Carnosinase inhibition enhances reactive species scavenging in high fat diet.

Aims: Life expectancy is typically reduced by 2-4 years in people with a body mass index (BMI) of 30-35 kg/m and by 8-10 years in people with a BMI of 40-50 kg/m. Obesity is also associated with onset, or exacerbation of, multiple chronic diseases. Mechanistically, this, in part, involves formation of advanced glycation and lipidation end-products that directly bond with proteins, lipids, or DNA, thereby perturbing typical cellular function. Here we seek to prevent these damaging adduction events through inhibition of carnosinase enzymes that rapidly degrade the physiological reactive species scavenger, carnosine, in the body.

Main Methods: Herein we performed in silico computational modelling of a compound library of ∼53,000 molecules to identify carnosine-like molecules with intrinsic resistance to carnosinase turnover.

Key Findings: We show that leading candidate molecules reduced reactive species in C2C12 myotubes, and that mice fed N-methyl-[6-(2-furyl)pyrid-3-yl]methylamine alongside a high fat diet had significantly decreased amounts of damaging plasma 4-hydroxynonenal and 3-nitrotyrosine reactive species. Oral administration of N-methyl-[6-(2-furyl)pyrid-3-yl]methylamine to high fat-fed mice also resulted in a modest ∼10 % reduction in weight gain when compared to mice fed only high fat diet.

Significance: Our findings suggest that inhibition of carnosinase enzymes can increase the life-span, and thereby enhance the efficacy, of endogenous carnosine in vivo, thereby offering potential therapeutic benefits against obesity and other cardiometabolic diseases characterised by metabolic stress.