Abstract The scarcity of expandable, functional human islet cells remains a major barrier to diabetes therapy. Here, we identify PROCR+ cells within adult human islets and establish a defined culture system to generate pancreatic islet organoids. These organoids self-organize into α-, β-, δ-, and PP cells at near-native ratios, exhibit regulated insulin and glucagon secretion, and support exponential in vitro expansion. Single-cell transcriptomics reveals a unique progenitor-like cell population that is transcriptionally primed for endocrine differentiation but shares molecular features with fetal trunk cells and endocrine progenitors. When transplanted, the organoids rapidly ameliorate hyperglycemia in diabetic mice. Importantly, in a non-human primate model, intraportal transplantation of these organoids reduced exogenous insulin requirements, restored glucose-stimulated C-peptide secretion, and achieved sustained glycemic control-representing a critical step toward clinical translation. This study provides a strategy for expanding human islet organoids, offering a scalable platform for diabetes treatment, disease modeling, and regenerative medicine.

Aging commonly causes decline of testosterone or estrogen, leading to overaccumulation of fatness in men and women, respectively. Although such a phenomenon can be readily explained by estrogen's direct action on adipocytes in women, accumulative evidence does not support the direct action of testosterone in adipocyte lipid metabolism, suggesting there is a missing intermediary link. Herein, we propose that glycoprotein hormone β5 (GPHB5) is the intermediary linkage between testosterone and the regulation of adiposity. In clinical samples, blood levels of GPHB5 were correlated negatively with men's ages and positively with circulating testosterone. Testosterone directly stimulated the expression of GPHB5 in cultured cells; pharmacological blockade of androgen receptor (AR) functions abrogated this effect. Knockout of AR led not only to development of obesity but also reduction of GPHB5 expression. Genetic ablation of GPHB5 in men, but not women, reduced the browning of white adipose tissue, diminished energy expenditure, and caused severe obesity. Importantly, elevated blood testosterone levels did not exert catabolic actions in GPHB5-/- mice; yet, recombinant GPHB5 protein could stimulate energy expenditure and reduce adiposity. These results provide strong proof that GPHB5 is the "missing" intermediary hormone linking testosterone (and aging) and its well-known catabolic effect on adipose tissue.

Disturbances in the gut microbiota (GM) contribute to the pathogenesis of various prevalent metabolic disorders. Short-chain fatty acids act as signaling molecules and donors for host post-translational modifications. Here, we report a novel type of lysine modification, phenylacetylation (Kpaa), derived from the phenylalanine-dependent phenylacetic acid (PAA) metabolic pathway of the GM. Hepatic Kpaa levels were significantly elevated in mice with high-fat-diet-induced obesity and were reduced by the deacetylase sirtuin 3 (SIRT3). Proteome-wide substrates were significantly associated with mitochondria. PAA disrupted mitochondrial function and impaired insulin signaling. Mechanistically, PAA-induced K481paa of HSP60 triggered the mitochondrial unfolded protein response, which could be reversed by SIRT3. Finally, relatively low levels of hepatic SIRT3 in adults with obesity and metabolic dysfunction-associated steatohepatitis (MASH) were negatively correlated with increased Kpaa levels. Together, our study uncovered a microbiota-derived lysine acylation modification underlying its biological relevance in the development of metabolic dysfunction-associated steatotic liver disease (MASLD)/MASH.

ARTICLE HIGHLIGHTS:A rare loss-of-function variant in ZNRF3 (p.V228L) is enriched in individuals with obesity and is associated with increased subcutaneous white adipose tissue (sWAT) accumulation and lower fasting glucose levels. Both adipocyte-specific Znrf3 knockout and global variant knock-in impair sWAT browning, increase sWAT expansion, and improve glucose tolerance in mice. These findings establish ZNRF3 as a genetic regulator of fat distribution and thermogenic capacity, informing precise phenotyping of obesity. GWAS has implicated ZNRF3 in human fat distribution, yet its role in adipose tissue biology remains unknown.

