Circumventricular Organ-Hypothalamic Circuit Endoplasmic Reticulum Stress Drives Hepatic Steatosis During Obesity

Objective: Nonalcoholic fatty liver disease (NAFLD), characterized by excess liver triglyceride accumulation (hepatic steatosis), leads to an increased risk for cardiometabolic diseases and obesity-related mortality. Emerging evidence points to endoplasmic reticulum (ER) stress in the central nervous system as critical in NAFLD pathogenesis. Here, we tested the contribution of ER stress in a circumventricular organ-hypothalamic circuit in NAFLD development during obesity. Methods: C57BL/6J male mice were fed a high-fat diet (HFD) or normal chow. A combination of histological, viral tracing, intersectional viral targeting, and in vivo integrative physiological approaches were used to examine the role of ER stress in subfornical organ to hypothalamic paraventricular nucleus projecting neurons (SFOaPVN) in NAFLD during diet-induced obesity. Results: Immunohistochemical analysis revealed marked unfolded protein response activation in the SFO, particularly in excitatory SFOaPVN neurons of HFD-fed animals. Moreover, intersectional viral inhibition of ER stress in SFOaPVN neurons resulted in a reduction in hepatomegaly, hepatic steatosis, and a blunted increase in body weight gain during diet-induced obesity, independent of changes in food intake, substrate partitioning, energy expenditure, and ambulatory activity. Conclusions: These results indicate that ER stress in an SFOaPVN neural circuit contributes to hepatic steatosis during obesity.