Abstract
Obesity-induced inflammation engenders insulin resistance and type 2 diabetes mellitus (T2DM) but the inflammatory effectors linking obesity to insulin resistance are incompletely understood. Here, we show that hepatic expression of Protein Tyrosine Phosphatase Receptor Gamma (PTPR-γ) is stimulated by inflammation in obese/T2DM mice and positively correlates with indices of inflammation and insulin resistance in humans. NF-κB binds to the promoter of Ptprg and is required for inflammation-induced PTPR-γ expression. PTPR-γ loss-of-function lowers glycemia and insulinemia by enhancing insulin-stimulated suppression of endogenous glucose production. These phenotypes are rescued by re-expression of Ptprg only in liver of mice lacking Ptprg globally. Hepatic PTPR-γ overexpression that mimics levels found in obesity is sufficient to cause severe hepatic and systemic insulin resistance. We propose hepatic PTPR-γ as a link between obesity-induced inflammation and insulin resistance and as potential target for treatment of T2DM.
Highlights
Obesity-induced inflammation engenders insulin resistance and type 2 diabetes mellitus (T2DM) but the inflammatory effectors linking obesity to insulin resistance are incompletely understood
We found that hepatic PTPRG mRNA contents increase proportionally to the severity of non-alcoholic fatty liver disease (NAFLD); a condition associated with increased inflammation and insulin resistance[22, 23]
Chronic feeding on a HCD caused obesity in Ptprg−/− and Ptprg+/+ mice as their body weight, fat mass, and circulating level of the adipocytes-secreted hormone leptin were all significantly higher compared to their genetically-matched STD-fed controls; Ptprg mRNA level
Summary
Obesity-induced inflammation engenders insulin resistance and type 2 diabetes mellitus (T2DM) but the inflammatory effectors linking obesity to insulin resistance are incompletely understood. We directly measured PTPRG expression in liver biopsies from another human cohort and found a strong positive correlation between PTPRG expression and the expression of NF-κB targets IkBA, MnSOD, and IL624 (Supplementary Fig. 1c–e) and subjects’ homeostatic model assessment of insulin resistance (HOMA-IR; an index of insulin resistance), and circulating insulin and glucose levels (Fig. 1f–h). These data demonstrate that in the context of obesity and inflammation PTPR-γ is upregulated in metabolic relevant tissues and suggest that it could play a causative role in insulin resistance in humans
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