Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin

Excess of body fat, or obesity, is a major health problem and confers a hig her risk of cardiovascular and metabolic disorders such as diabetes, hypert ension, and coronary heart disease. Leptin is an adipocyte-derived satiety factor that plays an important role in the regulation of energy homeostasis , and its synthesis and secretion are markedly increased in obese subjects. To explore the metabolic consequences of an increased amount of leptin on a long-term basis in vivo, we generated transgenic skinny mice with elevate d plasma leptin concentrations comparable to those in obese subjects. Overe xpression of leptin in the liver has resulted in complete disappearance of white and brown adipose tissue for a long period of time in mice. Transgeni c skinny mice exhibit increased glucose metabolism accompanied by the activ ation of insulin signaling in the skeletal muscle and liver. They also show small-sized livers with a marked decrease in glycogen and lipid storage. T he phenotypes are in striking contrast to those of recently reported animal models of lipoatrophic diabetes and patients with lipoatrophic diabetes wi th reduced amount of leptin. The present study provides evidence that lepti n is an adipocyte-derived antidiabetic hormone in vivo and suggests its pat hophysiologic and therapeutic implications in diabetes.