The role of the midbrain dopaminergic reward circuitry in ghrelin's effects on food intake and body weight
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 ghrelinâ€™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 ghrelinâ€™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.
The mission of FPWR is to eliminate the challenges of Prader-Willi syndrome through the advancement of research. High-quality research will lead to more effective treatments and an eventual cure for this disorder. By working together, we intend to free our loved ones from the burdens of PWS, allowing them to lead full and independent lives.
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