Leptin’s role on autonomic innervation plasticity in organs regulating energy balance

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Project Summary Obesity is a major challenge for public health that predisposes individuals for metabolic diseases such as diabetes. It arises because of a dysregulation in homeostatic maintenance of energy balance, resulting in excess intake/storage relative to expenditure. By driving the storage of energy into white fat via parasympathetic nerve driven release of the pancreatic hormone insulin, the autonomic nervous system plays a key regulatory role in energy homeostasis. It also drives the expending of energy from fat by activation of the sympathetic nervous system. The adipose hormone leptin orchestrates the communication between the nervous system and energy storage organ, fat, that is necessary for homeostatic maintenance of energy balance. Leptin was previously understood to do this by acting in a negative feedback loop with the brain to reduce fat mass via reduction of food intake and sympatho-excitatory effects on adipose. Surprisingly, we discovered that leptin also regulates plasticity in levels of sympathetic innervation inside of adipose tissue. These regulatory effects on the sympathetic nerve architecture innervating adipose has functional implications for energy regulation by both white fat lipolysis and brown fat thermogenesis. While we have delineated the brain circuit controlling this process, the mechanisms that leptin uses to regulate adipose innervation plasticity, and whether this process occurs in other metabolic organs, is still unknown. In the mentored phase of this grant, I will pursue a mechanistic understanding of how leptin-dependent brain signals are translated into adipose sympathetic innervation plasticity. Specifically, I will dissect how activity of a pre-autonomic neural population, BDNF-expressing neurons in the paraventricular hypothalamus, dynamically regulates sympathetic innervation levels in adipose. Furthermore, to identify the molecular changes associated with plasticity in sympathetic ganglia innervating fat, I will develop a proximity protein tagging strategy to enrich these factors from nerves inside fat for quantitative proteomics. Finally, in the independent phase, I will explore the generality of leptin’s effects on autonomic innervation plasticity in organs beyond adipose tissue. Here, I will study the role of leptin on innervation plasticity in an organ important for energy storage, the pancreas, using the tools developed during the mentored part of this proposal. Altogether, this work will uncover the mechanisms by which leptin regulates the plasticity of autonomic innervation inside of adipose and the pancreas. Understanding these mechanisms will enable the identification of downstream targets which directly modulate autonomic innervation and their functional role in regulating energy balance, forming a foundation for new therapies to treat obesity and diabetes.