Role of fatty acid elongase Elovl6 in the regulation of energy metabolism and pathophysiological significance in diabetes.

Type 2 diabetes mellitus (T2DM) is an expanding epidemic, closely linked to obesity. Peripheral insulin resistance and impaired insulin secretion remain the core defects in T2DM. Despite significant advances in unraveling the underlying these defects, many of the metabolic pathways and regulators involved in insulin resistance and β-cell dysfunction are not completely understood. This review proposes that manipulating the fatty acid (FA) composition by blocking ELOVL fatty acid elongase 6 (Elovl6) could protect against insulin resistance, impaired insulin secretion, and obesity-related disorders. The molecular mechanism of this new paradigm is also discussed. Elovl6 is a microsomal enzyme involved in the elongation of C16 saturated and monounsaturated FAs to form C18 FAs. We have reported that mice with Elovl6 deletion are protected against obesity-induced insulin resistance or β-cell failure when mated to leptin receptor-deficient db/db mice because the cellular FA composition is changed, even with concurrent obesity. Therefore, Elovl6 appears to be a crucial metabolic checkpoint, and limiting Elovl6 expression or activity could be a new therapeutic approach to treat T2DM. © The Japan Diabetes Society 2020.