Chronic rapamycin treatment exacerbates metabolism and does not down-regulate mTORC2/Akt signaling in diabetic mice induced by high-fat diet and streptozotocin.
Rapamycin, a classical inhibitor of the mammalian target of rapamycin (mTOR), has been intensively studied for its role in metabolism and verified to induce metabolic defects through mTORC2/Akt pathway. However, disparity of the results exists depending on the differences of the animal models or the detailed procedures. Moreover, data regarding the effect of rapamycin treatment in diabetic models are sparse. Therefore, we investigated its influence on glucose and lipid metabolism, and further analyzed its effect on the mTORC2/Akt pathway in a high-fat diet- and streptozotocin-induced diabetic mice model. Three-weeks old C57BL/6J mice were fed with a high fat diet (60 kcal% fat) and intraperitoneally injected with streptozotocin (100 mg/kg) at 6 weeks of age. Rapamycin (2 mg/kg) was orally given to the mice daily for consecutive 6 weeks. Body weight, blood lipid parameters and HbA(1c)% values were evaluated. Oral glucose test and insulin tolerance test were performed. Furthermore, western blot assay was applied to investigate the protein epression levels of Akt and PKCα, two key targets of the mTORC2/Akt pathway. Rapamycin-treated diabetic mice demonstrated less weight gain, more profound symptoms of polydipsia, polyphagia and polyuria, significant liver fat accumulation and exacerbated metabolic disorders including insulin resistance, hyperglycemia and dyslipidemia. Contrary to what have been expected, though significantly inhibiting mTORC1/S6K1 signaling, chronic rapamycin treatment failed to down-regulate mTORC2/Akt pathway. Our findings provide evidence that chronic rapamycin treatment may exacerbate metabolism in diabetic subjects and does not down-regulate mTORC2/Akt signialing in a high-fat diet- and streptozotocin-induced diabetic mice model.
Yan
Y
Wang
Zhi
Z
He
Xianhui
X
Li
Wenwei
W
Chen
Jiewen
J
Lu
Xiangping
X
Chen
Liang
L
Cao
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D059305:Diet, High-Fat; D004326:Drinking; D004435:Eating / Q000187:drug effects; D005951:Glucose Tolerance Test; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000473:pathology; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D046912:Multiprotein Complexes; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus