Comparison of rapamycin schedules in mice on high-fat diet

Abstract

At a wide range of doses, rapamycin extends life span in mice. It was shown that intraperitoneal injections (i.p.) of rapamycin prevent weight gain in mice on high-fat diet (HFD). We further investigated the effect of rapamycin on weight gain in female C57BL/6 mice on HFD started at the age of 7.5 months. By the age of 16 and 23 months, mice on HFD weighed significantly more (52 vs 33 g; p D 0.0001 and 70 vs 38 g; p < 0.0001, respectively) than mice on low fat diet (LFD). The i.p. administration of 1.5 mg/kg rapamycin, 3 times a week every other week, completely prevented weight gain, whereas administration of rapamycin by oral gavash did not. Rapamycin given in the drinking water slightly decreased weight gain by the age of 23 months. In addition, metabolic parameters were evaluated at the age of 16 and 23 months, 6 and 13 days after last rapamycin administration, respectively. Plasma leptin levels strongly correlated with body weight, (P < 0.0001, rD0.86), suggesting that the difference in weight was due to fat tissue mass. Levels of insulin, glucose, triglycerides and IGF1 were not statistically different in all groups, indicating that these courses of rapamycin treatment did not impair metabolic parameters at least after rapamycin discontinuation. Despite rapamycin discontinuation, cardiac levels of phospho-S6 and pAKT(S473) were low in the i.p.-treated group. This continuous effect of rapamycin can be explained by prevention of obesity in the i.p. group. We conclude that intermittent i.p. administration of rapamycin prevents weight gain without causing gross metabolic abnormalities. Intermittent gavash administration minimally affected weight gain. Potential clinical applications are discussed.

Leptin signaling enhances cell invasion and promotes the metastasis of human pancreatic cancer via increasing MMP-13 production

“…This study suggests leptin signaling as an attractive target for the treatment of pancreatic cancer, especially for patients with metabolic disorders. Recently, studies from Blagosklonny's group have found that intermittent administration of rapamycin could prevent weight gain and reduce peripheral leptin level in mice on high-fat diet without changing metabolic parameters such as insulin, glucose, triglycerides and insulin-like growth factor 1 [ 55 , 56 ]. Another study has shown that in a rat model of obesity, rapamycin was able to normalize elevated serum leptin by alleviating obesity and decreasing leptin synthesis in white adipose tissues [ 57 ].…”

Esophageal adenocarcinoma and obesity: peritumoral adipose tissue plays a role in lymph node invasion

“…Furthermore, this study suggests that the prevention or inhibition of potentially negative effects of adipose tissue on cancer progression should be considered in the therapeutic approach of EAC patients. It was shown that obesity, leptin levels and adipocyte size can be reduced by rapamycin, an immunosuppressive chemical able to bind mTOR Complex 1 (mTORC1) and inhibit downstream signaling [ 43 , 44 ]. More importantly, rapamycin might prevent cancer onset possibly in part due to these effects on fat tissues [ 45 ].…”

PI3Kα inhibition reduces obesity in mice

“…Therefore, the beneficial metabolic effects of reduced PI3K signaling could explain, at least in part, the improved healthspan and delayed aging. Furthermore, inhibition of the PI3K downstream effector mTOR by rapamycin also increases longevity [6] and reduces body weight [7]. …”