The epidemics of obesity and diabetes represent a public health emergency. We must understand the mechanisms that link energy balance and glucose homeostasis, as these may represent potential therapeutic targets. In this proposal, entitled, "A leptin-regulated neural pathway that modulates the counter-regulatory response," we will analyze novel leptin receptor (LepRb)-expressing neural pathways in the brainstem lateral parabrachial (lPBN) and periaqueductal grey (PAG) nuclei. Together, these regions contain the majority of brainstem LepRb neurons;each contains numbers of LepRb neurons similar to those found in major hypothalamic nuclei. The projections from lPBN and PAG LepRb cells (along with their activation by physiologic stressors such as hypoglycemia and discomfort) suggest the importance of these neurons in modulating the counter-regulatory response. Indeed, ablation of LepRb in a subpopulation of lPBN and PAG LepRb neurons enhances the counter-regulatory response to glucoprivic and noxious stimuli, suggesting that leptin acts on these brainstem LepRb cells to restrain the counter-regulatory response. In this application, we will employ a variety of cre-dependent viral and genetic systems to understand the function, importance, and mechanisms of action of these brainstem LepRb neurons. These studies reveal the mechanisms by which leptin acts in the brainstem to contribute to overall leptin action and aspects of neural function that are crucial for glucose homeostasis. This information will in turn lay the groundwork for understanding mechanisms that modulate glycemic control, which is crucial as we seek to determine the pathogenesis of, and potential therapeutic targets for the twin epidemics of obesity and diabetes.

Public Health Relevance

The ongoing twin epidemics of obesity and diabetes in the United States represent a public health emergency that remains unchecked and without adequate therapy. To design specific treatments to prevent and treat these disorders, we must first understand the mechanisms that regulate energy balance and glucose homeostasis. In this proposal, we will determine the function and mechanisms of action for novel leptin- regulated neural pathways that contribute to the counter-regulatory response and glycemic control, and which represent potential therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK098853-01A1
Application #
8652155
Study Section
Special Emphasis Panel (ZRG1-EMNR-E (04))
Program Officer
Hyde, James F
Project Start
2013-12-17
Project End
2017-11-30
Budget Start
2013-12-17
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$338,213
Indirect Cost
$120,713
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Allison, Margaret B; Myers Jr, Martin G (2014) 20 years of leptin: connecting leptin signaling to biological function. J Endocrinol 223:T25-35