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.
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.
|Patterson, Christa M; Wong, Jenny-Marie T; Leinninger, Gina M et al. (2015) Ventral tegmental area neurotensin signaling links the lateral hypothalamus to locomotor activity and striatal dopamine efflux in male mice. Endocrinology 156:1692-700|
|Allison, Margaret B; Myers Jr, Martin G (2014) 20 years of leptin: connecting leptin signaling to biological function. J Endocrinol 223:T25-35|
|Bergner, Annette J; Stamp, Lincon A; Gonsalvez, David G et al. (2014) Birthdating of myenteric neuron subtypes in the small intestine of the mouse. J Comp Neurol 522:514-27|
|Xu, Lu; Janssen, Donny; van der Knaap, Noortje et al. (2014) Integration of stress and leptin signaling by CART producing neurons in the rodent midbrain centrally projecting Edinger-Westphal nucleus. Front Neuroanat 8:8|
|Goforth, Paulette B; Leinninger, Gina M; Patterson, Christa M et al. (2014) Leptin acts via lateral hypothalamic area neurotensin neurons to inhibit orexin neurons by multiple GABA-independent mechanisms. J Neurosci 34:11405-15|
|Opland, Darren; Sutton, Amy; Woodworth, Hillary et al. (2013) Loss of neurotensin receptor-1 disrupts the control of the mesolimbic dopamine system by leptin and promotes hedonic feeding and obesity. Mol Metab 2:423-34|
|Kempadoo, Kimberly A; Tourino, Clara; Cho, Saemi L et al. (2013) Hypothalamic neurotensin projections promote reward by enhancing glutamate transmission in the VTA. J Neurosci 33:7618-26|
|Garfield, Alastair S; Patterson, Christa; Skora, Susanne et al. (2012) Neurochemical characterization of body weight-regulating leptin receptor neurons in the nucleus of the solitary tract. Endocrinology 153:4600-7|
|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|
|Louis, Gwendolyn W; Greenwald-Yarnell, Megan; Phillips, Rebecca et al. (2011) Molecular mapping of the neural pathways linking leptin to the neuroendocrine reproductive axis. Endocrinology 152:2302-10|
Showing the most recent 10 out of 26 publications