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.
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.
|Shin, Andrew C; Filatova, Nika; Lindtner, Claudia et al. (2017) Insulin Receptor Signaling in POMC, but Not AgRP, Neurons Controls Adipose Tissue Insulin Action. Diabetes 66:1560-1571|
|Kang, Soojeong; Dahl, Russell; Hsieh, Wilson et al. (2016) Small Molecular Allosteric Activator of the Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) Attenuates Diabetes and Metabolic Disorders. J Biol Chem 291:5185-98|
|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|