Central Regulation of Peripheral Adiposity by Nos1PVHNeurons

Within the CNS, the paraventricular nucleus of the hypothalamus (PVH) is critical for energy homeostasis, as developmental or mechanical lesions targeting the PVH lead to massive obesity. The PVH is composed of multiple cell types expressing an assortment of neuropeptides, receptors, and enzymes, including a subset of neurons expressing nitric oxide synthase-1 (Nos1PVH) . Nos1PVH neurons project to the nucleus of the solitary tract and the intermediolateral column of the spinal cord suggesting a neural substrate through which Nos1PVH neurons might directly modulate sympathetic output and energy balance [1]. To understand the necessity of Nos1PVH neurons in basal energy balance regulation, we bilaterally injected the PVH of Nos1-iCre mice with an AAV expressing a Cre-dependent tetanus toxin (Nos1TT) . Chronic silencing of the Nos1PVH resulted in acute onset of subcutaneous and visceral obesity without changes in food intake. Surprisingly, metabolic analyses indicated no significant changes in energy expenditure, although Nos1TT treated animals preferred to utilize fat as the predominant fuel source. Pair feeding experiments also confirmed that the obesity observed in Nos1TT animals was not secondary to increased caloric intake. Adipose tissues receive input from CNS cell groups that are part of the general SNS outflow from the brain [2, 3]. Analysis of subcutaneous white adipose tissue of Nos1TT animals revealed a significant decrease in tyrosine hydroxylase (TH) immunoactivity within WAT suggesting decreased capacity for sympathetic activation of lipolysis. These data indicate that Nos1PVH neurons regulate energy homeostasis possibly through changes in peripheral aspects of energy balance without the influence of energy consumption. Therefore, the main goal of this project is to clarify the physiological roles of Nos1PVH neurons in the regulation of peripheral adiposity, which may lead to the development of more refined anti-obesity therapies. 1. PMID: 25392498 2. PMID: 9688991 3. PMID: 15142857 Disclosure L. D. Faulkner: n/a. K. Lewis: None. T. H. Meek: Employee; Novo Nordisk. A. J. Mercer: Employee; Novo Nordisk. O. A. Macdougald: None. D. Olson: Research Support; AstraZeneca, Novo Nordisk A/S. Funding American Diabetes Association (7-21-PMF-020) ; Novo Nordisk A/S; National Institutes of Health (5R01DK104999-05)