To understand the etiology of metabolic disorders, including obesity and type II diabetes, it is essential that we gain better insight into how stored and available energy sources are monitored by the central nervous system. In particular, a comprehension of the fine cellular interplay and intracellular mechanisms that enable appropriate hypothalamic and consequent endocrine and behavioral responses to both circulating hormonal and nutrient signals remains elusive. Recent data, including those from our laboratories (Andrews et al., 2008;Benani et al., 2007;Anderson et al., 2009;Jaillard et al., 2009;Campanucci et al., 2010;Diano et al., 2011) raised the notion that ROS generation is not merely a by-product of substrate oxidation, but it plays a crucial role in modulating cellular responses involved in the regulation of energy metabolism. We have observed that suppression of ROS levels diminish pro-opiomelanocortin (POMC) cell activation and promote the activity of neuropeptide Y- (NPY)/ agouti related peptide- (AgRP) neurons and feeding, whereas ROS activates POMC neurons and reduces feeding. We found that ROS levels in POMC neurons are positively correlated with leptin levels in lean and ob/ob animals, a relationship that is diminished in diet-induced obese (DIO) mice. Furthermore, high fat feeding resulted in hypothalamic proliferation of peroxisomes and elevated PPAR mRNA levels. Peroxisome proliferation in POMC neurons by the PPAR agonist, rosiglitazone, decreases ROS levels and increases food intake in lean mice on high fat diet. On the other hand, suppression of peroxisome proliferation in the hypothalamus by the PPAR antagonist, GW9662, increases ROS and c-fos expression in POMC neurons, reversed high fat feeding-triggered elevated NPY/AgRP and low POMC neuronal firing, and, resulted in decreased feeding of DIO mice. Intriguingly, central administration of ROS alone increased c-fos and pStat3 expression in POMC neurons and reduced feeding of DIO animals. Taken together these observations gave impetus to the central hypothesis of this application, which is that peroxisome proliferation governed by PPAR in the hypothalamic leptin-targeted neurons confers to cellular leptin resistance. The following specific aims are proposed to test our hypotheses:
SPECIFIC AIM 1 to determine the effect of ablation of leptin receptors selectively in AgRP or POMC neurons on high fat diet-induced peroxisome proliferation and impaired hypothalamic neuronal activity.
SPECIFIC AIM 2 To assess the effect of selective ablation of PPARgamma in POMC-, AgRP- and leptin receptor -expressing neurons on hypothalamic circuit activity and metabolic phenotype development of mice on standard chow and high fat diet. Understanding hypothalamic sub-cellular mechanisms that underlie cellular and behavioral responses to metabolic alterations will enhance the potential to develop better strategies to combat metabolic disorders, including obesity and diabetes.

Public Health Relevance

This proposal aims to investigate signaling modality connecting specific neuronal function and associated feeding behavior. Successful completion of these studies will deliver new drug targets for metabolic disorders, including obesity and type 2 diabetes. To understand the etiology of metabolic disorders, including obesity and type II diabetes, it is essential that we gain better insight into cellular mechanisms used by the central nervous system to monitor circulating signals and to respond appropriately. One of the remaining enigmas is the mechanism that determines leptin resistance in diet-induced obesity. To date, the neurobiological substrate of leptin resistance, a mechanism that entails the inability of increased leptin levels to promote a decreased feeding and body weight in diet- induced obese subjects remains elusive. Thus, the understanding of these hypothalamic cellular mechanisms is important and will lead to the development of better strategies to combat metabolic disorders, including obesity and diabetes.

National Institute of Health (NIH)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
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Yale University
Obstetrics & Gynecology
Schools of Medicine
New Haven
United States
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