Overfeeding and body weight regulation

Mammals resist large rapid changes in body weight. Studies dating back to at least the 1940?s show that forced increases or decreases in body weight elicit neuroendocrine responses favoring restoration of previous body mass. Despite the existence of a system that defends against weight gain, obesity has been on the rise for more than four decades suggesting that there are factors that can attenuate or alter this system, allowing, or even encouraging, weight gain to occur. This system that defends against weight gain is poorly defined due, in-part, to technical challenges impeding study of the overfed state in model organisms. Our lab has developed a novel intragastric feeding paradigm to induce rapid weight gain, making possible the study of the overfeeding in mice. Using this system, mice gain 25-40% of their initial body weight in 10-14 days. Consistent with body weight being defended, once overfeeding ceases, the mice lose weight until returning to their initial weight and adiposity. The 7-10 day return to initial body weight is caused, in large measure, by reduced feeding. After overfeeding is stopped, animals abstain from eating for 2-3 days and slowly increase intake until reaching their initial body weight. Characterizing the physiology and molecular components of this graded hypophagic response, we believe, will provide insights into regulation of body weight. This proposal focuses on one molecular component ? neurons implicated in anorexia, and one aspect of the physiology of overfeeding ? the ability of palatable food to alter caloric intake. Calcitonin-gene related peptide (CGRP) neurons in the parabrachial nucleus (PBN) have been implicated in anorexia and regulation of meal termination. We hypothesize that these neurons are required for overfeeding induced anorexia to occur. Aim 1 will test whether CGRP neurons in the PBN mediate overfeeding induced anorexia. If the hypothesis is correct, these studies will establish a neuronal pathway that defends against weight gain and will permit future studies to identify down- and up-stream pathways. If CGRP neurons are not required for overfeeding induced anorexia, we will have uncovered evidence for a distinct system that limits food intake. There is controversy about how macronutrients and palatability contribute to weight gain. Diets high in fat and/or sucrose increase weight in many rodent strains, but it remains unclear as to whether the obesogenic nature of these diets is due to palatability or to another, perhaps, metabolic aspect of their macronutrient content. Our overfeeding paradigm will permit us to explore how palatability, i.e. pregastric component of eating, modulates the defense against weight gain. Based on our preliminary data, we hypothesize that macronutrients associated with palatable diets will attenuate the response to overfeeding through a post-ingestive mechanism. Aim 2 will test how increased intake and weight gain on a preferred diet affect body weight defense in overfeeding and whether this requires tasting the diet or occurs via post-ingestive effects. Defining how palatable food alters feeding behavior will provide insights into factors that regulate body weight.