Metabolic adaptations in the absence of perilipin: increased beta-oxidation and decreased hepatic glucose production associated with peripheral insulin resistance but normal glucose tolerance in perilipin-null mice.
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.
Saha
Pradip K
PK
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Kojima
Hideto
H
Martinez-Botas
Javier
J
Sunehag
Agneta L
AL
Chan
Lawrence
L
D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000096:biosynthesis* / Q000235:genetics; D005951:Glucose Tolerance Test; D007333:Insulin Resistance / Q000235:genetics; D008066:Lipolysis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics
D002352:Carrier Proteins; D005227:Fatty Acids; D000070778:Perilipin-1; D010750:Phosphoproteins; D005947:Glucose