adipokines and proinflammatory mediators (IL-6, TNF-á, etc.) on cartilage and bone homeostasis and, as expected, to evaluate their participation in the development of OA. So understanding immune regulation and resolution of inflammation in obesity is critical to developing treatments approaches to OA for these patients. The article also analyzes current researches on the effect of drug therapy (liraglutide, orlistat, sibutramine) and bariatric surgery of obesity on the course of inflammatory joint diseases.

The Cardiovascular-Kidney-Metabolic (CKM) syndrome is a systemic disorder involving obesity, diabetes, chronic kidney disease (CKD), and cardiovascular disease, characterized by complex pathophysiological mechanisms that interact and lead to increased morbidity and mortality. In recent years, sodium-glucose transport protein 2 inhibitors (SGLT2i), as a new class of antidiabetic medications, have shown remarkable efficacy in the management of diabetes, renal and cardiovascular diseases. Research has confirmed their ability to reduce cardiovascular events and all-cause mortality. These inhibitors lower blood glucose levels by decreasing renal reabsorption of glucose and sodium, and offer multiple benefits, including lowering blood pressure, reducing body weight, exerting antioxidant, anti-inflammatory, and anti-fibrotic effects, as well as reducing proteinuria and improving glomerular filtration rate. These effects collectively contribute to the improvement of cardiovascular and renal health. Furthermore, SGLT2i have shown potential therapeutic roles at various stages of CKM syndrome, including improving cardiac function, slowing CKD progression, promoting weight loss, and improving lipid profiles. However, the precise mechanisms of action and off-target effects of SGLT2i still require further investigation to evaluate their efficacy and safety under different clinical conditions. Future research directions should include strategies for multiple disease management, combination therapy effects, interdisciplinary collaboration, and long-term follow-up studies to fully understand and optimize the application of SGLT2i in the treatment of CKM syndrome.

Obesity increases the risk of diabetic neuropathy. This study investigates the impact of visceral (VAT) and subcutaneous adipose tissue (SAT) volume on peripheral neuropathy.

A total of 302 adults from the Qatar Biobank (QBB) underwent iDXA to measure VAT and SAT volumes, intima media thickness (IMT), and peripheral neuropathy assessments using corneal confocal microscopy (CCM), vibration perception threshold (VPT), and the DN4 questionnaire.

The QBB cohort was aged 43.9 ± 12.9 years, of whom 43.7% were women, 42.1% had obesity, 17.4% had type 2 diabetes (T2D) and 10.9% had hypertension. VAT was associated with T2D, hypertension, higher HbA1c, diastolic blood pressure, triglycerides, and inflammatory markers, and lower HDL (p < 0.0001). There were no significant associations between SAT and these cardiovascular risk factors. VAT volume was associated with lower corneal nerve inferior whorl length (IWL) (p < 0.05) and higher VPT (p = 0.01), partially mediated by elevated HbA1c (p < 0.05, p = 0.001) and IMT (p < 0.0001), while its association with neuropathic symptoms was fully mediated by systolic blood pressure (p < 0.05), T2D (p < 0.01), and triglycerides (p = 0.05). SAT showed no associations with measures of neuropathy.

VAT but not SAT is associated with peripheral neuropathy. This study underscores the need to target VAT to improve neuropathy.

Lactobacillus johnsonii is a microbial biomarker associated with lipid deposition, but the mechanism by which it accelerates fatty acid absorption and deposition remains unclear. In this study, we isolated a strain of L. johnsonii MS0621 from the feces of Ningxiang pigs, an obese animal model, and evaluated its probiotic properties with high resistance to temperature and intestinal fluids. Colonization by L. johnsonii MS0621 increased the abundance of gut Lactobacillus in lean DLY pigs, concomitant with increases in fatty acid absorption in the intestine and lipid depositions in the fat and muscle tissues. The lipid absorption-promoting effect was further detected in IPEC-J2 cells treated with live L. johnsonii MS0621 and the bacteria-free supernatants, as evidenced by high triglyceride synthesis and the expression of CD36, a key lipid transporter. Metabolomics analysis showed that (R)-leucic acid is a potential metabolite targeting CD36 expression to guarantee lipid absorption and deposition. The mechanism might involve direct interaction with CD36, as molecular docking and inhibition of CD36 blocked L. johnsonii MS0621 or derived metabolite-mediated lipid absorption. In conclusion, we uncovered an important role of L. johnsonii MS0621 derived (R)-leucic acid in regulating the absorption and deposition of intestinal fatty acids via regulation of CD36 expression.

