1776-P: ROCK1 Deletion in Sim1-Expressing Neurons of the Hypothalamus Leads to Obesity Despite Hypophagia

The paraventricular nucleus of the hypothalamus (PVN) is a key site in the brain for regulating energy balance. ROCK1 has also been shown to be a major regulator of energy balance and metabolism in the hypothalamus, but its role in the PVN is still unclear. To explore this role, mice selectively lacking ROCK1 in single-minded homolog 1 gene (Sim1) neurons (Sim1-ROCK1^-/-), which are densely expressed in the PVN and in parts of the amygdala, were studied. ROCK1 deficiency in Sim1 expressing neurons leads to obesity on regular chow in male and female mice after 11-12 weeks. This effect is due to increased fat mass as assessed by EchoMRI and direct dissection of fat depots. Serum levels of insulin, leptin and free fatty acid in Sim1-ROCK1^-/- mice were markedly increased compared to control mice. Surprisingly, daily food intake in Sim1-ROCK1^-/- mice were significantly decreased compared with control mice. Moreover, the ability of melanocortin to decrease food intake was impaired when ROCK1 was deleted from Sim1-expressing neurons. No differences in O₂ consumption and CO₂ production measured by the Comprehensive Lab Animal Monitoring System (CLAMS) were found between obese and lean mice with or without ROCK1 deletion. These data identify ROCK1 as an important mediator of energy balance in the PVN, which leads to a paradoxical obese/hypophagic phenotype. The underlying mechanisms for the divergence in obesity, energy expenditure and caloric intake are being further explored in our lab.