Leptin is a major adipocyte-derived
hormone that is involved in the regulation of food intake and energy expenditure. Plasma
leptin concentrations are elevated in obese subjects, suggesting its pathophysiological role in
obesity-related lifestyle-related diseases. We have recently succeeded in the generation of transgenic skinny mice overexpressing
leptin. They exhibit increased
glucose metabolism and
insulin sensitivity accompanied by a significant increase in
insulin signaling for
glucose utilization in the skeletal muscle and liver. They also show blood pressure elevation through the sympathetic activation. Introduction of the lethal yellow agouti (A(y)) allele into transgenic skinny mice results in late-onset
obesity and diabetes with blood pressure elevation similar to those found in nontransgenic agouti mice (A(y)/+ mice). After
caloric restriction, blood pressure elevation is reversed but
insulin resistance still remains in A(y)/+ mice in parallel with a reduction of plasma
leptin concentrations. By contrast, blood pressure elevation is sustained but
insulin resistance is reversed in transgenic mice overexpressing
leptin with the A(y) allele (Tg/+:A(y)/+ mice), which remain hyperleptinemic. Collectively, our data suggest the pathophysiologic and therapeutic implication of
leptin in
obesity-related
insulin resistance and
hypertension.