A missing link in body weight homeostasis: the catabolic signal of the overfed state

Mammals regulate fat mass so that increases or reductions in adipose tissue mass activate responses that favor return to one's previous weight. A reduction in fat mass activates a system that increases food intake and reduces energy expenditure; conversely, overfeeding and rapid adipose tissue expansion reduces food intake and increases energy expenditure. With the identification of leptin nearly two decades ago, the central circuit that defends against reductions in body fat was revealed. However, the systems that defend against rapid expansion of fat mass remain largely unknown. Here we review the physiology of the overfed state and evidence for a distinct regulatory system, which unlike the leptin-mediated system, we propose primarily measures a functional aspect of adipose tissue and not total mass per se.