Adaptations of the Hypothalamic Arcuate Nucleus in Response to Exercise and Hunger

Abstract

The arcuate nucleus of the hypothalamus serves as a critical node for regulation of mammalian energy balance with the ability to sense the status of many organ systems and exert control over effector arms that potently regulate feeding behavior and energy expenditure. The goals of this dissertation were 1) To identify hypothalamic adaptations driven by exercise induced energy expenditure related to conferral of whole body health improvement and 2) To investigate synaptic adaptations that occur in AgRP/NPY neurons of the hypothalamus in response to hunger. Chronic ad libitum feeding on high fat diet induces energy surplus, while exercise increases energy expenditure. To investigate the role of exercise to offset the effects of energy surplus, 8 week-old male C57BL/6J mice were provided with 1) normal chow, 2) with western style high fat diet, or 3) with high fat diet and voluntary running wheel exercise training for 12 weeks. Exercise training decreased high fat diet induced adiposity by increased energy expenditure, without impacting caloric consumption. Along with changes to body composition, mice that exercised exhibited improved glucose clearance and skeletal muscle insulin sensitivity paired with reduced liver lipid accumulation and less adipose tissue expansion than their sedentary counterparts. These peripheral adaptations occur in concordance with improved hypothalamic leptin sensitivity and reduced pro-opiomelanocortin neuronal apoptosis. On the other hand, short term energy deficit induced by an overnight fast elicits activation of hypothalamic AgRP/NPY neurons to drive feeding behavior. Many hormonal and neuronal inputs contribute to the activation of AgRP/NPY neurons, including release of the excitatory neurotransmitter glutamate. Therefore, we investigated the influence of fasting on synaptic integration of glutamate by metabotropic glutamate receptor 1 (mGluR1) on AgRP/NPY neurons. Fasting enhances function of mGluR1 to increase excitability of AgRP/NPY neurons, while loss of mGluR1 function reduces AgRP/NPY neuronal firing and reduces feeding behavior. Perturbation of hypothalamic action by intake/expenditure components of energy balance provides insight into mechanisms that can be leveraged for many disease states, including obesity and diabetes. Taken together, these discoveries elucidate adaptations of the arcuate nucleus hypothalamus to support its role as a critical node involved in maintenance of energy balance in the mammalian biological system.