The paraventricular hypothalamus (PVH) is vital for energy balance regulation, as developmental or mechanical lesions targeting the PVH lead to massive obesity. We have shown that activation of PVH neurons expressing nitric oxide synthase-1 (Nos1PVH) suppresses food intake and increases energy expenditure. This differentiates these neurons from the well-studied melanocortin 4 receptor-expressing population (Mc4RPVH), as activation of Mc4RPVH neurons suppresses feeding but does not alter energy expenditure. In situ hybridization studies in our laboratory show that Mc4R and Nos1 mRNAs do not overlap in the PVH, suggesting that these cell populations may regulate energy balance independently. We hypothesize that the contributions of Nos1PVH neurons to maintaining metabolic homeostasis are independent of Mc4RPVH neurons. To test this hypothesis, we used established Nos1 and Mc4R Cre-expressing lines to create a Nos1Cre+Mc4RCre dual recombinase model. Then, we inactivated Nos1PVH and Mc4RPVH neurons alone or in combination. Several metabolic parameters were monitored for 8 weeks post-injection. These experiments allowed us to examine the interdependency of Nos1 and Mc4R PVH populations in energy balance control. Silencing the Nos1PVH population alone resulted in the acute onset of obesity without affecting feeding behavior. This phenotype was exacerbated when we simultaneously silenced both Nos1 and Mc4R PVH neurons. This suggests an additive interaction between the two groups; although a synergistic effect cannot be excluded. Future studies will focus on the effects of Nos1PVH inactivation on energy expenditure and defining theNos1 neurocircuitry that facilitates PVH-mediated metabolic regulation. Our overall goal is to unravel the cellular and neurobiological mechanisms engaged by Nos1PVH neurons and open new avenues for treating obesity.


L.D. Faulkner: None. I.E. Gonzalez: None. D. Olson: Research Support; Self; MedImmune, Inc, Novo Nordisk A/S. T.H. Meek: Employee; Self; Novo Nordisk Inc.

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