Angiotensin Type 1a Receptors (AT 1a R) in the Forebrain Subfornical Organ (SFO) Protect Against High Fat Diet (HFD)‐Induced Hepatic Steatosis

Brain angiotensin II (Ang‐II), signaling through AT 1a R, is a key player in metabolic regulation. We recently showed a role for the central nervous system (CNS) in HFD‐induced hepatic steatosis, a hallmark of the metabolic syndrome. Since the role of brain Ang‐II in this pathology is unknown, we tested the hypothesis that CNS AT 1a R protect against hepatic steatosis during HFD. C57 mice were fed HFD for 20 wks and were then implanted with ICV cannulae for CNS delivery of the AT 1 R blocker losartan or vehicle control. Daily ICV treatment with losartan (3 days) exacerbated HFD‐induced hepatomegaly (1.4±0.1 vs 1.9±0.1 g, vehicle vs losartan, p<0.05) and liver triglyceride accumulation (531±70 vs 630±17 mg/dl, p=0.09), with no changes in body weight, food intake, or adiposity. To examine the CNS regions involved we focused on the SFO, a circumventricular area dense with AT 1a R and emerging as a metabolic control center. AT 1a flox mice underwent SFO‐targeted delivery of an adenovirus encoding Cre‐recombinase for selective deletion of AT 1a Ror control vector (n=4‐5). SFO‐AT 1a R deletion did not influence increases in body weight, food intake, or adiposity to HFD feeding. However, histological examination revealed exaggerated hepatic lipid accumulation in SFO‐AT 1a R ablated mice compared to controls (2.5±1.0 7 vs 0.3±0.8 7 au, p<0.05, Fig). These findings reveal a novel role for AT 1a R, particularly within the SFO, in the development of hepatic steatosis during HFD. Targeting CNS AT 1a R may provide a new therapeutic approach for this disease. HL63887, HL84207, K99HL166776