Obesity exhibits a high heritability with heterogeneity; however, the genetic variants identified as obesity-causing factors are still underexplored. By performing deep sequencing on 2295 cases of young-onset obesity from East Asian populations and 2292 lean controls, we identified five genes (TUB, NR4A3, HIST1H4D, DXO, and TELO2) with an excess burden of rare predicted loss-of-function (LoF) variants in cases. Among the variants, TUB p.R364G was identified as a potential deleterious variant that disrupted TUB protein's subcellular localization. Knock-in mice carrying the homologous p.R363G variant exhibited hyperphagia and obesity in an allele dose-dependent manner when fed a high-fat diet. The TUB p.R363G variant also blunted responses to leptin-induced suppression of food intake, leading to leptin resistance in mice. Furthermore, we demonstrated that TUB acted as a positive regulator of the leptin pathway through its interaction with STAT3, and this interaction was impaired by the p.R364G variant. TUB silencing mitigated the inhibitory effects of leptin on the activities of agouti-related protein (AgRP)-expressing neurons. Consistently, conditional ablation of TUB in AgRP+ neurons in mice led to hyperphagic obesity and attenuated leptin-induced appetite suppression in mice. Thus, our study demonstrates that rare LoF variants in TUB predispose to young-onset obesity in humans, likely through impairing leptin sensitivity in AgRP+ neurons.

OBJECTIVE:This study examined sex-stratified effects of R-spondin 3 (RSPO3) expression levels on body fat and blood lipids and their potential mediation effects through sex hormones. METHODS:We performed a sex-stratified genome-wide association study (GWAS) of RSPO3 protein (N = 18,529 men and 21,323 women). We used two-sample Mendelian randomization (MR) to examine associations of RSPO3 expression with the outcomes. Sex-stratified MR estimates were compared using the pairwise z score test and Cochran's Q test. We conducted two-step MR analyses to explore mediation effects through sex hormones. RESULTS:Sex-stratified GWAS identified nine loci associated with RSPO3 protein levels, including three novel signals and four female-stratified loci. In women, RSPO3 protein levels were associated with visceral adipose tissue (β = 0.22, 95% CI = 0.10 to 0.34), waist circumference (0.10, 0.05 to 0.15), hip circumference (0.10, 0.05 to 0.15), triglycerides (0.22, 0.18 to 0.26), high-density lipoprotein cholesterol (-0.17, -0.21 to -0.13), and apolipoprotein A (-0.11, -0.15 to -0.06). We also observed sex differences in these associations. Two-step MR showed that RSPO3 protein levels affected six outcomes via sex hormone-binding globulin in women, with little evidence in men. CONCLUSIONS:Our findings indicated that RSPO3 could be a drug target for regulating body fat distribution and blood lipids in women.

Primary aldosteronism (PA), a major cause of secondary hypertension, is characterized by autonomous aldosterone overproduction. Although the gut microbiota is closely linked to blood pressure regulation, its role in PA remains unclear. We performed metagenomic sequencing on fecal samples from 13 patients with essential hypertension (EH), 57 with unilateral PA (UPA), and 51 with bilateral PA (BPA). Despite comparable overall microbial diversity, gut microbial compositional differences were observed among EH and PA subtypes, particularly at finer taxonomic levels. We next identified 39 microbial species that were positively associated with plasma aldosterone concentration (PAC), and 29 that were negatively associated. In the co-abundance network, Ruminococcus gnavus emerged as one of the top three central nodes and was negatively correlated with PAC. Functionally, R. gnavus efficiently degraded aldosterone and multiple natural steroid hormones in vitro, and aldosterone degradation was accompanied by the generation of 3α,5β-tetrahydroaldosterone. R. gnavus-colonized germ-free mice showed reduced fecal aldosterone levels and downregulated expression of aldosterone downstream genes in the intestine. In an aldosterone infusion model, R. gnavus similarly decreased fecal aldosterone and improved systolic blood pressure (SBP) and serum potassium. Logistic regression further revealed that the presence of R. gnavus was associated with lower odds of having a historical highest SBP ≥ 160 mmHg in patients with PA. Collectively, this study reveals different gut microbial signatures in PA and highlights the aldosterone-metabolizing capacity and blood pressure regulation of R. gnavus. These findings advance our understanding of gut microbiota-steroid hormone interactions in PA and provide a basis for exploring microbiota-based stratification and intervention strategies in steroid hormone-related conditions.

