Hepatic TGFβ1 signaling impairs insulin sensitivity via inducing insulin receptor substrate 1 degradation.

Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes (T2D), yet the underlying mechanisms remain incompletely defined. We hypothesized that elevated transforming growth factor beta 1 (TGFβ1) level is associated with impaired insulin sensitivity. Using primary hepatocytes, and mouse models with hepatic TGFβ1 overexpression or hepatic TGFβ1 signaling disruption, we examined the impact of TGFβ1 signaling on hepatic insulin signaling and glucose metabolism. We performed bulk RNA sequencing of liver samples identify potential mediator of obesity-induced insulin resistance. Immunoprecipitation, in vitro kinase assay, and mass-spec assay were used to explore the mechanisms underlying TGFβ1-induced insulin receptor substrate (IRS1) degradation. We further evaluated the therapeutic potential of targeting TGFβ1 signaling to improve glycemic control using the TGFβ1 signaling inhibitor LY2157299. Prolonged TGFβ1 exposure markedly reduced IRS1 protein abundance and impaired insulin-stimulated Akt activation in hepatocytes. Hepatic TGFβ1 overexpression exacerbated insulin resistance, whereas hepatic TGFβ1 signaling disruption improved insulin sensitivity by increasing IRS1 protein abundance. Mechanistically, TGFβ1 signaling increased Cullin 7 (CUL7) expression and promoted IRS1 phosphorylation at serine 685, leading to ubiquitin-dependent IRS1 degradation. Pharmacological inhibition of TGFβ1 signaling by LY2157299 improved insulin sensitivity in both lean and diabetic db/db mice. These findings identify TGFβ1 as a key driver of hepatic insulin resistance by promoting CUL7-dependent IRS1 degradation, establishing a mechanistic link between obesity-associated cytokine signaling and impaired insulin action and highlighting the TGFβ1-CUL7-IRS1 axis as a potential therapeutic target for T2D.