Obesity and its associated conditions such as
type 2 diabetes mellitus are major causes of morbidity and mortality. The iminosugar N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin (
AMP-DNM) improves
insulin sensitivity in rodent models of
insulin resistance and
type 2 diabetes mellitus. In the current study, we characterized the impact of
AMP-DNM on substrate oxidation patterns, food intake, and
body weight gain in obese mice. Eight ob/ob mice treated with 100 mg/(kg d)
AMP-DNM mixed in the food and 8 control ob/ob mice were placed in metabolic cages during the first, third, and fifth week of the experiment for measurement of substrate oxidation rates, energy expenditure, activity, and food intake. Mice were killed after 6 weeks of treatment. Initiation of treatment with
AMP-DNM resulted in a rapid increase in fat oxidation by 129% (P = .05), a decrease in
carbohydrate oxidation by 35% (P = .01), and a reduction in food intake by approximately 26% (P < .01) compared with control mice. Treatment with
AMP-DNM decreased hepatic
triglyceride content by 66% (P < .01) and, in line with the elevated fat oxidation rates, increased hepatic
carnitine palmitoyl
transferase 1a expression. Treatment with
AMP-DNM increased plasma levels of the appetite-regulating
peptide YY compared with control mice. Treatment with
AMP-DNM rapidly reduces food intake and increases fat oxidation, resulting in improvement of the obese phenotype. These features of
AMP-DNM, together with its
insulin-sensitizing capacity, make it an attractive candidate
drug for the treatment of
obesity and its associated metabolic derangements.