Prader-Willi Syndrome is a disorder characterized by numerous medical conditions, including excessive eating, low metabolic rate, growth hormone deficiency, hypogonadism and various cognitive deficits. In fact, obese individuals with PWS are described as having a nearly constant state of hunger, which manifests in various maladaptive feeding behaviors including binge eating, food hoarding, foraging for food and ingestion of inedible substances. The severe obesity that results from the overeating and slow metabolism is considered to be the most significant health problem of PWS and also is one of the most difficult-to-control features of the syndrome. One proposed explanation for the obesity and excessive eating is massive elevation of plasma levels of the stomach-derived hormone ghrelin. Several studies have demonstrated high ghrelin levels in obese individuals with PWS. This is relevant because ghrelin can potently stimulate food intake, decrease metabolic rate, and cause obesity when its levels are chronically elevated. A role for ghrelin in the debilitating food-seeking behaviors associated with PWS has become even more plausible given a few recent studies suggesting that at least some of ghrelin's effects on body weight may involve direct interaction with an area of the brain that more traditionally has been associated with reward-seeking behaviors aimed at obtaining drugs of abuse. The experiments offered in this application are designed to further elucidate the interaction of ghrelin with the dopamine-containing neurons located within this important brain site. We hypothesize that ghrelin does engage these neurons, resulting in a set of behaviors that motivates us to obtain food. Furthermore, we hypothesize that expression of ghrelin's receptor within these neurons is sufficient for the usual food-seeking and metabolic responses to ghrelin. It is hoped that these studies will allow us to directly link the massively elevated ghrelin levels found in PWS individuals with their extreme food-seeking behavior.
Research Outcomes: Project Summary
Our preliminary results seem to indicate that genetic blockade of ghrelin signaling decreases motivation to obtain food rewards, and furthermore that restricting expression of ghrelin receptors to a certain group of catacholaminergic neurons, including the dopamine neurons of the midbrain reward circuitry is sufficient to partially restore normal orexigenic responses to ghrelin. Finally, we conclusively described a new role for ghrelin in mediating antidepressant and anxiolytic-like responses and some of the usual defensive behavioral responses to chronic stress. Our preliminary data supports a role for ghrelin in the extreme food-seeking, motivated behaviors characteristic of PWS, and furthermore supports our hypothesis that ghrelin utilizes midbrain dopaminergic reward pathways originating in the VTA to induce food intake. Our more conclusive data on stress may be relevant in the psychopathology associated with PWS and may be relevant to potential future therapies for PWS which target ghrelin signaling.
Research Outcomes: Publications
Ghrelin mediates stress- induced food-reward behavior in mice. Chuang JC, Perello M, Sakata I, Osborne-Lawrence S, Savitt JM, Lutter M, Zigman JM. Journal of Clinical Investigation. 2011 Jul 1;121(7):2684-92.
Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner. Perello M, Sakata I, Birnbaum S, Chuang JC, Osborne-Lawrence S, Rovinsky SA, Woloszyn J, Yanagisawa M, Lutter M, Zigman JM. Biological Psychiatry 67:880-6, 2010.
The orexigenic hormone ghrelin defends against depressive symptoms in chronic stress. Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, Birnbaum S, Yanagisawa M, Elmquist JK, Nestler EJ, Zigman JM. Nature Neuroscience. 11:7530753, 2008.
Jeffrey Zigman, MD, PhD
University of Texas Southwestern Medical Center