The ongoing epidemic of obesity in the United States represents a public health emergency that remains unchecked and without specific therapy. To design specific treatments to prevent and treat obesity, we must first understand the mechanisms that regulate feeding and energy expenditure in order to identify potential therapeutic targets. In this proposal, entitled, "Role of the lateral hypothalamic area in leptin action," we will analyze leptin-regulated neural pathways in the lateral hypothalamic area (LHA) that contribute to body energy homeostasis, incentive, and activity. During the previous funding period, we developed and utilized genetic mouse models to demonstrate that LHA LepRb neurons directly innervate OX neurons and the VTA, and are required to modulate orexin action, the mesolimbic DA system and energy balance (in addition to analyzing some related leptin-regulated neural circuitry). In this renewal application, we will employ existing and novel genetic systems to understand the sufficiency of this circuit for a variety of parameters. We will also understand distinct and overlapping roles for subpopulations of LHA LepRb neurons for the control of orexin, the midbrain DA system, and feeding, as well as defining the circuits and neural mechanisms underlying the regulation of these important processes. These studies will enable us to understand the mechanisms by which the LHA leptin action contributes to overall leptin action, energy balance, and aspects of neural function that are crucial for hedonically-driven overeating. This information will in turn lay the groundwork for understanding mechanisms by which feeding may be regulated, which is crucial as we seek to determine the pathogenesis of, and potential therapeutic targets for the ongoing epidemic of obesity.

Public Health Relevance

The ongoing epidemic of obesity in the United States represents a public health emergency that remains unchecked and without specific therapy. To design specific treatments to prevent and treat obesity, we must first understand the mechanisms that regulate feeding and energy expenditure in order to identify potential therapeutic targets. In this proposal, we will analyze novel lateral hypothalamic neural pathways in the brain that likely contribute to hedonic feeding and body energy homeostasis to define these mechanisms and the potential therapeutic targets that they represent.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DK078056-06A1
Application #
8720920
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Leinninger, Gina M; Opland, Darren M; Jo, Young-Hwan et al. (2011) Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Cell Metab 14:313-23
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Xu, Lu; Scheenen, Wim J J M; Leshan, Rebecca L et al. (2011) Leptin signaling modulates the activity of urocortin 1 neurons in the mouse nonpreganglionic Edinger-Westphal nucleus. Endocrinology 152:979-88
Grossberg, Aaron J; Zhu, XinXia; Leinninger, Gina M et al. (2011) Inflammation-induced lethargy is mediated by suppression of orexin neuron activity. J Neurosci 31:11376-86
Perry, Maura L; Leinninger, Gina M; Chen, Rong et al. (2010) Leptin promotes dopamine transporter and tyrosine hydroxylase activity in the nucleus accumbens of Sprague-Dawley rats. J Neurochem 114:666-74
Opland, Darren M; Leinninger, Gina M; Myers Jr, Martin G (2010) Modulation of the mesolimbic dopamine system by leptin. Brain Res 1350:65-70

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