Beneficial metabolic effects of rapamycin are associated with enhanced regulatory cells in diet-induced obese mice.
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.
Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France; Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France.
Kassem
K
Makki
Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France; Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France.
Solenne
S
Taront
Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France; Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1011, Lille Pasteur Institute, Lille, France.
Olivier
O
Molendi-Coste
Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France; Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1011, Lille Pasteur Institute, Lille, France.
Emmanuel
E
Bouchaert
Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France; Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France.
Bernadette
B
Neve
Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France; Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France.
Elodie
E
Eury
Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France; Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France.
Stéphane
S
Lobbens
Lille 2 University, Lille, France; Immunology Institute, Centre Hospitalier Régional Universitaire (CHRU) Lille and Equipe d'Accueil (EA)2686, Lille 2 University, Lille, France.
Myriam
M
Labalette
Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France; Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1011, Lille Pasteur Institute, Lille, France.
Hélène
H
Duez
Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France; Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1011, Lille Pasteur Institute, Lille, France.
Bart
B
Staels
Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France; Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1011, Lille Pasteur Institute, Lille, France.
David
D
Dombrowicz
Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France; Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France; Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom.
Philippe
P
Froguel
Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France; Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France.
Isabelle
I
Wolowczuk
D000273:Adipose Tissue / Q000276:immunology / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007333:Insulin Resistance / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D009765:Obesity / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000276:immunology
D004041:Dietary Fats; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus