One third of U.S. adults are obese and at risk to develop type-2 diabetes, yet few effective treatments exist to promote healthy body weight. Improved understanding of the physiologic mechanisms that control energy balance is needed to develop treatments for obesity. Neurons in the lateral hypothalamic area (LHA) of the brain exert opposing control of feeding and energy balance by engaging dopamine (DA) neurons in the ventral tegmental area (VTA). DA release from the VTA regulates goal-driven physical activity and palatable food- seeking, behaviors that are disrupted in, and contribute to obesity. The Leinninger lab has begun to characterize a population of LHA neurons that expresses neurotensin (Nts), a neuropeptide that promotes DA release, suppresses feeding and increases locomotor activity. LHA Nts neurons project to the VTA, where many DA neurons express neurotensin receptor-1 (NtsR1). In contrast to other LHA neuronal sub-types that promote feeding, LHA Nts neurons respond to anorectic cues and are poised to suppress feeding. I therefore hypothesize that LHA Nts neurons engage the mesolimbic DA system to restrain food intake and increase physical activity, thus favoring negative energy balance.
In Aim 1, I will define the neuronal circuit by which Nts and NtsR1 neurons engage the DA system.
In Aim 2, I will selectively activate LHA Nts neurons to test the hypothesis that action via the LHA Nts neuronal circuit suppresses food intake and promotes locomotor activity to induce weight loss. Via my co-sponsors Dr. Gina Leinninger and Dr. Cheryl Sisk, I will learn to combine novel genetic reagents, pharmacogenetics, metabolic phenotyping and neurobehavioral paradigms to determine the role of the LHA Nts neuronal circuit in energy balance. Training in these state-of- the-art techniques that bridge metabolism and neuroscience will enable me to complete this proposal and are essential skills to promote my development into a physician-scientist studying and treating obesity.

Public Health Relevance

Obesity is an increasing worldwide health problem, but limited understanding of the systems that regulate food intake and weight has hindered development of effective therapies for this disease. This proposal will investigate the mechanisms by which a unique group of neurons in the lateral hypothalamus regulate motivated feeding behavior, physical activity, and body weight. This work will add to our understanding of the development of obesity, and characterization of these neurons may suggest potential strategies to treat obesity and prevent co-morbid diseases. .

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DK107163-04
Application #
9482711
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Castle, Arthur
Project Start
2015-06-01
Project End
2020-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
4
Fiscal Year
2018
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
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
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
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