OBJECTIVE: To identify predictive biomarkers from the perspectives of gut microbiota and bile acid metabolites for polycystic ovary syndrome (PCOS) remission following metabolic bariatric surgery in patients with PCOS and obesity. METHODS: We conducted a one-year follow-up of patients with obesity and PCOS who underwent sleeve gastrectomy (SG) to assess their PCOS remission status. Metagenomics and bile acid metabolomics were performed and compared between the remission and non-remission groups to identify differential microbial species and bile acid metabolites. The associations between these biomarkers and PCOS remission was then evaluated using Generalized Estimating Equations (GEE) models and Receiver Operating Characteristic (ROC) analysis. RESULTS: SG led to marked improvements in metabolic parameters and hyperandrogenemia. These changes were accompanied by substantial shifts in the gut microbiome, which correlated with alterations in gonadal hormone levels. Based on PCOS outcomes, patients were categorized into remission and non-remission groups. The remission group showed a higher abundance of A. equolifaciens and Clostridium sp CAG 299, along with lower baseline circulating levels of ursodeoxycholic acid (UDCA). These factors were positively associated with PCOS remission. ROC analysis demonstrated that the combination of A. equolifaciens, Clostridium sp CAG 299, UDCA, and average follicle number yielded an AUC of 0.93 for predicting remission. CONCLUSION: A composite biomarker signature incorporating specific gut microbiota profiles, circulating UDCA levels, and ovarian follicle count shows strong potential as an effective predictor of PCOS remission after SG.

Myocardial infarction (MI) remains a leading cause of global mortality, with risk varying substantially across demographic and clinical subgroups. Although SCORE2 is widely implemented for cardiovascular risk stratification, the extent to which clinical subgroup specific plasma proteomics can further refine personalized MI risk prediction remains uncertain. SCORE2-Pro, a clinical subgroup-stratified plasma proteome prediction model was built stratified by sex, age, smoking status, non-high-density lipoprotein (non-HDL) cholesterol, and systolic blood pressure. In 51,010 UK Biobank participants (aged 40–69 years; 54.9

Cancer cachexia is a systemic metabolic disorder, with body weight loss and adipose tissue wasting as key features, and adipose tissue remodeling often preceding weight loss. Using pre-cachexia and cachexia models in Lewis lung carcinoma (LLC) tumor-bearing mice, transcriptomic analysis of white adipose tissue (WAT) identified Otopetrin 1 (Otop1) as a dynamically regulated gene, increased in pre-cachexia and decreased in cachexia. In patients with cancer, OTOP1 expression in subcutaneous WAT was reduced in cachexia and positively correlated with BMI in cachectic patients. In adipocytes treated with tumor-conditioned medium, OTOP1 overexpression alleviated metabolic dysfunction, accompanied by suppression of NF-κB signaling and activation of PPARγ, leading to reduced lipolysis and enhanced adipogenesis; these effects were partially attenuated by the PPARγ antagonist. Moreover, overexpression of OTOP1 in adipose tissue of LLC tumor-bearing mice alleviated adipose tissue wasting and improved lipid metabolism. These findings suggest a role for OTOP1 in adipose tissue remodeling during cancer cachexia.

