Leptin-induced mitochondrial fusion mediates hepatic lipid accumulation.

Abstract

Leptin alleviates metabolic conditions such as insulin resistance and obesity, although the precise mechanism of action is unclear. Mitochondrial fusion/fission states affect energy balance, but the association between mitochondrial fusion and lipid metabolism is also unknown. The aim of this study was to determine whether mitochondrial fusion/fission state regulates lipid accumulation and to understand the role of leptin in mitochondrial function and its mechanism of action in metabolic regulation. Primary mouse hepatocytes were isolated from C57BL/6J mice and treated with leptin (25 ng ml(-1)) for 3 days before determinations of mitochondrial morphology and fatty acid accumulation. Hyperglycemia in C57BL/6J mice was induced by providing a 30% fructose-rich diet (FRD) for 6 months, followed by intraperitoneal injections of leptin (1 mg kg(-1) per body weight) for 6 weeks (twice per week). Leptin triggered mitochondrial fusion and alleviated high glucose-induced fatty acid accumulation in primary hepatocytes by promoting mitochondrial fusion-associated transcription factor peroxisome proliferative-activated receptor-α and co-activator peroxisome proliferative-activated receptor-γ co-activator (PGC)-1α. In turn, these activate the fusion protein mitofusin 1 (Mfn-1). RNA silencing of Mfn-1 or PGC-1 blocked the inhibitory effect of leptin. Leptin treatment also elevated liver Mfn-1 and PGC-1α and improved lipid profiles in FRD mice. Mitochondrial fusion has a critical role in alleviating hepatic fatty acid accumulation. Leptin switches mitochondrial morphology via a PGC-1α-dependent pathway to improve hyperlipidemia.