Obesity and type 2 diabetes mellitus (T2DM) are metabolic diseases at epidemic proportions. The economic burden for these diseases is at an all-time high, and as such, there is an urgent need for advancements in identifying targets for treating these complex disorders. The extracellular matrix (ECM), comprising collagen, fibronectin, laminin, elastin, and proteoglycan, surrounds skeletal muscles and plays a critical role in maintaining tissue homeostasis by providing structural support and facilitating cell-to-cell communication. Disruption of the ECM signaling results in changes to its micro/macroenvironment, thereby modifying tissue homeostasis. Skeletal muscle ECM remodeling has been shown to be associated with insulin resistance, an underlying feature of obesity and T2DM. This narrative review explores the critical components of skeletal muscle ECM and its accumulation and remodeling in metabolic diseases. In addition, we discuss potential treatments to mitigate the effects of ECM remodeling in skeletal muscle. We conclude that targeting ECM remodeling in skeletal muscle represents a promising yet underexplored therapeutic avenue in the management of metabolic disorders.

Lipolysis in white adipose tissue (WAT) provides fatty acids as energy substrates for thermogenesis to increase energy expenditure. Syndecan-4 (Sdc4) is a transmembrane proteoglycan bearing heparan sulfate chains. Although single nucleotide polymorphisms (SNPs) of the Sdc4 gene have been identified linking to metabolic syndromes, its specific function in adipose tissue remains obscure. Here, we show that Sdc4 serves as a regulator of lipid metabolism and adaptive thermogenesis. Sdc4 expression and shedding are elevated in the white adipose tissue (WAT) of diet-induced obese mice. Adipocyte-specific deletion of Sdc4 promotes lipolysis and WAT browning, thereby raising whole-body energy expenditure to protect against diet-induced obesity. Mechanistically, fibroblast growth factor 2 (FGF2) is a paracrine factor that maintains energy homeostasis. Elevated shed Sdc4 concentrates and delivers FGF2 to fibroblast growth factor receptor 1 (FGFR1) on adipocytes, which in turn suppresses lipolysis by reducing hormone-sensitive lipase (HSL) activity, thus exaggerating adipose tissue dysfunction upon high-fat diet induction. Sdc4-deficient adipocytes show higher lipolytic and thermogenic capacity by enhancing HSL phosphorylation and UCP1 expression. Overall, our study reveals that adipocyte-derived shed Sdc4 is a novel suppressor of lipolysis, contributing to decreased energy expenditure, thus exaggerating obesity. Targeting shed Sdc4 is a potential therapeutic strategy for obesity.

In this study, the potential anti-obesity effects of Lactococcus lactis subsp. lactis CAB701, a probiotic strain isolated from cabbage, were investigated using in vitro and in vivo assays. L. lactis subsp. lactis CAB701 inhibited adipocyte differentiation of 3T3-L1 cells by 67%. In an in vivo model of high-fat diet-induced obese mice, treatment with L. lactis subsp. lactis CAB701 markedly reduced body weight and peri-epididymal fat mass, and significantly reduced serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels. Molecular analysis revealed a significant modulation of key genes and proteins involved in lipid metabolism and adipogenesis. Specifically, fatty acid synthase and peroxisome proliferator-activated receptor gamma were significantly downregulated in peri-epididymal adipose tissue, alluding to the molecular mechanism underlying the anti-obesity effects exerted by L. lactis subsp. lactis CAB701. Furthermore, histological examination revealed a significant reduction in adipocyte size in the treated group, indicating effective adipose tissue remodeling. Our findings suggest that L. lactis subsp. lactis CAB701 mediates anti-obesity effects through the modulation of critical molecular markers and lipid profiles. L. lactis subsp. lactis CAB701 thus represents a promising candidate for combating obesity and related metabolic disorders.

Social isolation and loneliness have increasingly emerged as closely linked to onset and progression of non-communicable chronic diseases (NCDs). The aim of this review is to highlight the importance of addressing social isolation in the prevention and management of NCDs such as obesity, type 2 diabetes, and cardiovascular diseases in order to hinder their development and improve their outcomes.

