title: Rapamycin-induced metabolic defects are reversible in both lean and obese mice.
abstract: The inhibition of mTOR (mechanistic target of rapamycin) by the macrolide rapamycin has many beneficial effects in mice, including extension of lifespan and reduction or prevention of several age-related diseases. At the same time, chronic rapamycin treatment causes impairments in glucose metabolism including hyperglycemia, glucose intolerance and insulin resistance. It is unknown whether these metabolic effects of rapamycin are permanent or whether they can be alleviated. Here, we confirmed that rapamycin causes glucose intolerance and insulin resistance in both inbred and genetically heterogeneous mice fed either low fat or high fat diets, suggesting that these effects of rapamycin are independent of genetic background. Importantly, we also found that these effects were almost completely lost within a few weeks of cessation of treatment, showing that chronic rapamycin treatment does not induce permanent impairment of glucose metabolism. Somewhat surprisingly, chronic rapamycin also promoted increased accumulation of adipose tissue in high fat fed mice. However, this effect too was lost when rapamycin treatment was ended suggesting that this effect of rapamycin is also not permanent. The reversible nature of rapamycin's alterations of metabolic function suggests that these potentially detrimental side-effects might be managed through alternative dosing strategies or concurrent treatment options.
authors.affiliation: The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio TX 78245, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio TX 78245, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Diaz
authors.affiliation: The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio TX 78245, USA. The Geriatric Research Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX 78229, USA. Departments of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio TX 78245, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fernandez
authors.affiliation: The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio TX 78245, USA. The Geriatric Research Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX 78229, USA. Departments of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio TX 78245, USA.
authors.forename: Randy
authors.initials: R
authors.lastname: Strong
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Ye
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Baur
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison WI 53726, USA.
authors.forename: Dudley W
authors.initials: DW
authors.lastname: Lamming
authors.affiliation: Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center and Oklahoma City VA Medical Center, Oklahoma OK 73104, USA.
authors.forename: Arlan
authors.initials: A
authors.lastname: Richardson
authors.affiliation: The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio TX 78245, USA. The Geriatric Research Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX 78229, USA. Departments of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio TX 78245, USA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Salmon
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D044882:Glucose Metabolism Disorders / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D000903:Antibiotics, Antineoplastic; D020123:Sirolimus