Obesity is a disorder of energy balance(1). Hormone-sensitive lipase (HSL)
mediates the hydrolysis of triacylglycerol(2). the major form of stored ene
rgy in the body. Perilipin (encoded by the gene Plin), an adipocyte protein
, has been postulated to modulate HSL activity(3-5). We show here that targ
eted disruption of Plin results in healthy mice that have constitutively ac
tivated fat-cell HSL. Plin(-/-) mice consume more food than control mice, b
ut have normal body weight. They are much leaner and more muscular than con
trols, have 62% smaller white adipocytes, show elevated basal lipolysis tha
t is resistant to beta -adrenergic agonist stimulation, and are cold-sensit
ive except when fed. They are also resistant to diet-induced obesity. Breed
ing the Plin(-/-) alleles into Lepr(db/db) mice reverses the obesity by inc
reasing the metabolic rate of the mice. Our results demonstrate a role for
perilipin in mining in basal HSL activity and regulating lipolysis and ener
gy balance; thus, agents that inactivate perilipin may prove useful as anti
-obesity medications.