Mapping the Neural Mechanisms by which Leptin Regulates Distinct Physiological Functions.

Abstract

Body fat stores are essential to provide energy for physiological functions. When body adiposity is extremely low (as in starvation, lipodystrophy and anorexia), energy-sparing changes in physiological functions are executed that may lead to problems such as: hypothalamic amenorrhea, suppressed thyroid function, and cold intolerance. Leptin is an adipocyte hormone secreted in proportion to body adiposity to maintain energy homeostasis by suppressing feeding and promoting energy expenditure. Leptin binds to its receptor, LepRb, to control feeding and other physiological processes such as growth and reproduction. Populations of LepRb neurons are dispersed throughout the brain. While the connectivity of the hypothalamic arcuate nucleus (ARC) is well-characterized, much less is known about the neurocircuitry of other LepRb-containing loci, which has deterred understanding of their contribution to physiology. In this study, we examined specific LepRb-expressing populations and their connectivity with distinct neural targets that control unique physiological processes. Using novel tract tracing tools to selectively study LepRb circuitry, we first examined LepRb neurons in the lateral hypothalamic area (LHA) and showed direct innervation of dopamine (DA)-containing neurons of the VTA, a core component of the mesolimbic DA system that controls hedonic reward. LHA LepRb populations also synapsed with LHA neurons that express the appetite-inducing neuropeptide orexin (OX), which innervate the mesolimbic DA system. Furthermore, leptin action on LHA LepRb neurons activated neurons in the VTA and upregulated OX expression in the LHA. We additionally investigated the LepRb pathways involved with the control of reproduction, focusing on populations that express GnRH and those that express kisspeptin (also called Kiss1). We determined that while LepRb neurons synapse with Kiss1 populations in both the ARC and AVPV nuclei, only the ARC population innervated GnRH neurons and was regulated by leptin, suggesting that ARC-Kiss1 neurons are the main conduit for the leptin-regulation of the hypothalamic reproductive system in the mouse. Furthermore, LepRb neurons in the PMv directly synapse with GnRH neurons to presumably control reproduction. Taken together, understanding the regulation of these distinct LepRb neuronal pathways by leptin leads to the overall understanding of how changes in energy homeostasis may influence whole body physiology.Ph.D.Molecular and Integrative PhysiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/77675/1/glouis_1.pd