Control Of Energy Balance And Circadian Food Entrainment Via Neurons And Neurotrophin Receptors InThe Hypothalamus

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Podyma, Brandon, Neuroscience - School of Medicine, University of Virginia
Deppmann, Christopher, AS-Biology, University of Virginia
Guler, Ali, AS-Biology, University of Virginia

Obesity and associated metabolic disorders (e.g., type 2 diabetes) represent a growing health crisis. The most common treatment for obesity is to reduce caloric intake through dieting, however, this largely fails to sustain weight loss or decrease comorbidity risks. Why do diets so often fail? We now appreciate that long term calorie restriction leads to increased hunger drive, decreased body temperature, increased general activity, and eventually decreased utilization of peripheral energy stores. These adaptations pose a formidable barrier to lifestyle interventions as a sustainable treatment strategy for obesity. Our lack of knowledge related to the molecular and neural basis of homeostatic adaptation to energy deficit represents a significant barrier to progress. In part 1 of this dissertation, I explore the roles of hypothalamic neurotrophin receptors in regulating feeding and energy balance.
Circadian rhythms governed by the suprachiasmatic nucleus (SCN) control vital aspects of physiology including rest/activity cycles, body temperature, and metabolism, thereby maintaining proper energy homeostasis: perturbation of their rhythmicity predisposes individuals to metabolic syndrome. Indeed, mistimed energy-rich food consumption, even when isocaloric, leads to weight gain due to increased energy storage. These findings suggest that when we eat may be as important as what we eat, and serve as the basis for modern time-restricted-feeding (TRF) style diets. However, precisely how the SCN influences metabolic function, especially under conditions of scarcity such as TRF that depend on the circadian clock, is unclear. It has been known for nearly a century that food deprived animals fed at regular times develop a heightened period of activity which immediately precedes the presentation of food (food anticipatory activity, or FAA); this has subsequently been described as an indication of circadian entrainment to food availability. Strikingly, lesion of the SCN and knockouts of genes that drive circadian activity have demonstrated that known circadian machinery is not necessary for the generation of FAA, though it has been suggested that SCN activity may dampen its generation. Indeed there are very few known cellular and molecular contributors to FAA. In part 2, I explore how a satiety hormone interacts with hypothalamic circuits to control circadian regulation of feeding.

PHD (Doctor of Philosophy)
Hypothalamus, Neurotrophin, Circadian, Feeding
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