Social isolation and loneliness affect a significant portion of the older adult population, due to decrease in social interactions, chronic illnesses and sensory impairments. However, many other vulnerable populations may experience social isolation because of psychiatric or disabling health conditions, substances abuse, low socioeconomic status, unemployment and belonging to ethnic or marginalized minorities. The unprecedented COVID-19-related social distancing can be taken as a proof-of-concept of the detrimental role of poor interactions in NCDs prevention and management not only at individual level but also in a public health perspective. Indeed, social isolation has been linked to unhealthy lifestyle choices, disrupted sleep quality, low utilization of healthcare, preventive services and adherence to treatments. Underlying mechanisms like inflammation and stress responses may also play a role in the association between social isolation and worse NCDs outcomes.

Social isolation negatively impacts on the development, progression and management of NCDs. Effective interventions for social isolation should address both societal factors and healthcare-related needs. To counteract the detrimental effects of social distancing during COVID-19 pandemic, the use of telemedicine was implemented. However, telemedicine is not always available, and legislative and age-related barriers persist.

Background/Objectives: Disruptions in adipose tissue dynamics contribute to obesity-related metabolic disorders, emphasizing the need for targeted therapies focusing on adipose tissue cells, including progenitor cells and adipocytes. Peroxisome proliferator-activated receptor gamma (PPARG) ligands are potent insulin sensitizers used in type 2 diabetes treatment. This study investigated the effects of rosiglitazone, a PPARG agonist, and betulinic acid, a PPARG antagonist, on adipogenesis and apoptosis in 3T3-L1 pre-adipocytes. Method: 3T3-L1 pre-adipocytes were treated with rosiglitazone or betulinic acid during adipogenic differentiation. Lipid droplet formation was used to evaluate adipogenesis. Cell growth and cell death were assessed using the resazurin-based cell viability assay, trypan blue exclusion assay, LDH assay, and Annexin V/PI staining. Quantitative PCR was conducted to examine the expression of genes associated with adipogenesis and apoptosis. Results: Betulinic acid reduced adipogenesis only when administered daily for eight days. Rosiglitazone did not alter the overall lipid quantity; however, it promoted a shift toward fewer but larger lipid droplets. Both compounds increased Adipoq and Cfd expression, and betulinic acid also elevated Fabp4. Rosiglitazone induced stronger cell aggregation. Despite increased cell death, overall viability was maintained. Apoptotic cell death was enhanced by both compounds and confirmed via Annexin V/PI staining and flow cytometry, accompanied by downregulation of Ccnd1 and Bcl2. Additionally, rosiglitazone markedly increased the expression of Cebpa, a key regulator that can modulate lipid droplet formation and the balance between cell growth and death. Conclusions: Rosiglitazone and betulinic acid differentially modulate adipogenesis and apoptosis in 3T3-L1 cells, revealing a complex interplay between lipid accumulation and programmed cell death. Together, the findings underscore the potential of dual PPARG-targeting approaches for metabolic disease interventions.

The fat-to-muscle mass ratio (FMR) has served as a marker for various diseases. This study aimed to explore sex-specific associations between FMR in different body regions (whole body, trunk, arm, and leg) and cancer incidence.

We included 435,986 cancer-free participants (203,133 men and 232,853 women) from the UK Biobank at baseline. FMR was calculated as the ratio of fat mass to muscle mass in each body region. Multivariable Cox proportional hazards models, along with Cox models incorporating restricted cubic splines (RCS) function, were employed to examine both linear and non-linear associations between FMR and cancer risk in men and women. Additionally, a combined grouping of body mass index (BMI) and FMR was used to assess the joint impact of body composition on cancer incidence.

During the follow-up period, 62,060 new cancer cases were recorded. Our analysis showed significant associations between both total and regional FMR and the risk of several cancers. In men, higher whole body FMR was associated with an increased risk of esophagus, stomach, colorectal, liver, pancreas, and kidney cancers, while a decreased risk was observed for prostate and non-melanoma skin cancers (FDR < 0.05). In women, higher FMR was associated with a higher incidence of gallbladder, pancreas, kidney, thyroid, breast, and uterus cancers (FDR < 0.05). Non-linear associations were observed for several cancer types, with specific FMR cut-off points presented using RCS curves. The analysis by combining BMI and FMR suggested potential interaction patterns, revealing some masked risks; for example, a significant increase in cancer incidence was also observed in individuals exhibiting high FMRs despite having low BMI.

Our findings suggested that both total and regional FMR may serve as potential biomarkers for assessing the risk of overall and site-specific cancers.