Sex-dimorphic adipose mitochondrial function (lower activity in males) correlates with visceral adiposity and metabolic risk, yet the underlying mechanisms remain elusive. We find that androgen-androgen receptor (AR) signaling suppresses mitochondrial respiration and thermogenesis in visceral adipose tissue (VAT), promoting visceral fat accumulation. Mechanistically, androgen-AR signaling represses transcription of Pdhb, which encodes a pyruvate dehydrogenase (PDH) subunit, thereby reducing PDH activity, acetyl-CoA levels, H3K27 acetylation, and chromatin accessibility at the promoters of mitochondrial respiration-related genes. Notably, Pdhb overexpression largely reverses these alterations and restores mitochondrial function. Furthermore, sodium dichloroacetate, a PDH activator, enhances mitochondrial respiration and reduces visceral fat in male mice. Multi-omics analyses reveal that the androgen-PDH axis orchestrates a male-specific chromatin-based transcriptional landscape that encompasses mitochondrial and metabolic pathways in visceral adipocytes. Collectively, this study identifies the androgen-PDH axis as a key regulator of sexual dimorphism in mitochondrial metabolism and adipose homeostasis in VAT.

Background:Lifestyle-induced weight loss improves metabolic health, but weight regain is common. Its hepatic consequences, particularly in relation to metabolic dysfunction-associated steatotic liver disease (MASLD), remain insufficiently characterized. Methods:This retrospective observational study included 213 patients categorized as weight regain (≥5% lifestyle-induced weight loss followed by return to or exceeding baseline weight) or weight sustain (weight change within ±5% of baseline) over 3 years. Propensity score matching (PSM) balanced age, sex, weight, and body mass index. Clinical, biochemical, and noninvasive liver indices were compared. In a bariatric surgery subset, liver histology, transcriptomics, quantitative PCR, and immunohistochemistry were performed. Results:No significant differences were found in metabolic parameters between groups. After PSM, the weight regain group showed higher alanine aminotransferase (ALT) (median 59.00 vs 41.00 IU/L, P=0.007) and aspartate aminotransferase (AST) (33.50 vs 26.00 IU/L, P=0.041). In males, ALT (88.00 vs 47.00 IU/L, P<0.001) and AST (46.00 vs 30.00 IU/L, P=0.004) remained higher. Noninvasive indices of hepatic steatosis (Dallas Steatosis Index, DSI) and fibrosis (NFS, FIB-4) did not differ. In male patients with liver biopsy samples available, liver histology showed comparable NAFLD Activity Scores (NAS) and fibrosis stages, whereas transcriptomic analysis revealed immune-related pathway enrichment. Increased hepatic CD11B and CD68 expression was confirmed by quantitative PCR and immunohistochemistry. Conclusion:Weight regain after lifestyle-induced weight loss is associated with early liver-related biochemical abnormalities and hepatic innate immune activation in the absence of advanced fibrosis, underscoring the need for early liver risk assessment in individuals with weight cycling.

OBJECTIVE:Dysregulation of bile acid (BA) profiles is closely associated with obesity and its related metabolic abnormalities. This study aims to investigate the BA alterations between metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) and identify specific BA species associated with MUO. METHODS:We measured serum bile acid profiles in two cross-sectional studies. The discovery cohort included 261 normal-weight, 80 MHO, and 120 MUO individuals. The validation cohort, consisting of 104 MHO and 104 MUO participants (matched for age, sex, and BMI), was used for confirmation. RESULTS:Individual primary bile acids (PBAs), including cholic acid, glycocholic acid, chenodeoxycholic acid, and total PBA concentration, were markedly increased in MUO compared with both normal-weight and MHO subjects. Total secondary bile acids were decreased in both obesity phenotypes compared with normal-weight subjects, but did not differ between MUO and MHO. Among individuals with obesity, either individual PBA or total PBA levels were positively correlated with metabolic deterioration parameters such as WHR, HOMA-IR, HbA1c, and TG. Moreover, a higher total PBA level was associated with an increased proportion of MUO. These findings were further replicated in the validation cohort. CONCLUSIONS:Serum individual PBAs and total PBAs were significantly elevated in MUO compared with MHO. Higher PBA levels were associated with adverse metabolic parameters and an increased proportion of MUO. This study characterizes the distinct BA profiles across obesity phenotypes and highlights the associations between PBAs and MUO.

