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Deletion of the nuclear receptor ROR? in macrophages does not modify the development of obesity, insulin resistance and NASH.

ABSTRACT: Retinoic acid receptor-related orphan receptor-alpha (ROR?) is a transcription factor from the nuclear receptor family expressed by immune cells and involved in the development of obesity, insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). It was recently reported that mice deficient for ROR? in macrophages develop more severe NASH upon high fat diet (HFD) feeding due to altered Kupffer cell function. To better understand the role of ROR? in obesity and IR, we independently generated a macrophage ROR?-deficient mouse line. We report that ROR? deletion in macrophages does not impact on HFD-induced obesity and IR. Surprisingly, we did not confirm an effect on NASH development upon HFD feeding nor in the more severe and obesity-independent choline-deficient, L-amino acid-defined diet model. Our results therefore show that ROR? deletion in macrophages does not alter the development of obesity and IR and question its role in NASH.

SUBMITTER: L'homme L

PROVIDER: S-EPMC7713245 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Deletion of the nuclear receptor RORα in macrophages does not modify the development of obesity, insulin resistance and NASH.

L'homme Laurent L Sermikli Benan Pelin BP Molendi-Coste Olivier O Fleury Sébastien S Quemener Sandrine S Le Maître Mathilde M Joseph Marie-Laure ML Pineau Laurent L Duhem Christian C Gross Barbara B Vallez Emmanuelle E Tailleux Anne A Staels Bart B Dombrowicz David D

Scientific reports 20201203 1

Retinoic acid receptor-related orphan receptor-alpha (RORα) is a transcription factor from the nuclear receptor family expressed by immune cells and involved in the development of obesity, insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). It was recently reported that mice deficient for RORα in macrophages develop more severe NASH upon high fat diet (HFD) feeding due to altered Kupffer cell function. To better understand the role of RORα in obesity and IR, we independently genera ...[more]

PMID: 33273527

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Project description:ObjectiveThe nuclear receptor TAK1/TR4/NR2C2 is expressed in several tissues that are important in the control of energy homeostasis. In this study, we investigate whether TAK1 functions as a regulator of lipid and energy homeostasis and has a role in metabolic syndrome.Research design and methodsWe generated TAK1-deficient (TAK1⁻(/)⁻) mice to study the function of TAK1 in the development of metabolic syndrome in aged mice and mice fed a high-fat diet (HFD). (Immuno)histochemical, biochemical, and gene expression profile analyses were performed to determine the effect of the loss of TAK1 expression on lipid homeostasis in liver and adipose tissues. In addition, insulin sensitivity, energy expenditure, and adipose-associated inflammation were compared in wild-type (WT) and TAK1⁻(/)⁻ mice fed a HFD.ResultsTAK1-deficient (TAK1⁻(/)⁻) mice are resistant to the development of age- and HFD-induced metabolic syndrome. Histo- and biochemical analyses showed significantly lower hepatic triglyceride levels and reduced lipid accumulation in adipose tissue in TAK1⁻(/)⁻ mice compared with WT mice. Gene expression profiling analysis revealed that the expression of several genes encoding proteins involved in lipid uptake and triglyceride synthesis and storage, including Cidea, Cidec, Mogat1, and CD36, was greatly decreased in the liver and primary hepatocytes of TAK1⁻(/)⁻ mice. Restoration of TAK1 expression in TAK1⁻(/)⁻ hepatocytes induced expression of several lipogenic genes. Moreover, TAK1⁻(/)⁻ mice exhibited reduced infiltration of inflammatory cells and expression of inflammatory genes in white adipose tissue, and were resistant to the development of glucose intolerance and insulin resistance. TAK1⁻(/)⁻ mice consume more oxygen and produce more carbon dioxide than WT mice, suggesting increased energy expenditure.ConclusionsOur data reveal that TAK1 plays a critical role in the regulation of energy and lipid homeostasis, and promotes the development of metabolic syndrome. TAK1 may provide a new therapeutic target in the management of obesity, diabetes, and liver steatosis.

Dataset Information

Deletion of the nuclear receptor ROR? in macrophages does not modify the development of obesity, insulin resistance and NASH.

Publications

Deletion of the nuclear receptor RORα in macrophages does not modify the development of obesity, insulin resistance and NASH.

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