Obesity is a highly prevalent condition and is associated with an increased risk for the development of type 2 diabetes (T2D) and cardiovascular disease. As such, an understanding of how obesity develops and the identification of novel therapeutics aimed at controling obesity and its metabolic consequences are of utmost importance. Recent studies demonstrate that the dipeptide carnosine is depleted in the skeletal muscle of patients with T2D and that carnosine feeding decreases diet-induced obesity. Carnosine (ala-his) is a dipeptide present in skeletal muscle, brain, and heart. It buffers protons during glycolysis and it is a strong antioxidant. Carnosine is synthesized by the enzyme carnosine synthetase and is hydrolysed back to alanine and histidine by carnosinase.The homeostatic balance of carnosine is also maintained by the peptide transporter, Pept2 . Although obesity and T2D in humans is associated with a decrease in carnosine levels in the skeletal muscle, the mechanisms underiying carnosine depletion and its protective effects against obesity are not entirely known. Our intial studies show that high fat feeding in mice decreases carnosine levels and that restoration of these levels by carnosine supplementation restricts weight gain, increases energy expenditure, insulin senstivity and glucose tolerance. Based on these observations, we propose that chronic carnosine deficiency decreases energy expenditure and antioxidant capacity ofthe muscle, resulting in insulin resistance and oxidative stress. To test this hypothesis we will: (1) elucidate the mechanism of carnosine depletion in obesity;2) test whether carnosine supplementation prevents or reverses obesity and its metabolic consequences;and (3) investigate the mechanism by which carnosine regulates adiposity and insulin sensitivity. To evaluate the clinical relevance of our findings, we will also measure carnosine and carnosinase activity in obese and non-obese children. The findings of this project could lead to the development of a novel and validated anti-obesity strategy that could also prevent or reverse diet-induced insulin resistance. Successful completion ofthis project would lay the foundaton and form the rationale for testing the anti-obesogenic and anti-diabetic effects of carnosine in humans.

Public Health Relevance

Few options are available to prevent or reverse obesity and its metabolic consequences. In this project, we will test the role of the naturally occuring dipeptide, carnosine, in regulating adiposity and insulin resistance in a mouse model of diet-induced obesity. Results of these studies could lead to the identification of a safe and effective anti-obesity strategy that could be tested in humans.

Agency
National Institute of Health (NIH)
Type
Exploratory Grants (P20)
Project #
5P20GM103492-07
Application #
8711510
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Louisville
Department
Type
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40202
Watson, Lewis J; Long, Bethany W; DeMartino, Angelica M et al. (2014) Cardiomyocyte Ogt is essential for postnatal viability. Am J Physiol Heart Circ Physiol 306:H142-53
Conklin, Daniel J (2014) Recent developments in vascular biology. Circ Res 115:e79-82
Deng, Qipan; Becker, Lindsey; Ma, Xiaodong et al. (2014) The dichotomy of p53 regulation by noncoding RNAs. J Mol Cell Biol 6:198-205
Cummins, Timothy D; Holden, Candice R; Sansbury, Brian E et al. (2014) Metabolic remodeling of white adipose tissue in obesity. Am J Physiol Endocrinol Metab 307:E262-77
Sansbury, Brian E; Hill, Bradford G (2014) Regulation of obesity and insulin resistance by nitric oxide. Free Radic Biol Med 73:383-99
Spite, Matthew; Claria, Joan; Serhan, Charles N (2014) Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases. Cell Metab 19:21-36
O'Toole, Timothy E; Abplanalp, Wesley; Li, Xiaohong et al. (2014) Acrolein decreases endothelial cell migration and insulin sensitivity through induction of let-7a. Toxicol Sci 140:271-82
Salabei, Joshua K; Gibb, Andrew A; Hill, Bradford G (2014) Comprehensive measurement of respiratory activity in permeabilized cells using extracellular flux analysis. Nat Protoc 9:421-38
Sansbury, Brian E; Hill, Bradford G (2014) Antiobesogenic role of endothelial nitric oxide synthase. Vitam Horm 96:323-46
Hong, Kyung U; Guo, Yiru; Li, Qian-Hong et al. (2014) c-kit+ Cardiac stem cells alleviate post-myocardial infarction left ventricular dysfunction despite poor engraftment and negligible retention in the recipient heart. PLoS One 9:e96725

Showing the most recent 10 out of 21 publications