Secretory kinase FAM20C triggers adipocyte dysfunction, inciting insulin resistance and inflammation in obesity
Ankit Gilani, Benjamin D. Stein, Anne Hoffmann, Renan Pereira de Lima, Elizabeth E. Ha, Edwin A. Homan, Lunkun Ma, Alfonso Rubio-Navarro, Tint Tha Ra Wun, Gabriel Jose Ayala Carrascal, Bhavneet Bhinder, Adhideb Ghosh, Falko Noé, Olivier Elemento, Christian Wolfrum, Matthias Blüher, James C. Lo
Ankit Gilani, Benjamin D. Stein, Anne Hoffmann, Renan Pereira de Lima, Elizabeth E. Ha, Edwin A. Homan, Lunkun Ma, Alfonso Rubio-Navarro, Tint Tha Ra Wun, Gabriel Jose Ayala Carrascal, Bhavneet Bhinder, Adhideb Ghosh, Falko Noé, Olivier Elemento, Christian Wolfrum, Matthias Blüher, James C. Lo
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Research Article Cell biology Metabolism

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

Abstract

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.

Authors

Ankit Gilani, Benjamin D. Stein, Anne Hoffmann, Renan Pereira de Lima, Elizabeth E. Ha, Edwin A. Homan, Lunkun Ma, Alfonso Rubio-Navarro, Tint Tha Ra Wun, Gabriel Jose Ayala Carrascal, Bhavneet Bhinder, Adhideb Ghosh, Falko Noé, Olivier Elemento, Christian Wolfrum, Matthias Blüher, James C. Lo

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Figure 1

FAM20C is an obesity-induced serine/threonine kinase in adipocytes.

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FAM20C is an obesity-induced serine/threonine kinase in adipocytes. (A) ...
(A) Schematic of VIS WAT collection from diet-induced obesity (DIO) model of B6/J mice and its fractionation into adipocyte and stromal vascular compartments. (B) Volcano plot of DEGs from whole AT, (C) adipocyte fraction, and (D) SVFs of HFD- versus CD-fed B6/J mice. (E) Relative mRNA expression of proinflammatory genes in primary adipocytes of B6/J transduced with respective viral constructs (n = 3 per group). (F) Schematic of mouse FAM20C protein with highlighted key domains and catalytic sites. NLS, nuclear localization signal. (G) Fam20c mRNA expression from VIS WAT of CD- and HFD-fed B6/J mice at respective time points (n = 4 per group). (H) Fam20c mRNA expression from VIS WAT of 6-week-old WT B6/J and leptin-deficient ob/ob mice on CD (n = 5 per group). *P < 0.05, **P < 0.01; unpaired, 2-tailed Student’s t test. Data are shown as the mean ± SEM.