8449 A Chronic Treatment of Interleukin-12 Restores Diet-Induced Hepatic Insulin Resistance and Liver Fibrosis in Mice with Interferon-gamma Signaling Deficient Macrophages

Abstract Disclosure: S.D. Rao: None. B. Kim: None. B. Kim: None. K. Kasina: None. E. Narouz: None. L.A. Tauer: None. X. Hu: None. J.K. Kim: Advisory Board Member; Self; Elevian. Inflammation and insulin resistance play a major role in metabolic dysfunction-associated steatotic liver disease, and macrophages and their release of cytokines modulate the underlying pathogenesis. We have recently found that mice with interferon-γ (IFNγ) signaling-deficient macrophages (Lyz-IFNγR2 KO) are protected from diet-induced insulin resistance in the liver and further rescued from developing liver fibrosis following NASH diets. Here, we examined the role of interleukin-12 (IL-12) as a macrophage-derived pro-inflammatory cytokine mediating the effects of macrophage IFNγ signaling on liver pathology. Mouse recombinant IL-12 (0.05 ng/hour/g body weight) was chronically administered via subcutaneously implanted osmotic pumps for 2 weeks in male Lyz-IFNγR2 KO and wild-type (WT) mice after 10 weeks of a high-fat diet (HFD) (n=3∼4/group). A 2-hour hyperinsulinemic-euglycemic clamp with 3H-glucose and [1]4C-2-deoxyglucose was performed to measure insulin action and glucose metabolism in mice. A chronic IL-12 treatment caused hyperglycemia (179±15 mg/dl) and insulin resistance in the liver with 30.6±15.7% suppression of hepatic glucose production (HGP) during insulin clamps in HFD-fed WT mice. IL-12 treatment also restored hyperglycemia and hepatic insulin resistance in HFD-fed Lyz-IFNγR2 KO mice with 45.3±21.2% suppression of HGP during insulin clamps. This is in stark contrast to euglycemia (145±5 mg/dl) and 77.3±9.7% suppression of HGP during insulin clamps in HFD-fed Lyz-IFNγR2 KO mice that were protected from diet-induced insulin resistance in the liver. Next, mouse recombinant IL-12 was chronically administered for 2 weeks in male Lyz-IFNγR2 KO and WT mice after 8 weeks of a Gubra Amylin NASH (GAN) diet (n=4∼6/group). Using a 3D-ultrasound imaging system, we found that IL12-treated WT mice developed fatty liver (54.3±3.9 counts in brightness) and fibrosis (4.8±0.4 kPa in Young’s Modulus) after the GAN diet. Similarly, IL12-treated Lyz-IFNγR2 KO mice developed fatty liver (53.8±7.7 counts) and fibrosis (4.9±0.7 kPa) after the GAN diet. Histological analysis of liver samples from both groups of mice further confirmed fibrosis and lipid droplets after IL-12 treatment. Overall, these results showed that a chronic IL-12 treatment restored diet-induced hepatic insulin resistance and liver fibrosis after GAN diet in Lyz-IFNγR2 KO mice, indicating a critical role for IL-12 as a macrophage-derived cytokine and downstream effector of IFNγ signaling in mediating metabolic liver disease. Presentation: 6/1/2024