293-OR: Macrophage-Derived Interleukin-12 Regulates Obesity-Mediated Insulin Resistance in the Liver

Inflammation and insulin resistance play a major role in nonalcoholic fatty liver disease (NAFLD), and IL-12, a pro-inflammatory cytokine primarily secreted by macrophages, is elevated in obesity. Here, we examined the effects of acute treatment with IL-12 in vivo on glucose metabolism in male C57BL/6J mice. Mouse recombinant IL-12 (0.25 μg/hour) or saline (control) was infused for 4 hours, followed by insulin clamps in mice (n=5/group). Glucose infusion rates during clamps were significantly reduced in IL-12-treated mice, resulting in a 34% decrease compared to controls (Fig. 1-2). Basal hepatic glucose production (HGP) did not differ, but clamp HGP was significantly increased in IL-12-treated mice (Fig. 3). As a result, IL-12 treatment caused a 43% decrease in hepatic insulin action compared to controls (Fig. 4). These IL-12 effects were associated with a 4-fold increase in STAT4 tyrosine-phosphorylation (0.071±0.026 vs. 0.018±0.004 in controls) and a 47% decrease in IRS1 protein levels (0.264±0.044 vs. 0.496±0.112 in controls) in the liver. Attenuated liver IL-12 level was further associated with improved hepatic insulin action in diet-induced obese mice with conditional loss of IFNγ signaling in myeloid cells. CONCLUSION: Our findings identify IL-12 as a novel cytokine regulating obesity-mediated insulin resistance and inflammation in the liver and a potential therapeutic target to treat NAFLD.