The neurogenetics of energy balance

Abstract

Energy balance is tightly controlled in humans and other animals: perturbations that increase or decrease energy (fat) stores provoke countervening responses to restore adiposity to baseline. Changes in energy expenditure, whether at the level of basal metabolic rate or activity, generally impact energy balance only modestly due to compensatory changes in feeding. Thus, alterations in systems that modulate food intake relative to energy expenditure, rather than systems that regulate energy utilization alone, dominate in the control of adiposity. Genetic perturbations that alter body weight, both in animal models and in human patients and populations have aided in the identification and study of the systems that control energy balance. The genetic causes of obesity for which we have a rudimentary understanding of underlying mechanism fall within the CNS, and many of these lesions lie in genes important to the function of crucial hypothalamic circuits that control feeding. Others encode more general modulators of neurophysiology that impact feeding systems in addition to other neural circuits. From the standpoint of neural mechanism, however, a great many genetic lesions associated with altered energy balance remain incompletely understood. Understanding the neural systems impacted by these genetic alterations will not only reveal the physiologic underpinnings of energy homeostasis, but may also identify targets for therapeutic intervention.