SERPINA3G participates in the antiadipogenesis and insulin resistance induced by TNF-α in 3T3-F442A murine cells. Here, we show that the human orthologue SERPINA3 is expressed in human subcutaneous and visceral adipose depots of normal-weight individuals and that TNF-α and RA induced the overexpression of SERPINA3 mRNA in cultured human subcutaneous and visceral adipocytes, although only TNF-α induced the expression of serpin A3 protein. We also demonstrate that vitamin B6 abrogated the expression of the SERPINA3 gene and diminished the anti-adipogenic effects of TNF-α on mature adipocytes. Our results indicate that SERPINA3 is expressed in human adipose tissues and modulates the antiadipogenic effects of TNF-α, and suggest serpin A3 could be a promissory target in the inflammatory processes linked to obesity and other adipose dysfunctions.

Background/Objectives: Obesity is a risk factor for several diseases; however, less has been researched about how diet-induced obesity may affect the auditory system. In this sense, the purpose of this study was to evaluate the effect of diet-induced obesity on the functionality and integrity of the outer hair cells, a key component of the organ of Corti, inside the cochlea. Furthermore, we hypothesized that adipose tissue (AT) status is associated with impaired outer hair cell auditory amplification in young C57BL/6 mice, contributing to increased vulnerability to hearing damage. Methods: Weaning male C57BL/6J mice (7 weeks old) weighing 22-23 g were divided into two diet groups: (i) a control diet or (ii) a high-fat diet (HFD) for 12 or 16 weeks. Metabolic parameters (body and AT weight, glucose tolerance test), AT dysfunction markers (AT remodeling, adipocyte size, crown-like structures), and outer hair cell function (distortion products otoacoustic emissions (DPOAEs) threshold and amplitudes) and integrity (hair cells cell count) were evaluated. Results: We observed that mice fed an HFD for 16 weeks showed a higher DPOAE threshold against stimuli at 16 KHz and a lower count of outer hair cells in the medial section of the cochlea. These results demonstrate a correlation between body and AT weight specifically at 16 weeks of treatment, the time point at which we observed a marked AT dysfunction. Conclusions: Taken together, our results suggest that obese mice with AT dysfunction have an altered auditory efferent system, characterized by a higher DPOAE threshold and a lower outer hair cell count in the medial section, which may impact signal transduction.

Cardiovascular-kidney-metabolic syndrome is a progressive disorder driven by perturbed interorgan crosstalk among adipose, liver, kidney, and heart, leading to multiorgan dysfunction. Capturing the complexity of human cardiovascular-kidney-metabolic syndrome pathophysiology using conventional models has been challenging. Multi-organ-on-a-chip platforms offer a versatile means to study underlying interorgan signaling at different stages of cardiovascular-kidney-metabolic syndrome and bolster clinical translation.

Obesity is a growing global health concern, contributing to diseases such as cancer, autoimmune disorders, and neurodegenerative conditions. Adipose tissue dysfunction, characterized by abnormal adipokine secretion and chronic inflammation, plays a key role in these conditions. Adipose-derived extracellular vesicles (ADEVs) have emerged as critical mediators in obesity-related diseases. However, the study of mature adipocyte-derived EVs (mAdipo-EVs) is limited due to the short lifespan of mature adipocytes in culture, low EV yields, and the low abundance of these EV subpopulations in the circulation. Additionally, most studies rely on rodent models, which have differences in adipose tissue biology compared to humans. To overcome these challenges, we developed a standardized approach for differentiating human preadipocytes (preAdipos) into mature differentiated adipocytes (difAdipos), which produce high-yield, human adipocyte EVs (Adipo-EVs). Using visceral adipose tissue from bariatric surgical patients, we isolated the stromal vascular fraction (SVF) and differentiated preAdipos into difAdipos. Brightfield microscopy revealed that difAdipos exhibited morphological characteristics comparable to mature adipocytes (mAdipos) directly isolated from visceral adipose tissue, confirming their structural similarity. Additionally, qPCR analysis demonstrated decreased preadipocyte markers and increased mature adipocyte markers, further validating successful differentiation. Functionally, difAdipos exhibited lipolytic activity comparable to mAdipos, supporting their functional resemblance to native adipocytes. We then isolated preAdipo-EVs and difAdipo-EVs using tangential flow filtration and characterized them using bulk and single EV analysis. DifAdipo-EVs displayed classical EV and adipocyte-specific markers, with significant differences in biomarker expression compared to preAdipo-EVs. These findings demonstrate that difAdipos serve as a reliable surrogate for mature adipocytes, offering a consistent and scalable source of adipocyte-derived EVs for studying obesity and its associated disorders.

Obesity, characterized by excessive fat accumulation, stems from an imbalance between energy intake and expenditure, with the gut microbiota playing a crucial role. This review highlights how gut microbiota influences metabolic pathways, inflammation, and adipose tissue regulation in obesity. Specific bacteria and metabolites, such as lipopolysaccharides (LPS) and short-chain fatty acids (SCFAs), modulate gut permeability, inflammation, and energy harvest, impacting obesity development. Certain gut bacteria, including Clostridium XIVb, Dorea spp., Enterobacter cloacae, and Collinsella aerofaciens, promote obesity by increasing energy harvest, gut permeability, and inflammatory response through LPS translocation into the bloodstream. Conversely, beneficial bacteria like Akkermansia muciniphila, Lactobacillus spp., and Bifidobacterium spp. enhance gut barrier integrity, regulate SCFA production, and modulate fasting-induced adipose factor, which collectively support metabolic health by reducing fat storage and inflammation. Metabolites such as SCFAs (acetate, propionate, and butyrate) interact with G-protein coupled receptors to regulate lipid metabolism and promote the browning of white adipose tissue (WAT), thus enhancing thermogenesis and energy expenditure. However, LPS contributes to insulin resistance and fat accumulation, highlighting the dual roles of these microbial metabolites in both supporting and disrupting metabolic function. Therapeutic interventions targeting gut microbiota, such as promoting WAT browning and activating brown adipose tissue (BAT), hold promise for obesity management. However, personalized approaches are necessary due to individual microbiome variability. Further research is essential to translate these insights into microbiota-based clinical therapies.

Fat deposition is a crucial economic trait during sheep growth and development, closely linked to economic returns. Current research on sheep's digestive tract predominantly focuses on the rumen, but the composition of the cecal microbiota and its relationship with host fat deposition remains largely unexplored. In this study, we sequenced the cecal microbiota of 60 Hu sheep, exhibiting marked differences in traits. The most abundant species in the sheep cecum were Firmicutes and Bacteroidota. Statistical analyses revealed significant differences in microbial community structures among different fat-deposition groups (P < 0.05). Using a random forest regression model and linear regression, 15 microbial biomarkers, including Lachnospiraceae_NK3A20_group, Turicibacter, and Bacteroides, were identified as key contributors to fat deposition. Additionally, volatile fatty acids (VFAs) in the cecum and biochemical indices in serum were measured. Acetic acid was the most abundant VFA in the cecum, while isobutyric acid levels were significantly higher in the low-fat group than in other groups (P < 0.05). Serum triglyceride (TG) levels were significantly higher in the high-fat group (P < 0.05). Correlation analysis revealed a significant association between Lachnospiraceae_NK3A20_group and acetic acid levels, as well as between TG levels and fat deposition traits (P < 0.05). TG levels were negatively correlated with acetic acid concentrations (P < 0.05). These findings suggest that the cecal microbiota influences fat deposition in sheep, potentially via the VFAs-TG metabolic pathway.

Compared with muscle development, fat deposition consumes more energy, and controlling the fat deposition process can effectively reduce energy waste. Current research on rumination mainly focuses on the rumen but lacks research on the hindgut. This study identifies differences in the cecal microbiota of sheep with varying fat deposition levels and highlights significant correlations between specific microorganisms, cecal metabolites, and host traits. Therefore, the regulation of cecal microorganisms can help improve the fat deposition characteristics of sheep.

Previous studies have shown that epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, demonstrates promising antiobesity effects. While autophagy mediates obesity via preadipocyte differentiation and lipogenesis, EGCG's potential autophagy-dependent antiobesity mechanism remains unclear. We used 3T3-L1 cells and high-fat-diet (HFD)-fed mice to examine how EGCG inhibits adipogenesis and lipogenesis via autophagy. EGCG (50 or 100 mg/kg) significantly attenuated HFD-induced weight gain, fat accumulation, hyperlipidemia, and glucose intolerance in mice. It also enhanced autophagy and lipolysis in white adipose tissue (WAT). EGCG profoundly inhibited terminal preadipocyte differentiation and lipid droplet formation in 3T3-L1 cells accompanied by reduced PPARγ, C/EBPα, and FASN expressions. Mechanistically, EGCG inhibited autophagy during the early stage of preadipocyte differentiation, as evidenced by increased autophagosome accumulation and impaired autophagic flux. The antiadipogenic effect of EGCG was further aggravated by the autophagy inhibitor chloroquine. Meanwhile, EGCG increased p38 and AMPK/ACC phosphorylation while inhibiting JNK phosphorylation in 3T3-L1 cells at an early stage of adipogenesis. Interestingly, EGCG reduced the expression of lipolytic enzymes HSL and ATGL, and it decreased glycerol contents in differentiated 3T3-L1 cells. These findings provide novel insights into the mechanism of using green tea EGCG in functional foods to combat obesity by targeting autophagy and lipolysis.

