Prevention and Reversal of Obesity and Glucose Intolerance in Mice by DHA Derivatives

Abstract

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 α‐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 α‐methyl DHA ethyl ester (Substance 1), α‐ethyl DHA ethyl ester (Substance 2), α,α‐di‐methyl DHA ethyl ester (Substance 3), or α‐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.

n-3 Fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet

“…Tissue lipid content Liver and muscle triacylglycerol content was estimated in ethanolic KOH tissue solubilisates [32]. Ceramide content was estimated in lipid extracts from soleus muscle homogenates using HPLC [34].…”

“…Light microscopy and immunohistochemical analysis Epididymal fat samples were processed to detect MAC-2/ galectin and perilipin, using specific antibodies [32,38] (see ESM).…”

“…Glucose tolerance test Intraperitoneal glucose tolerance test was performed in fasted mice as described [32].…”

“…In spite of the differences in the ability of TZDs and n-3 LC-PUFA to reverse IGT, both types of compounds reduce adipose tissue inflammation [24,30], one of the key factors contributing to the development of insulin resistance in obesity, while also increasing adiponectin [12,15,24,25,31,32].…”

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

“…Tissue lipid content The tissue content of TG was estimated in ethanolic KOH tissue solubilisates [25].…”