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 ␤-oxidation in muscle, liver, and adipose tissue resulting from a coordinated regulation of the enzymes and proteins involved in ␤-oxidation. The increased ␤-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 ␤-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.Obesity is a growing health problem with significant associated morbidity and mortality. Although obesity can result from environmental factors and a sedentary life-style, recent findings suggest that susceptibility to obesity is to a large extent genetically determined (1). One approach to study obesity and its associated morbidity is to investigate genes and pathways involved in the regulation of lipid metabolism and body fat deposition. A fat cell protein, perilipin, has recently been found to play a key role in determining body habitus as its absence leads to a lean and obesity-resistant phenotype in mice (2, 3). Perilipin belongs to a class of proteins found exclusively at the limiting surface of storage droplets in adipocytes and in steroidogenic cells (4 -7). It coats the lipid droplets and protects triglycerides from the lipolytic action of hormone-sensitive lipase (6). Hormone-sensitive lipase catalyzes the breakdown of triacylglycerols and the release of free fatty acids ...

FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets

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