Beneficial Metabolic Effects of Rapamycin Are Associated with Enhanced Regulatory Cells in Diet-Induced Obese Mice
Autor: | Olivier Molendi-Coste, Bart Staels, E. Eury, Hélène Duez, Emmanuel Bouchaert, Isabelle Wolowczuk, Myriam Labalette, Stéphane Lobbens, Kassem Makki, Philippe Froguel, David Dombrowicz, Bernadette Neve, Solenne Taront |
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Jazyk: | angličtina |
Rok vydání: | 2014 |
Předmět: |
Male
Physiology Microarrays Adipose tissue mTORC1 Pharmacology mTORC2 Biochemistry T-Lymphocytes Regulatory Monocytes White Blood Cells Mice Endocrinology Animal Cells Immune Physiology Medicine and Health Sciences Insulin Myeloid Cells Immune Response Multidisciplinary biology T Cells TOR Serine-Threonine Kinases Animal Models Bioassays and Physiological Analysis Physiological Parameters Adipose Tissue Liver Medicine Cytokines Female medicine.symptom Anatomy Cellular Types Immunosuppressive Agents Research Article Signal Transduction medicine.medical_specialty Science Immune Cells Immunology Inflammation Endocrine System Mouse Models Mechanistic Target of Rapamycin Complex 2 Mechanistic Target of Rapamycin Complex 1 Research and Analysis Methods Insulin resistance Model Organisms Internal medicine medicine Animals Obesity Mechanistic target of rapamycin PI3K/AKT/mTOR pathway Nutrition Cell Proliferation Diabetic Endocrinology Sirolimus Blood Cells Endocrine Physiology business.industry Body Weight Immunity Biology and Life Sciences Computational Biology Immunoregulation Cell Biology Molecular Development medicine.disease Dietary Fats Hormones Disease Models Animal Immune System Multiprotein Complexes biology.protein Insulin Resistance business Diet-induced obese Developmental Biology |
Zdroj: | PLoS ONE PLoS ONE, Vol 9, Iss 4, p e92684 (2014) |
ISSN: | 1932-6203 |
Popis: | The "mechanistic target of rapamycin" (mTOR) is a central controller of growth, proliferation and/or motility of various cell-types ranging from adipocytes to immune cells, thereby linking metabolism and immunity. mTOR signaling is overactivated in obesity, promoting inflammation and insulin resistance. Therefore, great interest exists in the development of mTOR inhibitors as therapeutic drugs for obesity or diabetes. However, despite a plethora of studies characterizing the metabolic consequences of mTOR inhibition in rodent models, its impact on immune changes associated with the obese condition has never been questioned so far. To address this, we used a mouse model of high-fat diet (HFD)-fed mice with and without pharmacologic mTOR inhibition by rapamycin. Rapamycin was weekly administrated to HFD-fed C57BL/6 mice for 22 weeks. Metabolic effects were determined by glucose and insulin tolerance tests and by indirect calorimetry measures of energy expenditure. Inflammatory response and immune cell populations were characterized in blood, adipose tissue and liver. In parallel, the activities of both mTOR complexes (e. g. mTORC1 and mTORC2) were determined in adipose tissue, muscle and liver. We show that rapamycin-treated mice are leaner, have enhanced energy expenditure and are protected against insulin resistance. These beneficial metabolic effects of rapamycin were associated to significant changes of the inflammatory profiles of both adipose tissue and liver. Importantly, immune cells with regulatory functions such as regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were increased in adipose tissue. These rapamycin-triggered metabolic and immune effects resulted from mTORC1 inhibition whilst mTORC2 activity was intact. Taken together, our results reinforce the notion that controlling immune regulatory cells in metabolic tissues is crucial to maintain a proper metabolic status and, more generally, comfort the need to search for novel pharmacological inhibitors of the mTOR signaling pathway to prevent and/or treat metabolic diseases. |
Databáze: | OpenAIRE |
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