Semicarbazide-sensitive amine oxidase (SSAO) is a vascular enzyme and expressed in high concentrations in vascular smooth muscle cells (VSMCs), localized in the caveolae of the plasma membrane, and the endothelial cells. SSAO is classified as a copper amine oxidase and encoded by the amine oxidase copper-containing 3 gene. SSAO exists both as a soluble protein and as a tissue-bound transmembrane protein. The latter is often called vascular adhesion protein 1. Vascular adhesion protein-1 or VAP-1, encoded by the AOC3 gene, is a pro-inflammatory and multifunctional molecule belonging to the SSAO family. It assists the transformation of primary amines to aldehydes resulting in the production of hydrogen peroxide and ammonia. Work from the last two decades, has shown that VAP-1/SSAO plays a role in several physiological and pathological processes, making it a potentially valuable target for therapeutic development. In this review, we provide a detailed overview of the inhibitors of VAP-1/SSAO that are being developed specifically for the treatment of inflammatory diseases. Here in we have highlighted important aspects of the compounds investigated in therapeutic applications. Furthermore, we have outlined potential avenues for innovation with the aim of maximizing the therapeutic efficacy of VAP-1/SSAO inhibitors in clinical settings.

The triglyceride-glucose body mass index (TyG-BMI) is acknowledged as a dependable surrogate biomarker for the evaluation of insulin resistance (IR). Current research indicates a significant correlation between TyG-BMI and the risk of subsequent cardiovascular events in individuals diagnosed with cardiovascular-kidney-metabolic syndrome (CKM) at stages 0-3. Nevertheless, the prognostic significance of TyG-BMI in patients with CKM stage 4 has not been extensively investigated, and there is a paucity of evidence available on this topic. The study utilized patient data from the Medical Information Mart for Intensive Care (MIMIC-IV) database, categorizing the data into quartiles based on the TyG-BMI index. The primary outcomes of interest were all-cause mortality at 180 days and at one year. To assess the relationship between the TyG-BMI index and these outcomes in patients diagnosed with stage 4 CKM, a Cox proportional hazards model was employed. Additionally, a restricted cubic splines(RCS) model was applied to further investigate the associations between the TyG-BMI index and the specified outcomes. A total of 1,885 patients participated in the study, with 62.49% of the cohort being male. The all-cause mortality rates were recorded at 30.50% at 180 days and 35.12% at one year. Analysis using a multivariate Cox proportional hazards model revealed that an increase in the TyG-BMI index was significantly correlated with a reduction in the risk of all-cause mortality at both the 180-day and one-year marks. Specifically, for each standard deviation increase in the TyG-BMI index, the risk of all-cause mortality decreased by 17% within 180 days (HR = 0.83, 95% CI: 0.76-0.91) and by 21% within one year (HR = 0.79, 95% CI: 0.71-0.87). Furthermore, regression analysis utilizing RCS indicated a linear decrease in all-cause mortality rates associated with increasing TyG-BMI index values over both the 180-day and one-year periods (P for nonlinearity = 0.171 and P for nonlinearity = 0.141, respectively). In patients diagnosed with stage 4 CKM syndrome, a reduced TyG-BMI index was found to be significantly correlated with a heightened risk of all-cause mortality within both 180 days and one year. Consequently, the TyG-BMI index may be utilized as an effective instrument for risk stratification and prognostic assessment in this patient population.

The prevalence of kidney stones (KSs) has been increasing globally, and their association with cardiovascular disease and metabolic syndrome suggests a shared underlying pathophysiology. However, the impact of different stages of cardiovascular-kidney-metabolic (CKM) syndrome on KS prevalence remains unclear.

This study aimed to investigate the association between the stages of CKM syndrome and the prevalence of KS in a nationally representative sample of adults in the USA.

