Ruixin Liu

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.

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.

Birthweight readily measurable marker of fetal growth that may influence health across the lifespan. We aimed to investigate the potential causal associati