PMID- 30117227 OWN - NLM STAT- MEDLINE DCOM- 20190529 LR - 20220408 IS - 1469-445X (Electronic) IS - 0958-0670 (Print) IS - 0958-0670 (Linking) VI - 103 IP - 11 DP - 2018 Nov TI - Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat. PG - 1469-1480 LID - 10.1113/EP087207 [doi] AB - NEW FINDINGS: What is the central question of this study? Whether chronic oral rapamycin promotes beneficial effects on glucose/lipid metabolism and energy balance when administered to mice with an obesogenic diet rich in saturated fat and sucrose has not been explored. What is the main finding and its importance? Chronic oral rapamycin reduces body weight and fat gain, improves insulin sensitivity and reduces hepatic steatosis when administered to mice with a high-fat, high-sucrose diet. In addition, we make the new observation that there appear to be tissue-specific effects of rapamycin. Although rapamycin appears to impart its effects mainly on visceral adipose tissue, its effects on insulin sensitivity are mediated by subcutaneous adipose tissue. ABSTRACT: Excess adiposity is commonly associated with insulin resistance, which can increase the risk of cardiovascular disease. However, the exact molecular mechanisms by which obesity results in insulin resistance are yet to be understood clearly. The intracellular nutrient-sensing protein, mechanistic target of rapamycin (mTOR), is a crucial signalling component in the development of obesity-associated insulin resistance. Given that increased tissue activation of mTOR complex-1 (mTORC1) occurs in obesity, diabetes and ageing, we hypothesized that pharmacological inhibition of mTORC1 would improve metabolic dysregulation in diet-induced obesity. We administered continuous rapamycin, a specific mTORC1 inhibitor, orally to C57BL/6J mice concurrently with a high-fat, high-sucrose (HFHS) diet for 20 weeks. The control group received placebo microcapsules. Rapamycin-treated mice showed significantly reduced weight gain and adiposity (33.6 +/- 4.9 versus 40.4 +/- 3.0% body fat, P < 0.001, n = 8 mice per group), despite increased or equivalent food intake compared with the placebo group. The rapamycin-fed mice also demonstrated reduced plasma glucose (252 +/- 57 versus 297 +/- 67 mg dl(-1) , P < 0.001) and improved insulin sensitivity during insulin and glucose tolerance testing. Rapamycin-treated mice also had lower plasma triglycerides (48 +/- 13 versus 67 +/- 11 mg/dL, P < 0.01) and hepatic triglyceride content (89 +/- 15 versus 110 +/- 19 mg/g liver, P < 0.05) compared with the placebo group. A moderately low dose of rapamycin decreased adiposity and improved the metabolic profile in a model of diet-induced obesity. These data suggest that low-grade chronic mTORC1 inhibition might be a potential strategy for anti-obesity therapies. CI - (c) 2018 University of Washington. Experimental Physiology (c) 2018 The Physiological Society. FAU - den Hartigh, Laura J AU - den Hartigh LJ AUID- ORCID: 0000-0002-6789-5916 AD - Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, 98019, USA. AD - Diabetes Institute, University of Washington, Seattle, WA, 98019, USA. FAU - Goodspeed, Leela AU - Goodspeed L AD - Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, 98019, USA. AD - Diabetes Institute, University of Washington, Seattle, WA, 98019, USA. FAU - Wang, Shari A AU - Wang SA AD - Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, 98019, USA. AD - Diabetes Institute, University of Washington, Seattle, WA, 98019, USA. FAU - Kenerson, Heidi L AU - Kenerson HL AD - Department of Surgery, University of Washington, Seattle, WA, 98019, USA. FAU - Omer, Mohamed AU - Omer M AD - Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, 98019, USA. AD - Diabetes Institute, University of Washington, Seattle, WA, 98019, USA. FAU - O'Brien, Kevin D AU - O'Brien KD AD - Diabetes Institute, University of Washington, Seattle, WA, 98019, USA. AD - Division of Cardiology, University of Washington, Seattle, WA, 98019, USA. FAU - Ladiges, Warren AU - Ladiges W AD - Department of Comparative Medicine, University of Washington, Seattle, WA, 98019, USA. FAU - Yeung, Raymond AU - Yeung R AD - Department of Surgery, University of Washington, Seattle, WA, 98019, USA. FAU - Subramanian, Savitha AU - Subramanian S AD - Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, 98019, USA. AD - Diabetes Institute, University of Washington, Seattle, WA, 98019, USA. LA - eng GR - HL092969/NH/NIH HHS/United States GR - DK035816/NH/NIH HHS/United States GR - AT007177/NH/NIH HHS/United States GR - K01 AT007177/AT/NCCIH NIH HHS/United States GR - P30 DK035816/DK/NIDDK NIH HHS/United States GR - P01 HL092969/HL/NHLBI NIH HHS/United States GR - DK017047/NH/NIH HHS/United States GR - P30 DK017047/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20180913 PL - England TA - Exp Physiol JT - Experimental physiology JID - 9002940 RN - 0 (Blood Glucose) RN - 0 (Dietary Fats) RN - 0 (Dietary Sucrose) RN - 0 (Triglycerides) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adiposity/*drug effects MH - Animals MH - Blood Glucose MH - Body Weight/drug effects MH - *Dietary Fats MH - *Dietary Sucrose MH - Insulin Resistance/*physiology MH - Lipid Metabolism/drug effects MH - Liver/*drug effects/metabolism MH - Male MH - Mice MH - Sirolimus/*pharmacology MH - Triglycerides/*metabolism PMC - PMC6446929 MID - NIHMS1010741 OTO - NOTNLM OT - browning OT - insulin sensitivity OT - mTORC1 OT - white adipose tissue COIS- Competing Interests Statement: the authors have no conflicts of interests to disclose. EDAT- 2018/08/18 06:00 MHDA- 2019/05/30 06:00 PMCR- 2019/04/03 CRDT- 2018/08/18 06:00 PHST- 2018/06/21 00:00 [received] PHST- 2018/08/09 00:00 [accepted] PHST- 2018/08/18 06:00 [pubmed] PHST- 2019/05/30 06:00 [medline] PHST- 2018/08/18 06:00 [entrez] PHST- 2019/04/03 00:00 [pmc-release] AID - 10.1113/EP087207 [doi] PST - ppublish SO - Exp Physiol. 2018 Nov;103(11):1469-1480. doi: 10.1113/EP087207. Epub 2018 Sep 13.