Metabolic Adaptations in the Absence of Perilipin

Abstract

Targeted disruption of the lipid droplet protein, perilipin, in mice leads to constitutional lipolysis associated with marked reduction in white adipose tissue as a result of unbridled lipolysis. To investigate the metabolic adaptations in response to the constitutive lipolysis, we studied perilipin-null (plin(-/-)) mice in terms of their fatty acid oxidation and glycerol and glucose metabolism homeostasis by using dynamic biochemical testing and clamp and tracer infusion methods. plin(-/-) mice showed increased beta-oxidation in muscle, liver, and adipose tissue resulting from a coordinated regulation of the enzymes and proteins involved in beta-oxidation. The increased beta-oxidation helped remove the extra free fatty acids created by the constitutive lipolysis. An increase in the expression of the transcripts for uncoupling proteins-2 and -3 also accompanied this increase in fatty acid oxidation. Adult plin(-/-) mice had normal plasma glucose but a reduced basal hepatic glucose production (46% that of plin(+/+)). Insulin infusion during low dose hyperinsulinemic-euglycemic clamp further lowered the glucose production in plin(-/-) mice, but plin(-/-) mice also showed a 36% decrease (p < 0.007) in glucose disposal rate during the low dose insulin clamp, indicating peripheral insulin resistance. However, compared with plin(+/+) mice, 14-week-old plin(-/-) mice showed no significant difference in glucose disposal rate during the high dose hyperinsulinemic clamp, whereas 42-week-old plin(-/-) mice displayed significant insulin resistance on high dose hyperinsulinemic clamp. Despite increasing insulin resistance with age, plin(-/-) mice at different ages maintained a normal glucose response during an intraperitoneal glucose tolerance curve, being compensated by the increased beta-oxidation and reduced hepatic glucose production. These experiments uncover the metabolic adaptations associated with the constitutional lipolysis in plin(-/-) mice that allowed the mice to continue to exhibit normal glucose tolerance in the presence of peripheral insulin resistance.