A total of 15 568 participants aged ≥20 years were included in the National Health and Nutrition Examination Survey 2007-2020 fasting subsample. CKM syndrome stages (0-4) were defined based on the 2023 American Heart Association Presidential Advisory on CKM Health. The KS history was determined using self-reported data. Multivariable logistic regression models were used to assess the association between the CKM syndrome stage and KS prevalence.

Of the 15 568 participants, 1501 (9.64%) reported a history of KS. The KS prevalence increased progressively with advancing CKM stage, rising from 5.10% in stage 0 to 16.55% in stage 4 (p<0.001). In the fully adjusted model, the ORs for KS were 1.18 (95% CI 0.83-1.68) for stage 1, 1.72 (95% CI 1.28 to 2.32) for stage 2, 2.00 (95% CI 1.29 to 3.10) for stage 3 and 2.36 (95% CI 1.64 to 3.40) for stage 4, compared with stage 0 (P for trend <0.001). Stratified analyses revealed no significant interactions between age, sex, race/ethnicity or other subgroups.

This study demonstrated a significant stepwise increase in KS prevalence with the advancing stages of CKM syndrome. These findings highlight the importance of monitoring and managing CKM syndromes to mitigate the risks of KS.

A long-term high-fat diet (HFD) leads to excessive lipid deposition, which may cause many diseases, including NAFLD, diabetes, and thyroid dysfunction. In addition, HFD leads to a decrease in serum growth hormone (GH) levels to further increase lipid deposition and obesity. However, the mechanism of such reduction of GH has not been fully elucidated.

Male Sprague-Dawley rats were fed a regular diet (CD) or a high-fat diet (HFD) for 29 weeks. GH synthesis and secretion were evaluated in pituitary and blood samples, respectively. An in vitro model was constructed by treating cultured cells with palmitic acid (PA). Vit D receptor (VDR) plasmids (OE-VDR), paricalcitol and VDR knockdown virus (sh-VDR) were used to overexpress or depress the activation of VDR during PA treatment of GH3 cells. The GH content, lipid content, and relevant expression of different molecules were measured in pituitary and cell samples.

A HFD decreased the levels of circulating GH and the expression of Gh in the anterior pituitary gland tissues of rats. In vitro, PA treatment decreased Pit1 and Gh expression in cultured GH3 cells. VDR expression was reduced in the rat pituitary tissues under HFD conditions and in PA-treated GH3 cells. The overexpression and knockdown of VDR increased and decreased the expression of Pit1 and Gh, respectively. Paricalcitol antagonized the decrease in the expression of Pit1 and Gh caused by PA treatment.

HFD induced lipid deposition in the pituitary may cause GH deficiency, and VDR - Pit1 may be at least partially involved in the process.

The triglyceride-glucose (TyG) index was associated with higher risk of mortality in individuals with Cardiovascular-Kidney-Metabolic (CKM) syndrome stages 0-3. However, the relationship between cumulative of TyG (cumTyG) and incidence of stroke remains unclear in individuals with CKM syndrome stages 0-3.

Participants with CKM syndrome stage 0-3 were enrolled from the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2015. TyG was calculated as ln [fasting triglyceride (mg/dL)×fasting glucose (mg/dL)/2], and the cumTyG, as an area-under-the-curve estimate (mean TyG × time span), was calculated as (TyG2012 + TyG 2015)/2 * time (2015-2012). TyG control levels were classified using k-mean clustering analysis. Logistic regression was used to analyze the effect of cumTyG and TyG control levels on the incidence of stroke. Restricted cubic spline models (RCS) were performed to explore the potential non-linear relationship between cumTyG and stroke risk at different CKM syndrome stages 0-3.

A total of 4,700 CKM syndrome stages 0-3 participants were enrolled, among 280 patients had developed stroke during the 3-year follow-up period. After adjusting for confounders, compared to class 1 group, the odds ratio (OR) of incidents of stroke for class 2 was 1.39 [95% confidence interval (CI) 1.003, 1.92], P = 0.046; the OR of incidents of stroke for class 3 was 1.28 (95% CI 0.92-1.77), P = 0.147, the OR of incidents of stroke for class 4 was 1.28 (95% CI 0.84-1.94), P = 0.238. Elevated cumTyG was associated with an increase in incidence of stroke (OR 1.13, 95% CI 1.05, 1.22, P = 0.002). The relationship between the cumTyG index and stroke was linear in restricted cubic spline regression.

