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. 2012 Jun 12;109(24):9635-40.
doi: 10.1073/pnas.1207287109. Epub 2012 May 29.

Development of Insulin Resistance in Mice Lacking PGC-1α in Adipose Tissues

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Free PMC article

Development of Insulin Resistance in Mice Lacking PGC-1α in Adipose Tissues

Sandra Kleiner et al. Proc Natl Acad Sci U S A. .
Free PMC article

Abstract

Reduced peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression and mitochondrial dysfunction in adipose tissue have been associated with obesity and insulin resistance. Whether this association is causally involved in the development of insulin resistance or is only a consequence of this condition has not been clearly determined. Here we studied the effects of adipose-specific deficiency of PGC-1α on systemic glucose homeostasis. Loss of PGC-1α in white fat resulted in reduced expression of the thermogenic and mitochondrial genes in mice housed at ambient temperature, whereas gene expression patterns in brown fat were not altered. When challenged with a high-fat diet, insulin resistance was observed in the mutant mice, characterized by reduced suppression of hepatic glucose output. Resistance to insulin was also associated with an increase in circulating lipids, along with a decrease in the expression of genes regulating lipid metabolism and fatty acid uptake in adipose tissues. Taken together, these data demonstrate a critical role for adipose PGC-1α in the regulation of glucose homeostasis and a potentially causal involvement in the development of insulin resistance.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Generation and characterization of FKO mice. (A) FKOs were generated by crossing mice with a floxed PGC-1α allele (Flox) to animals that transgenically express cre recombinase under the control of the adiponectin promoter (Adi Cre). Triangles designate LoxP sites. PCR analysis detected the presence of the LoxP sites and the Adi cre transgene. (B) PGC-1α protein levels in BAT and inguinal WAT at room temperature (RT) and after a 4-h cold challenge were determined by Western blot analysis. (C) Relative PGC-1α and PGC-1β mRNA expression was measured in different tissues by real-time PCR from mice housed at 21 °C. n = 6–8 per group.
Fig. 2.
Fig. 2.
Analysis of adipose tissues lacking PGC-1α. (A–C) Real-time quantitative PCR analysis of adipogenic, thermogenic, and mitochondrial genes in BAT (A), IWAT (B), and EWAT (C) from control Flox and FKO mice. n = 8 per group. (D) Representative H&E staining of BAT, IWAT, and EWAT of control and FKO mice.
Fig. 3.
Fig. 3.
Analysis of primary inguinal adipocytes derived from FKO mice. (A) Oil red O staining of differentiated primary adipocytes. (B) Real-time quantitative PCR analysis of adipogenic, thermogenic, and mitochondrial gene expression. (C) Basal and uncoupled oxygen consumption rates in differentiated inguinal adipocytes.
Fig. 4.
Fig. 4.
Glucose intolerance and insulin resistance in HFD-fed FKO mice. (A) Body weight gain in control and FKO mice. (B) Lean and fat body mass in control and FKO mice after 17 wk of the HFD measured by MRI. (C) Intraperitoneal glucose tolerance test of control and FKO mice after 8 wk on the HFD. (D) Intraperitoneal insulin sensitivity test of control and FKO mice after 16 wk on the HFD. (E–G) Serum FFA (E), TG (F), and insulin (G) levels in control and FKO mice after 12, 17, and 17 wk on the HFD, respectively. n = 11 per group.
Fig. 5.
Fig. 5.
Liver insulin resistance in HFD-fed FKO mice. Glucose infusion rate (A), glucose uptake (B), BAT glucose uptake (C), and suppression of hepatic glucose output (HGO) (D) of control and FKO mice after 8 wk on the HFD was measured by the hyperinsulinemic-euglycemic clamp technique. n = 7–9 per group.
Fig. 6.
Fig. 6.
Deregulated lipid metabolism in HFD-fed FKO mice. (A) Real-time quantitative PCR analysis of UCP1 gene expression in adipose depots of HFD-fed control and FKO mice. (B–D) Real-time quantitative PCR analysis of genes involved in FAO from BAT (B), IWAT (C), and EWAT (D) of HFD-fed control and FKO mice. (E and F) Liver FFA levels (E) and TG levels (F) from mice after 17 wk of HFD feeding.

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