Abstract

A high-fat diet increases bacterial lipopolysaccharide (LPS) in the circulation, and thereby stimulates glucagon-like peptide-1 (GLP-1)-mediated insulin secretion by up-regulating interleukin (IL)-6. Although microRNA-155-5p (miR-155-5p), which increases IL-6 expression, is upregulated by LPS and hyperlipidemia, and patients with familial hypercholesterolemia less frequently develop diabetes, the role of miR-155-5p in the islet stress response to hyperlipidemia is unclear. Here, we demonstrate that hyperlipidemia-associated endotoxemia up-regulates miR-155-5p in murine pancreatic β-cells, which improved glucose metabolism and the adaptation of β-cells to obesity-induced insulin resistance. This effect of miR-155-5p is due to suppression of v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B (Mafb), which promotes β-cell function through IL-6-induced GLP-1 production in α-cells. Moreover, reduced GLP-1 levels are associated with increased obesity progression, dyslipidemia, and atherosclerosis in hyperlipidemic Mir155 knockout mice. Hence, induction of miR-155-5p expression in β-cells by hyperlipidemia-associated endotoxemia improves the adaptation of β-cells to insulin resistance and represents a protective mechanism in the islet stress response.