ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2023
Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet-Induced Adiposity.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 20 citations in OpenAlex.
- The Sex-Stratified Effects of RSPO3 Expression on Body Fat and Blood Lipids: An Omics Mendelian Randomization Study.Obesity (Silver Spring, Md.) · 2026Article
- A novel A-to-G mutation in circBDP1 alters adipocyte proliferation and differentiation and affects bovine carcass traits.Journal of Zhejiang University. Science. B · 2026Article
- Maternal Separation Differentially Programs Structural and Functional Remodeling of Visceral Adipose Tissue Depots in Mice Exposed to a Post-Weaning High-Fat Diet.International journal of molecular sciences · 2026Article
- SEMA3E promotes beige adipocyte differentiation and thermogenesis via β-catenin signaling in mice.Apoptosis : an international journal on programmed cell death · 2026Article
- Plasma R-spondin 2 levels are associated with the progression of diabetic kidney disease.Frontiers in endocrinology · 2026Article
- Cryo-EM structure of the full-length LGR4-RSPOs complex and a targeting nanobody for anti-obesity therapy.Nature communications · 2025Article
- Nonlinear association between visceral fat metabolism score and heart failure: insights from LightGBM modeling and SHAP-Driven feature interpretation in NHANES.BMC medical informatics and decision making · 2025Article
- Regulation of placental development and function by ubiquitination.Molecular medicine (Cambridge, Mass.) · 2025Review
- A feeding-induced myokine modulates glucose homeostasis.Nature metabolism · 2025Article
- Hepatic Dyrk1b impairs systemic glucose homeostasis by modulating Wbp2 expression in a kinase activity-dependent manner.Heliyon · 2024Article
- Systems genetics analysis of human body fat distribution genes identifies adipocyte processes.Life science alliance · 2024Article
- R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis.Cell communication and signaling : CCS · 2024Article
- Prognostic and immunological roles of RSPO1 in pan-cancer and its correlation with LUAD proliferation and metastasis.American journal of cancer research · 2024Article
- Article
- Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet-Induced Adiposity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
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Authors and funding
20 authors at 3 institutions in 1 country.
Funding
Abstract
Recent genetic evidence has linked WNT downstream mutations to fat distribution. However, the roles of WNTs in human obesity remain unclear. Here, the authors screen all Wnt-related paracrine factors in 1994 obese cases and 2161 controls using whole-exome sequencing (WES) and identify that 12 obese patients harbor the same mutations in RSPO1 (p.R219W/Q) predisposing to human obesity. RSPO1 is predominantly expressed in visceral fat, primarily in the fibroblast cluster, and is increased with adiposity. Mice overexpressing human RSPO1 in adipose tissues develop obesity under a high-fat diet (HFD) due to reduced brown/beige fat thermogenesis. In contrast, Rspo1 ablation resists HFD-induced adiposity by increasing thermogenesis. Mechanistically, RSPO1 overexpression or administration significantly inhibits adipocyte mitochondrial respiration and thermogenesis via LGR4-Wnt/β-catenin signaling pathway. Importantly, humanized knockin mice carrying the hotspot mutation (p.R219W) display suppressed thermogenesis and recapitulate the adiposity feature of obese carriers. The mutation disrupts RSPO1's electrostatic interaction with the extracellular matrix, leading to excessive RSPO1 release that activates LGR4-Wnt/β-catenin signaling and attenuates thermogenic capacity in differentiated beige adipocytes. Therefore, these findings identify that gain-of-function mutations and excessive expression of RSPO1, acting as a paracrine Wnt activator, suppress fat thermogenesis and contribute to obesity in humans.
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