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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)
Verlagsversion Forschungsdaten 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Adipose Tissue ; Cell Biology ; Diabetes ; Metabolism ; Obesity; Adipose-tissue Inflammation; Rna-seq; Lipid-metabolism; Pathogenesis; Expression; Lipolysis; Molecule; Health; Tbk1
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Zeitschrift Journal of Clinical Investigation
Quellenangaben Band: 136, Heft: 1, Seiten: , Artikelnummer: e191075 Supplement: ,
Verlag American Society of Clinical Investigation
Verlagsort 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Förderungen Deutsches Zentrum fur Diabetesforschung
German Research Foundation
American Heart Association postdoctoral fellowship
Tri-I StARR National Institute of Allergy and Infectious Diseases (NIAID) Fellowship
American Diabetes Association
NIH