Short-term inhibition of peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression reverses diet-induced diabetes mellitus and hepatic steatosis in mice.
OBJECTIVE
The coactivator of nuclear receptors, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) has been implicated in a series of events that contribute to the control of glucose metabolism. We have recently reported the use of a PGC-1alpha antisense oligonucleotide (PGC-1alphaAS) that inhibits up to 60% of PGC-1alpha expression in pancreatic islets, leading to increased insulin secretion. This oligonucleotide was used in this study to try to ameliorate diet-induced type 2 diabetes in a genetically predisposed mouse strain (Swiss mice).


METHODS
Glucose and insulin tolerance tests, euglycaemic-hyperinsulinaemic clamp, immunoprecipitation assays, immunoblotting assays and immunohistochemistry were used in this investigation.


RESULTS
Swiss mice became obese and overtly diabetic after 8 weeks of feeding with chow containing 24% saturated fat. One daily dose (1.0 nmol) of PGC-1alphaAS significantly reduced glucose and increased insulin blood levels without affecting food intake and body weight. These effects were accompanied by a reduced area under the glucose curve during an intraperitoneal glucose tolerance test, an increased constant of glucose decay (K(itt)) during an insulin tolerance test, and an increased glucose consumption rate during a euglycaemic-hyperinsulinaemic clamp. Moreover, mice treated with PGC-1alphaAS presented an outstanding reduction of macroscopic and microscopic features of hepatic steatosis. These effects were accompanied by reduced expression or function of a series of proteins involved in lipogenesis.


CONCLUSIONS
PGC-1alpha is an attractive target for pharmacological therapeutics in type 2 diabetes mellitus and diet-induced hepatic steatosis.
De Souza
C T
CT
Department of Internal Medicine, Faculty of Medical Sciences (FCM), State University of Campinas (UNICAMP), Campinas, São Paulo, 13083-970, Brazil.
Araújo
E P
EP
Prada
P O
PO
Saad
M J A
MJ
Boschero
A C
AC
Velloso
L A
LA
D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000517:prevention & control*; D004032:Diet; D005234:Fatty Liver / Q000517:prevention & control*; D015971:Gene Expression Regulation, Enzymologic; D007328:Insulin / Q000097:blood; D051379:Mice; D008808:Mice, Inbred CBA; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014157:Transcription Factors
D001786:Blood Glucose; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors