Absence of perilipin results in leanness and reverses obesity in Leprdb/db mice

Abstract

Obesity is a disorder of energy balance¹. Hormone-sensitive lipase (HSL) mediates the hydrolysis of triacylglycerol², the major form of stored energy in the body. Perilipin (encoded by the gene Plin), an adipocyte protein, has been postulated to modulate HSL activity^3,4,5. We show here that targeted disruption of Plin results in healthy mice that have constitutively activated fat-cell HSL. Plin ^−/− mice consume more food than control mice, but have normal body weight. They are much leaner and more muscular than controls, have 62% smaller white adipocytes, show elevated basal lipolysis that is resistant to β-adrenergic agonist stimulation, and are cold-sensitive except when fed. They are also resistant to diet-induced obesity. Breeding the Plin ^−/− alleles into Lepr^db/db mice reverses the obesity by increasing the metabolic rate of the mice. Our results demonstrate a role for perilipin in reining in basal HSL activity and regulating lipolysis and energy balance; thus, agents that inactivate perilipin may prove useful as anti-obesity medications.