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)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103492-10
Application #
9300983
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
10
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Louisville
Department
Type
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Zafar, Nagma; Krishnasamy, Sathya S; Shah, Jasmit et al. (2018) Circulating angiogenic stem cells in type 2 diabetes are associated with glycemic control and endothelial dysfunction. PLoS One 13:e0205851
Hoetker, David; Chung, Weiliang; Zhang, Deqing et al. (2018) Exercise alters and ?-alanine combined with exercise augments histidyl dipeptide levels and scavenges lipid peroxidation products in human skeletal muscle. J Appl Physiol (1985) :
Baba, Shahid P; Bhatnagar, Aruni (2018) ROLE OF THIOLS IN OXIDATIVE STRESS. Curr Opin Toxicol 7:133-139
Abplanalp, Wesley; Wickramasinghe, Nalinie S; Sithu, Srinivas D et al. (2018) Benzene exposure induces insulin resistance in mice. Toxicol Sci :
Nystoriak, Matthew A; Bhatnagar, Aruni (2018) Cardiovascular Effects and Benefits of Exercise. Front Cardiovasc Med 5:135
Nystoriak, Matthew A; Navedo, Manuel F (2018) Regulation of microvascular function by voltage-gated potassium channels: New tricks for an ""ancient"" dog. Microcirculation 25:
Haberzettl, Petra; Conklin, Daniel J; Abplanalp, Wesley T et al. (2018) Inhalation of Fine Particulate Matter Impairs Endothelial Progenitor Cell Function Via Pulmonary Oxidative Stress. Arterioscler Thromb Vasc Biol 38:131-142
Mehra, Parul; Guo, Yiru; Nong, Yibing et al. (2018) Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair. Basic Res Cardiol 113:46
Ghosh Dastidar, Shubha; Jagatheesan, Ganapathy; Haberzettl, Petra et al. (2018) Glutathione S-transferase P Deficiency Induces Glucose Intolerance via JNK-dependent Enhancement of Hepatic Gluconeogenesis. Am J Physiol Endocrinol Metab :
Baba, Shahid P; Zhang, Deqing; Singh, Mahavir et al. (2018) Deficiency of aldose reductase exacerbates early pressure overload-induced cardiac dysfunction and autophagy in mice. J Mol Cell Cardiol 118:183-192

Showing the most recent 10 out of 110 publications