Beneficial metabolic effects of rapamycin are associated with enhanced regulatory cells in diet-induced obese mice

• Published in: PloS one Vol. 9; no. 4; p. e92684
• Main Authors: Makki, Kassem, Taront, Solenne, Molendi-Coste, Olivier, Bouchaert, Emmanuel, Neve, Bernadette, Eury, Elodie, Lobbens, Stéphane, Labalette, Myriam, Duez, Hélène, Staels, Bart, Dombrowicz, David, Froguel, Philippe, Wolowczuk, Isabelle
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2014; Public Library of Science (PLoS)
• Subjects: Adipocytes; Adipose tissue; Adipose Tissue - immunology; Adipose Tissue - pathology; Animal models; Animal tissues; Animals; Biology and Life Sciences; Calorimetry; Care and treatment; Cell Proliferation - drug effects; Cytokines; Diabetes; Diabetes mellitus; Dietary Fats - adverse effects; Dietary Fats - pharmacology; Disease Models, Animal; Drug development; Drugs; Energy expenditure; Female; Glucose tolerance; Health aspects; Hepatocytes; High fat diet; Immune system; Immunity; Immunological tolerance; Immunoregulation; Immunosuppressive agents; Immunosuppressive Agents - pharmacology; Inflammation; Inflammatory response; Inhibition; Inhibitors; Insulin; Insulin resistance; Insulin Resistance - immunology; Life Sciences; Liver; Liver - immunology; Liver - pathology; Lymphocytes T; Male; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Medicine and Health Sciences; Metabolic disorders; Metabolism; Mice; Multiprotein Complexes - immunology; Muscles; Myeloid Cells - immunology; Myeloid Cells - pathology; Obesity; Obesity - chemically induced; Obesity - immunology; Obesity - pathology; Pharmacology; Rapamycin; Research and Analysis Methods; Risk factors; Rodents; Signal transduction; Signal Transduction - drug effects; Signaling; Sirolimus - pharmacology; Suppressor cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; TOR protein; TOR Serine-Threonine Kinases - immunology; France; United Kingdom
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0092684

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.