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

Abstract

Aims/hypothesis Fatty acids of marine origin, i.e. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) act as hypolipidaemics, but they do not improve glycaemic control in obese and diabetic patients. Thiazolidinediones like rosiglitazone are specific activators of peroxisome proliferator-activated receptor γ, which improve wholebody insulin sensitivity. We hypothesised that a combined treatment with a DHA and EPA concentrate (DHA/EPA) and rosiglitazone would correct, by complementary additive mechanisms, impairments of lipid and glucose homeostasis in obesity.Methods Male C57BL/6 mice were fed a corn oil-based high-fat diet. The effects of DHA/EPA (replacing 15% dietary lipids), rosiglitazone (10 mg/kg diet) or a combination of both on body weight, adiposity, metabolic markers and adiponectin in plasma, as well as on liver and muscle gene expression and metabolism were analysed. Euglycaemic-hyperinsulinaemic clamps were used to characterise the changes in insulin sensitivity. The effects of the treatments were also analysed in dietary obese mice with impaired glucose tolerance (IGT). Results DHA/EPA and rosiglitazone exerted additive effects in prevention of obesity, adipocyte hypertrophy, Diabetologia (2009) 52:941-951

n-3 PUFA: bioavailability and modulation of adipose tissue function

“…In accordance with other studies (for review, see Ruzickova et al (11) ), the experiments on C57BL/6 mice have also demonstrated that substitution of 15% (w/w) lipids in cHF diets by the n-3 LC PUFA concentrate EPAX 1050 TG prevents fat accumulation with a preferential reduction in abdominal fat depots (11)(12)(13) . Using semi-synthetic high-fat diets a stronger anti-obesity effect has been observed with increasing DHA: EPA in the diets (11) .…”

“…In accordance with the general anti-inflammatory action of n-3 LC PUFA (6) (possibly mediated by NF-kB (7,34) ) low-grade inflammation of adipose tissue, which is associated with obesity, is also reduced by n-3 LC PUFA supplementation in obese diabetic db/db mice (59) , as well as in the experiments on C57BL/6 mice fed the cHF diet at the 15% (w/w) level of substitution (13) . The inflammation is suppressed even more potently by a DHA derivative (a-ethyl DHA ethyl ester) replacing only 1 .…”

“…In particular, long-chain (LC) PUFA of the n-3 series, DHA (22: 6n-3) and EPA (20: 5n-3), which are abundant in marine fish, lower TAG while increasing HDL-cholesterol levels in plasma, prevent the development of heart disease and exert anti-inflammatory properties in human Proceedings of the Nutrition Society subjects (5)(6)(7) . Studies in rats and mice fed a high-fat or lipogenic sucrose-rich diet have shown that n-3 LC PUFA counteract the development of both obesity and insulin resistance (8)(9)(10)(11)(12)(13) . Also, in human subjects n-3 LC PUFA could reduce fat accumulation and improve glucose metabolism (14)(15)(16) .…”

“…The hypolipidaemic and anti-obesity effects of n-3 LC PUFA probably depend on the in situ suppression of lipogenesis and increase in fatty acid oxidation in several tissues including liver, intestine, and adipose tissue (12,31,33,34) . This metabolic switch may reduce the accumulation of toxic fatty acid derivatives, while protecting the insulin signalling in liver and muscle (9,13,24,30,35) . Part of the metabolic effects of n-3 LC PUFA in the liver (36) , and possibly also in other tissues (24,37) (also, see later), is mediated by the stimulation of AMP-activated protein kinase (AMPK), a metabolic sensor controlling intracellular metabolic fluxes, i.e.…”

“…incorporation of EPA and DHA administered in the diet into plasma lipids) and tissue accumulation of n-3 LC PUFA, as well as describing the effects of n-3 LC PUFA on AMPK activity and low-grade inflammation of adipose tissue. All the experiments described in the present report were performed using adult male C57BL/6 mice fed a maize oil-based high-fat (cHF; approximately 35% (w/w) fat) diet, free of DHA and EPA and containing a low level of ALA (approximately 2-4 % (w/w) of total fatty acids (11,13) ), which induces the MS phenotype in the mice within several weeks of feeding. The effects of n-3 LC PUFA were studied using a concentrate (w/w; approximately 46% DHA and 14% EPA; EPAX 1050 TG; EPAX AS, Aalesund, Norway) to replace 5, 15 or 44 % (w/w) dietary fat in the cHF diet (11) .…”