Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance

Abstract

Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high-fat diet or mated to leptin-deficient ob/ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C epsilon activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.

Time-dependent effects of Prkce deletion on glucose homeostasis and hepatic lipid metabolism on dietary lipid oversupply in mice

“…The liver is therefore the most likely site of PKCε action, as previously suggested [6][7][8][9]24], and we therefore focused our investigation on this tissue.…”

Long-term effects of increased dietary polyunsaturated fat from walnuts on metabolic parameters in type II diabetes

“…Dietary fat can influence the expression of genes associated with body weight regulatory systems (Summers et al, 2002;Wang et al, 2002). The effect of increased dietary PUFA on insulin action is another possible mode of action where hepatic fatty acid composition may influence insulin sensitivity (independently of cellular energy balance) (Matsuzaka et al, 2007), and insulin itself may influence hypothalamic control of energy homeostasis through CNS pathways.…”

Is Palmitoleic Acid a Plausible Nonpharmacological Strategy to Prevent or Control Chronic Metabolic and Inflammatory Disorders?

“…[24] The deletion of ELOVL6 in mice increased the levels of palmitoleic acid and the ratio of C16:1n-7 to C16:0 in liver, an effect suggested to prevent the development of diet-induced insulin resistance, without amelioration of obesity or NAFLD. [33] Although increased in ELOVL6 knockout mice, as the substrate for the elongation to cis-VA, [25,27] palmitoleic acid seems to increase the elongation capacity itself by increasing the transcription of the genes encoding elongase enzymes, especially ELOVL5. [32] In agreement, our group observed in endothelial cells exposed to several concentrations of palmitoleic acid that the elongation to cis-VA was increased in a dose-dependent manner Souza et al (unpublished).…”