Role of forebrain-hindbrain fatty acid sensing in energy homeostasis

Abstract

The incidence of obesity and type II diabetes (T2DM) have reached epidemic levels in the United States and worldwide. These illnesses are characterized by pathological imbalances in nutrient availability and nutrient utilization. Energy balance requires the detection, processing, and integration of multiple peripheral signals by the central nervous system (CNS) to mediate physiologic and behavioral metabolic outcomes. In overweight or obese individuals, this network may be impaired, such that the CNS is unable to mount proper energy regulatory responses, and may promote the development of further deleterious metabolic consequences. Characterization of the CNS responses to nutrients in obesity has the potential to reveal novel targets for prevention and treatment of this growing disorder.;The hypothalamus and brainstem are two major CNS regions engaged in the control of two key effectors of energy homeostasis: feeding and glucose metabolism. Hypothalamic and brainstem neurons respond to signals reflecting whole body energy status, including nutrients, neuropeptides, and hormones. Fat, the most energy dense nutrient, plays a key role in signaling under conditions of nutrient excess, as it is palatable, overconsumed, and often increased in the plasma and tissue of overweight and obese people. Long chain fatty acids (LCFA) in particular have been shown to be important signaling molecules for the CNS control of energy metabolism and homeostasis (Obici et al., 2002a) 1.;This thesis work explores the role of LCFA in the nutrient sensing pathways of the hypothalamus and brainstem. First, we determine whether exogenous infusion of different LCFA to specific hypothalamic nuclei have equivalent effects on HGP. Next, we consider whether increasing endogenous concentrations of LCFA by blocking an enzyme involved in their metabolism in a small area of the brainstem recapitulates the suppression of food intake and HGP. Finally, we investigate downstream effectors within the cells of the hypothalamus to understand more about what other molecules and enzymes are involved in the biochemical signaling pathways that regulate peripheral energy homeostasis and metabolism.;1Obici, S., Feng, Z., Morgan, K., Stein, D., Karkanias, G., and Rossetti, L. 2002. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51:271-275.