Obesity with its complications - such as diabetes, cardiovascular diseases or cancer - poses one of the predominant health threats of our times. Several neuroendocrine circuits have been identified as regulators of adiposity. A better understanding of the relationship between these pathways and specific energy balance components is currently regarded as one of the most promising strategies toward identifying an efficient treatment for obesity. While substantial insight has been accumulated regarding the control of food intake, little is known about a direct CNS molecular control of cellular lipid storage. We recently observed potent and feeding-independent changes in white adipose tissue and liver triglyceride metabolism following direct and indirect inactivation or stimulation of the CNS melanocortin receptor system. To further dissect that phenomenon we combine neuropharmacology and genetic deletion studies with automated indirect calorimetry, insulin-glucose clamps, pair feeding models, and molecular biochemistry of lipid metabolism. Specifically we will combine nucleus specific microinjections in the rat central nervous system with virus mediated gene disruption and mutated mouse models to clarify which melanocortin receptor population in which CNS region modulates key components of peripheral triglyceride metabolism independent from food intake. Guided by these results we will test if those CNS melanocortin receptors employ downstream neuropeptides CRH/TRH and the efferent autonomic nervous system axis to control cellular lipid metabolism in liver and adipose tissue. For these studies we will use electrophysiology and molecular lipid biochemistry as well as a combination of pharmacological, surgical and genetic tools to site-specifically disrupt the efferent ANS. These studies will elucidate how the CNS melanocortin system """"""""remote"""""""" controls the peripheral metabolic balance between lipid synthesis, lipid deposition and lipid mobilization.

Public Health Relevance

Obesity with its complications - such as diabetes, cardiovascular diseases or cancer - poses one of the most important health threats of our times, while efficient drugs for the cure from obesity need to be discovered. Recent results from experiments in our laboratory indicate that one of the major brain networks known to regulate body weight, the so called """"""""melanocortin system"""""""", directly communicates with fat cells and the liver in order to regulate the amount of fat deposited in these important organs. We will perform a series of experiments to clarify which neuronal and hormonal systems are used for this kind of communication and, based on that knowledge, develop new strategies for the prevention and treatment of obesity and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077975-04
Application #
8231459
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2009-01-15
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$333,018
Indirect Cost
$113,930
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Heppner, Kristy M; Marks, Sarah; Holland, Jenna et al. (2015) Contribution of brown adipose tissue activity to the control of energy balance by GLP-1 receptor signalling in mice. Diabetologia 58:2124-32
Ottaway, Nickki; Mahbod, Parinaz; Rivero, Belen et al. (2015) Diet-induced obese mice retain endogenous leptin action. Cell Metab 21:877-82
Trivedi, Chitrang; Shan, Xiaoye; Tung, Yi-Chun Loraine et al. (2015) Tachykinin-1 in the central nervous system regulates adiposity in rodents. Endocrinology 156:1714-23
Heppner, Kristy M; Piechowski, Carolin L; Muller, Anne et al. (2014) Both acyl and des-acyl ghrelin regulate adiposity and glucose metabolism via central nervous system ghrelin receptors. Diabetes 63:122-31
Habegger, Kirk M; Heppner, Kristy M; Amburgy, Sarah E et al. (2014) GLP-1R responsiveness predicts individual gastric bypass efficacy on glucose tolerance in rats. Diabetes 63:505-13
Habegger, Kirk M; Al-Massadi, Omar; Heppner, Kristy M et al. (2014) Duodenal nutrient exclusion improves metabolic syndrome and stimulates villus hyperplasia. Gut 63:1238-46
Gadang, Vidya; Kohli, Rohit; Myronovych, Andriy et al. (2013) MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet. Am J Physiol Endocrinol Metab 305:E549-56
Habegger, Kirk M; Kirchner, Henriette; Yi, Chun-Xia et al. (2013) GLP-1R agonism enhances adjustable gastric banding in diet-induced obese rats. Diabetes 62:3261-7
Lockie, Sarah H; Heppner, Kristy M; Chaudhary, Nilika et al. (2012) Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes 61:2753-62

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