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
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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