Molecular and Neural Mechanisms of Leptin Action

Abstract Currently, obesity afflicts almost 40% of adult Americans, predisposing these people to diabetes and other diseases that reduce their quality of life and longevity and costing the US health care system over $150 billion/year. Unfortunately, our incomplete understanding of the processes that control energy balance continues to impede the design of new medical therapies to prevent and treat obesity. Leptin acts via its receptor (LepRb) on specialized hypothalamic neurons to control food intake, energy expenditure, and other aspects of energy balance-related neuroendocrine function and behavior. Understanding how leptin modulates LepRb neurons and how these neurons control energy balance (thereby identifying processes that may be targeted for the therapy of obesity) represent the long-term goals of our previous and proposed studies under this project (DK056731). In addition to our other work under this award, we determined roles in energy balance and metabolism for specific groups of LepRb neurons, revealing the importance of previously unidentified sets of LepRb neurons. We therefor used single-nucleus RNA-seq (snRNA-seq) and unbiased clustering to identify transcriptionally-defined groups of hypothalamic LepRb neurons (LepRb populations). This analysis identified previously-described (e.g., LepRbAgRP and LepRbPOMC) and novel (e.g., LepRbGlp1r and LepRbPirt) LepRb populations. Using new molecular tools that we have developed, we now propose to study several novel LepRb T- types, including DMH LepRbGlp1r neurons and ARC LepRbPirt cells. We hypothesize that leptin activates GABAergic LepRbGlp1r neurons, inhibiting downstream ARC AgRP cells to restrain food intake and body weight. We also postulate that leptin inhibits GABAergic LepRbPirt cells to activate specific endocrine axes. We propose to: Aim 1. Understand the regulation of individual LepRb populations; Aim 2. Determine the downstream targets and effects of individual LepRb populations; and Aim 3. Define physiologic roles for individual LepRb populations, including in leptin action. In addition to providing insight into the neural circuits and processes that modulate the control of food intake, energy expenditure, and neuroendocrine function, these studies may identify novel targets for therapeutic intervention in obesity and other metabolic diseases.