Neurons in the lateral hypothalamic area (LHA) exert opposing control of feeding and energy balance via incompletely understood neuronal circuits. Many LHA neurons express orexigenic neuropeptides and regulate limbic brain regions, including midbrain dopamine (DA) neurons, to induce hedonic feeding and promote weight gain. A separate population of LHA neurons expresses the anorectic neuropeptide neurotensin (Nts) and these LHA Nts neurons are selectively activated by stimuli that suppress feeding. Loss of action via LHA Nts neurons promotes overeating and blunts energy expenditure and DA signaling that leads to obesity, suggesting that LHA Nts neurons interface with DA circuits to regulate energy balance. Indeed, LHA Nts neurons synaptically regulate the midbrain, where many DA neurons express the receptors for neurotensin, neurotensin receptor-1 (NtsR1) and neurotensin receptor-2 (NtsR2). Nts acts via these receptors to activate DA neurons and suppress feeding, but loss of Nts action via NtsR1 promotes hedonic feeding and obesity. Collectively, these data implicate a novel LHA Nts neuronal circuit that synergizes anorectic cues and DA signaling to promote weight loss. To determine the mechanism(s) by which LHA Nts neurons regulate energy balance this proposal combines the use of novel genetic reagents and state of the art molecular tools to interrogate the constituent neurons within the LHA Nts neuronal circuit.
Aim 1 will establish the LHA Nts neuronal mechanisms that coordinate physiologic cues and behavior to adaptively regulate energy balance.
Aim 2 will determine how LHA Nts neurons interface with DA circuits, testing the hypothesis that Nts action via midbrain NtsR1 and/or NtsR2 neurons modulates DA signaling to regulate energy balance.
Aim 3 will selectively activate LHA Nts neurons to test the hypothesis that action via the LHA Nts neuronal circuit suppresses hedonic intake and promotes locomotor activity to induce weight loss. Collectively, these studies will determine the precise mechanisms by which LHA Nts neurons regulate DA- mediated feeding and energy expenditure, and the potential for modulation of this circuit in treating obesity.

Public Health Relevance

The obesity pandemic is propelled by individuals' overconsumption of palatable, calorie-dense foods and decreased physical activity. These studies will determine how a unique population of neurons in the lateral hypothalamic area of the brain promote physical activity and suppress feeding, including the hedonic 'craving' of palatable calorie-dense foods, to stimulate weight loss. Understanding the neuronal circuit by which these neurons regulate feeding and activity may suggest potential strategies to promote weight loss and treat obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK103808-04
Application #
9315804
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2014-09-15
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Michigan State University
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Woodworth, Hillary L; Brown, Juliette A; Batchelor, Hannah M et al. (2018) Determination of neurotensin projections to the ventral tegmental area in mice. Neuropeptides 68:57-74
Woodworth, Hillary L; Perez-Bonilla, Patricia A; Beekly, Bethany G et al. (2018) Identification of Neurotensin Receptor Expressing Cells in the Ventral Tegmental Area across the Lifespan. eNeuro 5:
Kurt, Gizem; Woodworth, Hillary L; Fowler, Sabrina et al. (2018) Activation of lateral hypothalamic area neurotensin-expressing neurons promotes drinking. Neuropharmacology :
Schroeder, Laura E; Leinninger, Gina M (2018) Role of central neurotensin in regulating feeding: Implications for the development and treatment of body weight disorders. Biochim Biophys Acta Mol Basis Dis 1864:900-916
Woodworth, Hillary L; Batchelor, Hannah M; Beekly, Bethany G et al. (2017) Neurotensin Receptor-1 Identifies a Subset of Ventral Tegmental Dopamine Neurons that Coordinates Energy Balance. Cell Rep 20:1881-1892
Woodworth, Hillary L; Beekly, Bethany G; Batchelor, Hannah M et al. (2017) Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms. Cell Rep 21:3116-3128
Brown, Juliette A; Bugescu, Raluca; Mayer, Thomas A et al. (2017) Loss of Action via Neurotensin-Leptin Receptor Neurons Disrupts Leptin and Ghrelin-Mediated Control of Energy Balance. Endocrinology 158:1271-1288
Brown, Juliette A; Woodworth, Hillary L; Leinninger, Gina M (2015) To ingest or rest? Specialized roles of lateral hypothalamic area neurons in coordinating energy balance. Front Syst Neurosci 9:9