Elevated cumTyG was associated with an increased risk of stroke events in the population of CKM syndrome stages 0-3. Long-term dynamic monitoring of changes of TyG may help in the early identification of patients at high risk of developing stroke in the individuals with CKM syndrome stages 0-3.

Background/Objectives: Obesity is a major health concern that can lead to various chronic diseases. Little is known about the anti-obesity effect of a standardized hot water extract from the stems of Ipomoea batatas (WIB). This study aimed to evaluate the therapeutic potential of WIB as a natural alternative to conventional anti-obesity treatments by assessing its effects on body weight, fat accumulation, and key metabolic biomarkers in a high-fat diet-induced obesity model. Methods: A high-fat diet (HFD) induced obesity in C57BL/6 mice. The mice were then treated orally with either orlistat (positive control) or WIB. Changes in body weight, food intake, and fat weight were measured, along with blood lipid profiles and adipokines. Western blot analyses were conducted to determine protein levels in each tissue. H&E staining in white adipose tissue and liver, and the gut microbiota composition were analyzed. Results: WIB treatment significantly reduced body weight and fat mass compared to the HFD group and demonstrated comparable effects to orlistat. WIB improved blood lipid profiles and adipokine levels. H&E staining revealed reduced fat accumulation in the white adipose tissue and liver. Also in those tissues, WIB restored expression levels of sterol regulatory element-binding protein-1 (SREBP-1) and CCAAT/enhancer-binding protein α (C/EBPα) and increased AMP-activated protein kinase (AMPK) phosphorylation. In brown adipose tissue, WIB enhanced AMPK phosphorylation and upregulated thermogenic-related proteins, including peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα), sirtuin 1 (SIRT1), uncoupling protein-1 (UCP-1), and cytochrome C oxidase subunit 4 (COX-IV). Analysis of gut microbiota revealed that WIB normalized β-diversity and reversed HFD-induced phyla imbalances (notably in Bacteroidetes, Firmicutes, and Proteobacteria). Conclusions: By reducing adiposity under the conditions tested in a murine model, improving metabolic markers, and favorably modulating gut microbiota, WIB demonstrates potential in mitigating obesity-related risks. These findings suggest that WIB may serve as a promising natural substance for the management of obesity. Further studies are warranted to confirm its efficacy and explore the potential underlying mechanisms in overweight or obese humans as a health supplement to help manage or prevent obesity.

Adipocyte dysfunction contributes to lipotoxicity and cardiometabolic diseases. Bone morphogenetic protein 4 (BMP4) is expressed in white adipocytes and remodels white adipose tissue, while liver-derived BMP9, a key circulating BMP, influences adipocyte lipid metabolism. The gene sets regulated by BMP4 and BMP9 signalling in mature adipocytes remain unclear. Here, we directly compare BMP4 and BMP9 signalling in mature brown and white adipocytes. While both BMPs showed comparable potency across adipocyte types, RNA sequencing analysis revealed extensive gene regulation, with many more differentially expressed genes and suppression of critical metabolic pathways in white adipocytes. Although BMP4 and BMP9 induced inhibitors of BMP and GDF signalling in both adipocytes, they selectively upregulated several TGF-β family receptors and BMP4 expression only in white adipocytes. These findings underscore a central role of BMP signalling in adipocyte homeostasis and suggest both BMP4 and BMP9 as regulators of white adipocyte plasticity with potential therapeutic implications.

Phloretin, a natural dihydrochalcone, exhibits significant potential in modulating lipid metabolism both in vitro and in vivo. This study investigated the effects of phloretin on lipid accumulation in HepG2 cells and Caenorhabditis elegans. In HepG2 cells, phloretin reduced lipid accumulation, ROS levels, and lipid peroxidation while ameliorating mitochondrial dysfunction. It downregulated lipid synthesis genes (SREBP, FASN) and upregulated PI3K-AKT pathway genes (AKT, FOXO, MTOR). In C. elegans, phloretin alleviated lipid accumulation-induced growth and locomotor impairments, reduced lipofuscin, ROS, glucose, and triglyceride levels, and modulated amino acid and lipid metabolism pathways. Gene expression analysis revealed downregulation of sbp-1, mdt-15, fat-5, fat-6, and fat-7, and upregulation of daf-16, age-1, and skn-1. Mutant studies confirmed that phloretin's lipid-lowering effects were mediated through the IIS and sbp-1/SREBP pathways. These findings suggest phloretin is a promising candidate for regulating lipid metabolism and preventing hyperlipidemia.