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 4

Adipocyte-specific deletion of Fam20c shifts adipocyte size distribution toward smaller adipocytes, decreases ATMs, and improves insulin sensitivity.

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Adipocyte-specific deletion of Fam20c shifts adipocyte size distribution...
(A) Representative images of H&E-stained VIS WAT sections of HFD-fed control and iAd-Fam20c–KO mice following chronic Fam20c deletion. Scale bars: 100 μm. (B) Mean adipocyte diameter and (C) frequency size distribution for adipocyte size in HFD-fed control and iAd-Fam20c–KO mice following chronic Fam20c deletion (n = 6 per group). (D) Number of ATMs (F4/80+CD11b+), B cells (CD19+), CD4+ cells, and CD8+ cells in control and iAd-Fam20c–KO mice fed HFD for 4 weeks followed by acute Fam20c deletion (n = 4–6 per group). (E) Representative images of Mac-2 staining, (F) quantification of macrophage (Mac-2–stained) area represented as percentage of total adipose area, and (G) quantification of CLSs represented as CLS per 10,000 adipocytes from VIS WAT sections of control and iAd-Fam20c–KO mice fed HFD for 4 weeks followed by acute Fam20c deletion (n = 4 per group). Scale bars: 100 μm. (H) Representative Western blot images for insulin-mediated p-AKT stimulation in SC and VIS WAT of control and iAd-Fam20c–KO mice fed HFD for 4 weeks followed by acute Fam20c deletion. (I and J) Quantifications of p-AKT/AKT from H for SC and VIS WAT, respectively (n = 4 per group). (K) Representative Western blot images for insulin-mediated p-AKT stimulation in liver and skeletal muscle of control and iAd-Fam20c–KO mice fed HFD for 4 weeks followed by acute Fam20c deletion. (L and M) Quantifications for p-AKT/AKT from K for liver and skeletal muscle, respectively. *P < 0.05, **P < 0.01, ****P < 0.0001; unpaired, 2-tailed Student’s t test. Data are shown as the mean ± SEM.