The proposed research describes a mentored training program in neuroendocrine regulation of metabolism, designed to provide the candidate the necessary skills and resources that will allow him to achieve the long- term goal of developing a career as an independent neurobiologist at a research-oriented university. Department of Medicine at Mount Sinai School of Medicine has well-established programs with state-of-the-art analytical instrumentations. The primary mentor, Dr. Christoph Buettner, is an established investigator and is well respected in the field of energy metabolism, while the co-mentors are authorities in metabolomics, gut- brain communication and bariatric surgery, and metabolic syndrome. The abundant institutional resources and excellent mentorship from these experts will provide an ideal training environment for the candidate to develop independence. The research plan focuses on central insulin action and its role in the regulation of branched- chain amino acid (BCAA) metabolism. Combining physiological and metabolic targeting tools with genetic, pharmacological, and surgical approaches, the experiments described in the proposal will identify: (1) the role of hypothalamic insulin on circulating BCAAs and their intermediates;() hepatic BCAA catabolism as controlled by the central insulin action;and (3) systemic and liver BCAA metabolism affected by Roux-en-Y gastric bypass (RYGB) surgery, and the potential role of central insulin action after RYGB. The proposed studies will advance our understanding of BCAA homeostasis that is under the control of hypothalamic insulin, and explain how this is perturbed in obesity and diabetes. Importantly, identifying central insulin action as a mechanism through which RYGB successfully improves BCAA metabolism holds promise for future development of non-invasive pharmacological treatments that mimic the surgery-induced effects.

Public Health Relevance

Communication between the brain and peripheral organs through insulin is critical for the regulation of energy metabolism. Here we propose to investigate the role of brain insulin in the control of branched-chain amino acid (BCAA) metabolism, and the results from the proposed studies will reveal how central insulin physiologically regulates BCAA metabolism and that this is impaired in obese and diabetic individuals. Importantly, applying the gained knowledge to examine the mechanisms by which bariatric surgery improves BCAA metabolism will ultimately facilitate development of non-invasive treatment options that mimic RYGB effects to fight obesity and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01DK099463-01
Application #
8566862
Study Section
Special Emphasis Panel (ZDK1-GRB-R (M2))
Program Officer
Hyde, James F
Project Start
2013-08-01
Project End
2017-05-30
Budget Start
2013-08-01
Budget End
2014-05-30
Support Year
1
Fiscal Year
2013
Total Cost
$144,504
Indirect Cost
$10,704
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Shin, Andrew C; Fasshauer, Martin; Filatova, Nika et al. (2014) Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. Cell Metab 20:898-909