AIMS:To determine whether 1-hour plasma glucose (1-h PG) during an OGTT outperforms other glycemic markers (FPG, 0.5-h PG, 2-h PG, HbA1c) in identifying impairments in insulin secretion, sensitivity, and β-cell compensation. METHODS:We analyzed 2178 Chinese young adults (18-40 years) with obesity (BMI ≥ 28 kg/m2) and without diabetes. Associations between glycemic markers and OGTT-derived indices were assessed using adjusted correlations, regression, and ROC analyses. In a subcohort (n = 495) with frequently sampled intravenous glucose tolerance test (FSIVGTT) data, markers were evaluated against minimal-model estimates of first-phase secretion (AIRg), insulin sensitivity (SI), and disposition index (DI). RESULTS:1-h PG showed superior performance over other glycemic markers for identifying early-phase insulin secretion defects. Among these markers, it demonstrated the strongest correlation with IGI30 (ρ =  - 0.413) and the highest discriminatory accuracy (AUC = 0.702); this was supported by FSIVGTT-derived AIRg. For insulin sensitivity, 1-h PG correlated more strongly with the Matsuda index, whereas 2-h PG was more strongly associated with FSIVGTT-derived SI. Elevated 1-h PG (≥8.6 mmol/L) identified individuals with impairments across all traits. CONCLUSIONS:1-h PG is a specific physiological marker of early-phase insulin secretion defects, supporting its role in early phenotyping and risk stratification in young adults with obesity.

Akkermansia muciniphila is a promising target for managing obesity and type 2 diabetes (T2D), but human studies are limited. We conducted a 12-week randomized, double-blind, placebo-controlled trial involving 58 participants with overweight or obese T2D, who received A. muciniphila (AKK-WST01) or placebo, along with routine lifestyle guidance. Both groups showed decreases in body weight and glycated hemoglobin (HbA1c), without significant between-group differences. In participants with low baseline A. muciniphila, AKK-WST01 supplementation showed high colonization efficiency and significant reductions in body weight, fat mass, and HbA1c, which were not found in the placebo group. However, AKK-WST01 supplementation showed poor colonization and no significant clinical improvements in participants with high baseline A. muciniphila. These findings were verified in germ-free mice receiving feces with low or high A. muciniphila. Our study indicates that metabolic benefits of A. muciniphila supplementation could depend on its baseline intestinal levels, supporting the potential for gut microbiota-guided probiotic supplementation. (ClinicalTrials.gov number, NCT04797442).

Adipose tissue serves as a crucial energy storage and metabolic organ in the human body. With the surging of elderly population in China comes significant challenges in preventing and managing age-associated diseases, while adipose tissue aging represents one of the pivotal initiating events for multi-organ senescence. To address these challenges, the Aging China Biomarkers Consortium (ABC) has established an expert consensus on biomarkers of adipose tissue aging by digesting literature and collecting insights from scientists and clinicians. This consensus provides a comprehensive evaluation of the key changes and characteristics, as well as biomarkers related to adipose tissue aging and proposes a systematic framework categorizing these biomarkers into functional, structural and humoral dimensions. Within each dimension, the ABC recommends clinically and empirically validated biomarkers and parameters for assessing both physiological and pathological changes in adipose tissue during aging, which aims to establish a foundation for future prediction, diagnosis, early warning and treatment for adipose tissue aging and its related diseases, with the ultimate goal of improving adipose tissue health and promoting healthy aging in elderly populations both in China and worldwide.

