Elevated tissue omega-3 fatty acid status prevents age-related glucose intolerance in fat-1 transgenic mice

Abstract

The objective of this study was to investigate the impact of elevated tissue omega-3 (n-3) polyunsaturated fatty acids (PUFA) status on age-related glucose intolerance utilizing the fat-1 transgenic mouse model, which can endogenously synthesize n-3 PUFA from omega-6 (n-6) PUFA. Fat-1 and wild-type mice, maintained on the same dietary regime of a 10% corn oil diet, were tested at two different ages (2 months old and 8 months old) for various glucose homeostasis parameters and related gene expression. The older wild-type mice exhibited significantly increased levels of blood insulin, fasting blood glucose, liver triglycerides, and glucose intolerance, compared to the younger mice, indicating an age-related impairment of glucose homeostasis. In contrast, these age-related changes in glucose metabolism were largely prevented in the older fat-1 mice. Compared to the older wild-type mice, the older fat-1 mice also displayed a lower capacity for gluconeogenesis, as measured by pyruvate tolerance testing (PTT) and hepatic gene expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G6Pase). Furthermore, the older fat-1 mice showed a significant decrease in body weight, epididymal fat mass, inflammatory activity (NFκ-B and p-IκB expression), and hepatic lipogenesis (acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) expression), as well as increased peroxisomal activity (70-kDa peroxisomal membrane protein (PMP70) and acyl-CoA oxidase1 (ACOX1) expression). Altogether, the older fat-1 mice exhibit improved glucose homeostasis in comparison to the older wild-type mice. These findings support the beneficial effects of elevated tissue n-3 fatty acid status in the prevention and treatment of age-related chronic metabolic diseases.

Keywords: 70-kDa peroxisomal membrane protein; ACC; ACOX1; Aging; FAS; G6Pase; GC; GTT; Gluconeogenesis; Glucose homeostasis; IKK; Inflammation; IκB kinase; JNK; Lipogenesis; MCP-1; NF-κB; Omega-3 fatty acid; PAI-1; PEPCK; PMP-70; PPARα; PTT; PUFA; TG; TNF-α; WT; acetyl-CoA carboxylase; acyl-CoA oxidase1; c-jun kinase; fatty acid synthase; gas chromatography; glucose 6 phosphatase; glucose tolerance test; monocyte chemoattractant protein; n-3; n-6; nuclear factor-κB; omega-3; omega-6; peroxisome proliferator-activated receptor-α; phosphoenolpyruvate carboxykinase; plasminogen activator inhibitor-1; polyunsaturated fatty acids; pyruvate tolerance test; triglyceride; tumor necrosis factor α; wild-type.