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, 100 (24), 14457-62

Compensation by the Muscle Limits the Metabolic Consequences of Lipodystrophy in PPAR Gamma Hypomorphic Mice

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Compensation by the Muscle Limits the Metabolic Consequences of Lipodystrophy in PPAR Gamma Hypomorphic Mice

Hana Koutnikova et al. Proc Natl Acad Sci U S A.

Abstract

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor, which controls adipocyte differentiation. We targeted with homologous recombination the PPAR gamma 2-specific exon B, resulting in a white adipose tissue knockdown of PPAR gamma. Although homozygous (PPAR gamma hyp/hyp) mice are born with similar weight as the WT mice, the PPAR gamma hyp/hyp animals become growth retarded and develop severe lipodystrophy and hyperlipidemia. Almost half of these PPAR gamma hyp/hyp mice die before adulthood, whereas the surviving PPAR gamma hyp/hyp animals overcome the growth retardation, yet remain lipodystrophic. In contrast to most lipodystrophic models, the adult PPAR gamma hyp/hyp mice only have mild glucose intolerance and do not have a fatty liver. These metabolic consequences of the lipodystrophy are relatively benign because of the induction of a compensatory gene expression program in the muscle that enables efficient oxidation of excess lipids. The PPAR gamma hyp/hyp mice unequivocally demonstrate that PPAR gamma is the master regulator of adipogenesis in vivo and establish that lipid and glucose homeostasis can be relatively well maintained in the absence of white adipose tissue.

Figures

Fig. 1.
Fig. 1.
Targeting of the PPARγ2 gene. (A) Schematic representation of the mouse PPARγ2 gene (Upper) and targeting vector (Lower). EcoRI (E), HindIII (H), loxP (left arrow), neomycin cassette (gray box), frt sites (right arrow), and exons (dark boxes) are indicated. (B) Southern blot and PCR analysis of ES cell clones and mice. (C) Quantitative RT-PCR analysis of PPARγ1 and PPARγ2 mRNA in WAT, BAT, liver, and muscle. (D) Quantitative RT-PCR analysis of PPARγ1 and PPARγ2 mRNA in WAT of WT and PPARγAla12Ala mice. (E) Body weight gain in males (n > 10). (Inset) Weight gain in the postnatal period (n > 17) is shown.
Fig. 2.
Fig. 2.
Lipodystrophy in young PPARγhyp/hyp mice. (A) Exposed ventral view of a 7-day-old PPARγ+/+ and PPARγhyp/hyp mouse and percentage of organ over body weights (n > 10). (B) Gross morphology and histology of interscapular BAT (×4,000). (C) Gross morphology, histology (×6,000), and Oil red O staining of the liver. (D) Hepatic TG and cholesterol content in both genotypes (n = 4). (E) Serum TG and FFA levels at 5 and 7 days of age (n = 6–8). (F) Serum ALT and AST levels at 5 and 7 days of age. (G) Liver mRNA levels of SREBP1c, SREBP2, FAS, ACC, acetyl-CoA synthetase (AceCS), PPARγ, UCP-2, and ACO were determined by quantitative RT-PCR.
Fig. 3.
Fig. 3.
Lipodystrophy and lack of liver steatosis in adults. (A) Exposed ventral view of a 20-week-old mouse and percentage of organ over body weights (n > 8). (B) Skin histology (×4,000). The white adipocytes in the hypodermis are shown in brackets. (C) Histology of the s.c. WAT (×4,000). (D) Serum FFA in the fed and fasted state. (E) Serum TG in the fasted mice. (F) Morphology of interscapular BAT, histological sections of BAT, liver, skeletal muscle, and heart of a representative PPARγ+/+ (Upper) and a PPARγhyp/hyp mouse (Lower) (hematoxylin/eosin stain, Oil red O staining in the Inset; ×4,000).
Fig. 4.
Fig. 4.
Metabolic consequences of PPARγ targeting. (A) Serum glucose levels after i.p. glucose tolerance test with PPARγ+/+ (○) and PPARγhyp/hyp (•) mice (n = 8). (B) Serum glucose in fasted and fed state in vehicle-treated or rosiglitazone (30 mg/kg per day for 2 weeks)-treated mice after meal tolerance test (n = 4–8). (C) Serum insulin in fasted and fed state (treated with either vehicle or rosiglitazone) after a meal tolerance test (n = 4–8). (D) Serum adiponectin (n > 8). (E) Serum leptin (n > 8).
Fig. 5.
Fig. 5.
Muscle compensation of lipodystrophy in adult PPARγhyp/hyp mice. Quantitative RT-PCR of mRNA levels in WAT (A), BAT (B), muscle (C), and liver (D) of WT (empty bars) and homozygous (filled bars) mice. MCD, malonyl-CoA decarboxylase; MCAD, medium chain acyl-CoA dehydrogenase; PDHK, pyruvate dehydrogenase kinase 4; LCAD, long chain acyl-CoA dehydrogenase; CPT, carnitine acyltransferase; PEPCK, phosphoenolpyruvate carboxykinase.

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