Forebrain Proenkaphalin Neurons Regulate Feeding

Baylor College Of Medicine, Houston TX

Investigators

Abstract

The prevalence of obesity has substantially increased since the 1950s. Obesity is primarily a consequence of the consumption of more food than the body requires. For some individuals, eating is primarily driven by hunger (homeostatic feeding) whereas others overeat in the absence of hunger to pursue the hedonic value of foods (hedonic feeding). While numerous neural populations can regulate homeostatic feeding and/or hedonic feeding, these regulations are usually unidirectional, either increasing or decreasing these two types of feeding. Here we found that GABAergic proenkephalin (Penk) neurons in the diagonal band of Broca (DBBPenk neurons) promote homeostatic feeding but suppress hedonic feeding, a “Healthy Eating” behavior that can ensure sufficient nutrition and at the same time avoid obesity. This striking finding led to a general hypothesis that DBBPenk neurons promote homeostatic feeding and suppress hedonic feeding through segregated downstream circuits. The first objective is to determine whether the DBBPenk to the paraventricular hypothalamus (PVH) circuit promotes homeostatic feeding. We will use both activation and ablation models to establish the function of the DBBPenkPVH circuit on feeding behavior when mice are provided with a free choice of the regular chow diet or high-fat high-sugar diet. We will examine effects of this circuit on animals’ feeding and valence behaviors at hungry or sated condition, in the anxiogenic or safe environment. We will also reveal the detailed neurotransmission of the DBBPenkPVH synapse as the neurobiological basis for behavior. The second objective is to use similar activation and ablation models to determine whether DBBPenk to the lateral hypothalamus (LH) circuit inhibits hedonic feeding. The third objective is to determine the physiological relevance of DBBPenk-originated circuits in feeding behavior and obesity development. We will test this possibility by examining the in vivo neural activity of these two distinct DBBPenk-originated circuits, as well as release of GABA and enkephalins (Penk cleavage peptides), in hungry or sated mice when challenged with various dietary/environmental conditions. In addition, we will compare these responses in lean vs. obese animals to explore the physiological relevance of the DBBPenk-originated circuits in obesity development. Completion of the proposed research will identify novel neural circuits that regulate feeding and body weight balance, and provide the necessary framework to develop therapeutic strategies towards treating obesity. .