Effects of Leptin on Lipid Metabolism

Introduction

The adipose tissue plays an important role in total energy homeostasis [1]. Glucose and lipid metabolism are regulated by complex interactions that occur within the adipoinsular axis. Leptin inhibits insulin secretion and is positively correlated with insulin resistance, at least in pregnant women [2]. Insulin stimulates lipogenesis acutely and decreases lipolysis [3], whereas leptin exerts opposite effects [4] [5]. Abnormal accumulation of triglycerides in nonadipose tissues, caused by the upregulation of lipogenesis, leads to a deleterious state known as lipotoxicity.

Lipotoxicity is characterized as the accumulation of triglycerides in surrounding hepatocytes and is thought to be a major contributor to islet cell transplantation failure in diabetics [6]. This accumulation is likely caused by increased lipogenesis, stimulated by local hyperinsulinemia and an abundance of nutrients. The hepatocytes release excess triacylglycerol, which is subsequently hydrolyzed by insular lipoprotein lipase of the islets [7]. This process exposes β-cells to increasing concentrations of fatty acids. The concept of lipotoxicity as a major cause of graft dysfunction is supported by the high incidence of hepatic steatosis (20%) in subjects with graft dysfunction [8]. Moreover, exposure of isolated human islets to fatty acids results in apoptosis [9]. Given that leptin is thought to oppose insulin action by decreasing hepatocyte lipogenesis, leptin administration may result in decreased lipotoxicity.

To better understand the effects of leptin on lipid metabolism in the context of hyperinsulinemia, we measured the levels of nonesterified fatty acids during euglycemic hyperinsulinemic clamps (EHC) performed in genetically leptin-deficient adults while on physiologic leptin replacement and after it was transiently interrupted.

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