Overfeeding Rapidly Induces Leptin and Insulin Resistance
- Medicine and Molecular Pharmacology, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York
In common forms of obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia coexist. Here, we demonstrate rapid induction of insulin and leptin resistance by short-term overfeeding. After 3 and 7 days on the assigned diet regimen, rats were tested for their biological responses to acute elevations in plasma insulin and leptin concentrations. Severe resistance to the metabolic effects of both leptin and insulin ensued after just 3 days of overfeeding. During the insulin clamp studies, glucose production was decreased by ∼70% in control rats and 28–53% in overfed rats. Similarly, leptin infusion doubled the contribution of gluconeogenesis to glucose output in control rats but failed to modify gluconeogenesis in overfed animals. These findings demonstrate a paradoxical and rapid collapse of the leptin system in response to nutrient excess. This partial failure is tightly coupled with the onset of insulin resistance.
Address correspondence and reprint requests to Dr. Luciano Rossetti, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. E-mail:.
Received for publication 20 April 2001 and accepted in revised form 6 September 2001.
HPLC, high-performance liquid chromatography; PEP, phosphoenolpyruvate.