The n-3
polyunsaturated fatty acids, especially
eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA), exert hypolipidemic effects and prevent development of
obesity and
insulin resistance in animals fed high-fat diets. We sought to determine the efficacy of alpha-substituted DHA derivatives as
lipid-lowering, antiobesity, and
antidiabetic agents. C57BL/6 mice were given a
corn oil-based high-fat (35% weight/weight) diet (cHF), or cHF with 1.5% of
lipids replaced with alpha-methyl DHA ethyl
ester (Substance 1), alpha-ethyl DHA ethyl
ester (Substance 2), alpha,alpha-di-methyl DHA ethyl
ester (Substance 3), or alpha-thioethyl DHA ethyl
ester (Substance 4) for 4 months. Plasma markers of
glucose and lipid metabolism,
glucose tolerance, morphology, tissue
lipid content, and gene regulation were characterized. The cHF induced
obesity,
hyperlipidemia, impairment of
glucose homeostasis, and adipose tissue
inflammation. Except for Substance 3, all other substances prevented
weight gain and Substance 2 exerted the strongest effect (63% of cHF-controls).
Glucose intolerance was significantly prevented (~67% of cHF) by both Substance 1 and Substance 2. Moreover, Substance 2 lowered fasting glycemia, plasma
insulin,
triacylglycerols, and
nonesterified fatty acids (73, 9, 47, and 81% of cHF-controls, respectively). Substance 2 reduced accumulation of
lipids in liver and skeletal muscle, as well as adipose tissue
inflammation associated with
obesity. Substance 2 also induced
weight loss in dietary obese mice. In contrast to DHA administered either alone or as a component of the EPA/DHA concentrate (replacing 15% of dietary
lipids), Substance 2 also reversed established
glucose intolerance in obese mice. Thus, Substance 2 represents a novel compound with a promising potential in the treatment of
obesity and associated metabolic disturbances.