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Gilani, A.* ; Stein, B.D.* ; Hoffmann, A. ; Pereira de Lima, R.* ; Ha, E.E.* ; Homan, E.A.* ; Ma, L.* ; Rubio-Navarro, A.* ; Tha Ra Wun, T.* ; Ayala Carrascal, G.J.* ; Bhinder, B.* ; Ghosh, A.* ; Noé, F.* ; Elemento, O.* ; Wolfrum, C.* ; Blüher, M.* ; Lo, J.C.*

Secretory kinase FAM20C triggers adipocyte dysfunction, inciting insulin resistance and inflammation in obesity.

J. Clin. Invest. 136:e191075 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Obesity is a major driver of type 2 diabetes (T2D) and related metabolic disorders, characterized by chronic inflammation and adipocyte dysfunction. However, the molecular triggers initiating these processes remain poorly understood. We identified FAM20C, a serine/threonine kinase, as an early obesity-induced mediator of adipocyte dysfunction. Fam20c expression was substantially upregulated in adipocytes in response to obesity, correlating with a proinflammatory transcriptional signature. Forced expression of Fam20c in adipocytes promoted robust upregulation of proinflammatory cytokines and induced insulin resistance that is dependent on its kinase activity. Conversely, deletion of adipocyte Fam20c after established obesity and hyperglycemia improved glucose tolerance, augmented insulin sensitivity, and reduced visceral adiposity, without altering body weight. Phosphoproteomic studies revealed that FAM20C regulates phosphorylation of intracellular and secreted proteins, modulating pathways critical to inflammation, metabolism, and ECM remodeling. We identified FAM20C-dependent substrates, such as CNPY4, whose phosphorylation contributes to proinflammatory adipocyte signaling. Of translational relevance, we showed that in humans, visceral adipose FAM20C expression positively correlates with insulin resistance. Our findings establish FAM20C as an early regulator of obesity-induced adipocyte dysfunction and systemic metabolic impairment. Our studies provide proof of concept that inhibition of FAM20C may serve as a potential therapy for T2D by restoring adipocyte health.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Adipose Tissue ; Cell Biology ; Diabetes ; Metabolism ; Obesity
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 136, Issue: 1, Pages: , Article Number: e191075 Supplement: ,
Publisher American Society of Clinical Investigation
Reviewing status Peer reviewed
Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)