Neuroendocrine Regulation of Adipocyte Metabolism

University Of Cincinnati, Cincinnati OH

Investigators

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Abstract

DESCRIPTION (provided by applicant): Obesity with its complications - such as diabetes, cardiovascular diseases or cancer - poses one of the predominant health threats of our times. Several neuroendocrine circuits have been identified as regulators of adiposity. A better understanding of the relationship between these pathways and specific energy balance components is currently regarded as one of the most promising strategies toward identifying an efficient treatment for obesity. While substantial insight has been accumulated regarding the control of food intake, little is known about a direct CNS molecular control of cellular lipid storage. We recently observed potent and feeding-independent changes in white adipose tissue and liver triglyceride metabolism following direct and indirect inactivation or stimulation of the CNS melanocortin receptor system. To further dissect that phenomenon we combine neuropharmacology and genetic deletion studies with automated indirect calorimetry, insulin-glucose clamps, pair feeding models, and molecular biochemistry of lipid metabolism. Specifically we will combine nucleus specific microinjections in the rat central nervous system with virus mediated gene disruption and mutated mouse models to clarify which melanocortin receptor population in which CNS region modulates key components of peripheral triglyceride metabolism independent from food intake. Guided by these results we will test if those CNS melanocortin receptors employ downstream neuropeptides CRH/TRH and the efferent autonomic nervous system axis to control cellular lipid metabolism in liver and adipose tissue. For these studies we will use electrophysiology and molecular lipid biochemistry as well as a combination of pharmacological, surgical and genetic tools to site-specifically disrupt the efferent ANS. These studies will elucidate how the CNS melanocortin system remote controls the peripheral metabolic balance between lipid synthesis, lipid deposition and lipid mobilization.