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. 2004 Jun 1;101(22):8437-42.
doi: 10.1073/pnas.0401013101. Epub 2004 May 20.

Nuclear receptor corepressor RIP140 regulates fat accumulation

Göran Leonardsson  1 , Jenny H Steel, Mark Christian, Victoria Pocock, Stuart Milligan, Jimmy Bell, Po-Wah So, Gema Medina-Gomez, Antonio Vidal-Puig, Roger White, Malcolm G Parker
Affiliations

Nuclear receptor corepressor RIP140 regulates fat accumulation

Göran Leonardsson et al. Proc Natl Acad Sci U S A. .

Abstract

Nuclear receptors and their coactivators have been shown to function as key regulators of adipose tissue biology. Here we show that a ligand-dependent transcriptional repressor for nuclear receptors plays a crucial role in regulating the balance between energy storage and energy expenditure. Mice devoid of the corepressor protein RIP140 are lean, show resistance to high-fat diet-induced obesity and hepatic steatosis, and have increased oxygen consumption. Although the process of adipogenesis is unaffected, expression of certain lipogenic enzymes is reduced. In contrast, genes involved in energy dissipation and mitochondrial uncoupling, including uncoupling protein 1, are markedly increased. Therefore, the maintenance of energy homeostasis requires the action of a transcriptional repressor in white adipose tissue, and ligand-dependent recruitment of RIP140 to nuclear receptors may provide a therapeutic target in the treatment of obesity and related disorders.

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Figures

Fig. 1.
Fig. 1.
Metabolic phenotype of RIP140-null mice is shown. (a) Body weights of WT (black) and RIP140-null (gray) mice fed a regular chow diet at 6 months (n = 7) and 15 months (WT, n = 14; RIP140-null, n = 11) of age. (b) Inguinal WAT weights of WT (black) and RIP140-null (gray) mice at 6 months (n = 7 for both groups) and 15 months (WT, n = 14; RIP140-null, n = 11) of age. (c) MRI and magnetic resonance spectroscopy (MRS) of body fat content. Whole-body proton content is quantified, with the lipid peak indicated. Calculations from three representative animals revealed an ≈70% reduction of total fat content in RIP140-null (KO) mice. (d) Morphology of metabolic tissues from WT and RIP140-null mice. WAT (inguinal), BAT, and liver were isolated from WT and RIP140-null (KO) mice fed a control chow diet. WAT and BAT were stained with hematoxylin/eosin. Liver tissues were stained with Oil red O to demonstrate lipid accumulation and counterstained with hematoxylin. (Scale bars = 50 μm.)
Fig. 2.
Fig. 2.
Histology of metabolic tissues and serum biochemistry is shown. (a) Serum free fatty acid (FFA) levels and triglyceride levels in WT (black) and RIP140-null (gray) mice fed a high-fat diet for 10 days (n = 6). (b) Serum levels of leptin in WT (black) or RIP140-null (gray) mice (n = 3-6) fed chow or a high-fat diet. (c) Morphology of inguinal WAT, BAT, and liver from WT and RIP140-null (KO) mice fed a high-fat diet (35% wt/wt) for 10 days. Tissues were stained as in Fig. 1d. (Scale bars = 50 μm.) (d) Comparison of cell size in WAT of WT and RIP140-null mice maintained on normal chow and high-fat (35%) diet.
Fig. 3.
Fig. 3.
RIP140 expression and adipocyte differentiation in vitro is shown. (a) Regulation of RIP140 mRNA levels during differentiation of 3T3-L1 adipocyte cells. Differentiation was induced in 2-day-confluent cells by using a standard hormone mixture of insulin, dexamethasone, and 3-isobutyl-1-methylxanthine preconfluent cells (pc). mRNA was quantitated by TaqMan real-time PCR analysis. (b and c) Embryonic fibroblasts at confluence (b) and after differentiation by using hormone mixture as above but with addition of a PPAR agonist, rosiglitazone (c), were stained with Oil red O. Differentiated cells were also subject to β-galactosidase activity analysis to demonstrate RIP140 promoter activity (d). Note the lack of β-galactosidase activity in WT cells and the correlation of fat droplet-containing cells staining with oil red O and β-galactosidase.
Fig. 4.
Fig. 4.
Expression profile of adipogenic regulators and marker genes in metabolic tissues. TaqMan real-time PCR analysis of gene expression in metabolic tissues from WT (black) and RIP140-null (gray) mice (n = 3-7). Mu, skeletal muscle; Li, liver.
Fig. 5.
Fig. 5.
Up-regulation of genes involved in energy dissipation in WAT. (a) TaqMan real-time PCR analysis of RIP140 mRNA levels in metabolic tissues. Tissue samples were from WAT, BAT, skeletal muscle (Mu), and liver (Li) from WT mice (n = 3-7). (b) TaqMan real-time PCR analysis of UCP1 and CPT1b gene expression in metabolic tissues from WT (black) and RIP140-null (gray) mice (n = 3-7). (c) Immunostaining of UCP1 expression in WAT from WT and RIP140-null (KO) mice. (Scale bars = 50 μm.)
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