Precision nutrition is pivotal to preventing cardiometabolic diseases. However, almost no single blood biomarker capable of predicting the metabolic benefits of specific dietary patterns has yet been identified. Here, we revealed the associations of plasma levels of the secreted protein acidic and rich in cysteine (SPARC), an inflammatory factor highly expressed in fat tissues, and insulin sensitivity improvement in a 6-month randomized controlled, calorie-restricted feeding trial recruiting 235 Chinese adults with overweight/obesity and prediabetes: the Mediterranean diet (MD) group (n = 81), the traditional Jiangnan diet (TJD) group (n = 81), and the control diet (CD) group (n = 73). The 1-h post-glucose loading plasma SPARC levels (SPARC-1H) decreased significantly from baseline to 3 months and 6 months in the MD group, whereas no significant changes were observed in the TJD or CD groups. Further analyses revealed that the individuals with higher baseline SPARC-1H levels were associated with fewer improvements in fasting insulin (β ± SE: 1.54 ± 0.43; P = 0.0007), fasting glucose (0.10 ± 0.04; P = 0.013), the homeostasis model assessment of insulin resistance (HOMA-IR, 0.47 ± 0.12; P = 0.0002), and the homeostasis model assessment of β-cell function (HOMA-β, 7.63 ± 3.27; P = 0.023) after 6 month in MD group. Moreover, baseline SPARC-1H levels were positively correlated with changes in lipidomic profiles, including three alkenylphosphatidylethanolamines (PE(P)s), which potentially mediate the cardiometabolic benefits of the MD group. No significant associations were observed in the other two diet groups. Our findings suggest postprandial SPARC as a predictor for the metabolic benefits of MD, offering a potential biomarker for individualized nutrition interventions against cardiometabolic diseases.

The role of hypothalamic branched-chain amino acid (BCAA) catabolism in the maintenance of energy homeostasis remains elusive. By using Mendelian randomization, we found that genetically predicted branched-chain keto acid dehydrogenase E1α subunit (BCKDHA) expression in the hypothalamus was negatively associated with fat mass. Hypothalamic deletion of BCKDHA (Bckdhaf/f;RIP-Cre) leads to increased fat mass, reduced energy expenditure, and blunted browning of white adipose tissue in mice, with decreases of thyrotropin-releasing hormone (TRH) expression in the paraventricular nucleus (PVN) and hypothalamic-pituitary-thyroid (HPT) axis activity. Mice with adeno-associated virus-mediated deletion of BCKDHA in the PVNTRH neurons displays a similar metabolic phenotype to Bckdhaf/f;RIP-Cre mice. TRH supplementation ameliorates the abnormal phenotypes of Bckdhaf/f;RIP-Cre mice. Defective BCAA catabolism in the hypothalamus results in hypoacetylation of histone H3 lysine 27 (H3K27) due to decreased acetyl-CoA content, reducing its binding to the Trh promoter. Our study highlights the crucial role of hypothalamic BCAA catabolism in maintaining energy homeostasis through HPT axis.

Mitochondrial rRNAs play important roles in regulating mtDNA-encoded gene expression and energy metabolism subsequently. However, the proteins that regulate mitochondrial 16S rRNA processing remain poorly understood. Herein, we generated adipose-specific Wbscr16-/-mice and cells, both of which exhibited dramatic mitochondrial changes. Subsequently, WBSCR16 was identified as a 16S rRNA-binding protein essential for the cleavage of 16S rRNA-mt-tRNALeu, facilitating 16S rRNA processing and mitochondrial ribosome assembly. Additionally, WBSCR16 recruited RNase P subunit MRPP3 to nascent 16S rRNA and assisted in this specific cleavage. Furthermore, evidence showed that adipose-specific Wbscr16 ablation promotes energy wasting via lipid preference in brown adipose tissue, leading to excess energy expenditure and resistance to obesity. In contrast, overexpression of WBSCR16 upregulated 16S rRNA processing and induced a preference for glucose utilization in both transgenic mouse models and cultured cells. These findings suggest that WBSCR16 plays essential roles in mitochondrial 16S rRNA processing in mammals, and is the key mitochondrial protein to balance glucose and lipid metabolism.