Jiqiu Wang

Zinc and ring finger protein 3 (ZNRF3) functions as a transmembrane E3 ubiquitin ligase. Although genome-wide association studies have implicated ZNRF3 in body fat distribution, the evidence from human genetics and animal models has been lacking. Here, through whole-exome sequencing of 1,944 obese individuals and 2,161 healthy lean control individuals, we identified a rare loss-of-function mutation in human ZNRF3 (p.V228L) observed exclusively in 8 obese individuals. These carriers exhibit increased hip circumference and subcutaneous fat area and lower fasting glucose levels compared with noncarriers. In mice, adipocyte-specific Znrf3 deletion leads to progressive adiposity, with expansion of subcutaneous white adipose tissue (sWAT) and improved glucose tolerance after a long-term high-fat diet. Furthermore, Znrf3 deficiency impairs the browning capacity of sWAT and cold-induced thermogenesis. A knock-in mouse model harboring the homologous human p.V228L mutation recapitulates key features of carriers and knockout mice, including reduced sWAT thermogenic function, altered fat distribution, and improved glucose tolerance. Mechanistically, Znrf3 loss attenuates the cAMP/cAMP-dependent protein kinase signaling pathway, suppressing UCP1 expression and mitochondrial respiration. Collectively, these findings provide genetic and biological evidence that ZNRF3 regulates thermogenic capacity and remodeling of sWAT, offering new insights into obesity heterogeneity. 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.

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.

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.

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.

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.