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Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure.

ABSTRACT: The role of the tumor suppressor retinoblastoma protein (pRb) has been firmly established in the control of cell cycle, apoptosis, and differentiation. Recently, it was demonstrated that lack of pRb promotes a switch from white to brown adipocyte differentiation in vitro. We used the Cre-Lox system to specifically inactivate pRb in adult adipose tissue. Under a high-fat diet, pRb-deficient (pRb(ad-/-)) mice failed to gain weight because of increased energy expenditure. This protection against weight gain was caused by the activation of mitochondrial activity in white and brown fat as evidenced by histologic, electron microscopic, and gene expression studies. Moreover, pRb(-/-) mouse embryonic fibroblasts displayed higher proliferation and apoptosis rates than pRb(+/+) mouse embryonic fibroblasts, which could contribute to the altered white adipose tissue morphology. Taken together, our data support a direct role of pRb in adipocyte cell fate determination in vivo and suggest that pRb could serve as a potential therapeutic target to trigger mitochondrial activation in white adipose tissue and brown adipose tissue, favoring an increase in energy expenditure and subsequent weight loss.

SUBMITTER: Dali-Youcef N

PROVIDER: S-EPMC1965576 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure.

Dali-Youcef Nassim N Mataki Chikage C Coste Agnès A Messaddeq Nadia N Giroud Sylvain S Blanc Stéphane S Koehl Christian C Champy Marie-France MF Chambon Pierre P Fajas Lluis L Metzger Daniel D Schoonjans Kristina K Auwerx Johan J

Proceedings of the National Academy of Sciences of the United States of America 20070607 25

The role of the tumor suppressor retinoblastoma protein (pRb) has been firmly established in the control of cell cycle, apoptosis, and differentiation. Recently, it was demonstrated that lack of pRb promotes a switch from white to brown adipocyte differentiation in vitro. We used the Cre-Lox system to specifically inactivate pRb in adult adipose tissue. Under a high-fat diet, pRb-deficient (pRb(ad-/-)) mice failed to gain weight because of increased energy expenditure. This protection against we ...[more]

PMID: 17556545

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Project description:ObjectiveMetainflammation is a chronic low-grade inflammatory state induced by obesity and associated comorbidities, including peripheral insulin resistance. Brown adipose tissue (BAT), a therapeutic target against obesity, is an insulin target tissue sensitive to inflammation. Therefore, it is necessary to find strategies to protect BAT against the effects of inflammation in energy balance. In this study, we explored the impact of moderate sirtuin 1 (SIRT1) overexpression on insulin sensitivity and β-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions.MethodsThe effect of inflammation on BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1Tg+) injected with a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies on differentiated BA (BA-WT and BA-SIRT1Tg+) exposed to a macrophage-derived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), and norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression.ResultsBAT from the db/db mice was susceptible to metabolic inflammation manifested by the activation of pro-inflammatory signaling cascades, increased pro-inflammatory gene expression, tissue-specific insulin resistance, and reduced UCP-1 expression. Impairment of insulin and noradrenergic responses were also found in the lean WT mice upon LPS injection. In contrast, BAT from the mice with moderate overexpression of SIRT1 (SIRT1Tg+) was protected against LPS-induced activation of pro-inflammatory signaling, insulin resistance, and defective thermogenic-related responses upon cold exposure. Importantly, the decline in triiodothyronine (T3) levels in the circulation and intra-BAT after exposure of the WT mice to LPS and cold was markedly attenuated in the SIRT1Tg+ mice. In vitro BA experiments in the two genotypes revealed that upon differentiation with a T3-enriched medium and subsequent exposure to a macrophage-derived pro-inflammatory CM, only BA-SIRT1Tg+ fully recovered insulin and noradrenergic responses.ConclusionsThis study has ascertained the benefit of the moderate overexpression of SIRT1 to confer protection against defective insulin and β-adrenergic responses caused by BAT inflammation. Our results have potential therapeutic value in combinatorial therapies for BAT-specific thyromimetics and SIRT1 activators to combat metainflammation in this tissue.

Dataset Information

Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure.

Publications

Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure.

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