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Rapamycin-induced metabolic defects are reversible in both lean and obese mice.

Liu Y, Diaz V, Fernandez E, Strong R, Ye L, Baur JA, Lamming DW, Richardson A, Salmon AB - Aging (Albany NY) (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

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Related in: MedlinePlus

(A) Fasting blood glucose levels after feeding indicated diets for 2 and 4 months. (B) Fasting and glucose stimulated insulin levels in whole blood. For all, symbols represent average (± SEM) values for n=6 mice treated with (solid) or without (open) encapsulated rapamycin (eRAPA) for the indicated diet. F and p values are given for either 2 way (A) or 3 way (B) ANOVA testing indicated variables.
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Figure 2: (A) Fasting blood glucose levels after feeding indicated diets for 2 and 4 months. (B) Fasting and glucose stimulated insulin levels in whole blood. For all, symbols represent average (± SEM) values for n=6 mice treated with (solid) or without (open) encapsulated rapamycin (eRAPA) for the indicated diet. F and p values are given for either 2 way (A) or 3 way (B) ANOVA testing indicated variables.

Mentions: Chronic rapamycin treatment has been shown to impair several measurements of glucose metabolism including increased circulating levels of glucose and insulin and impaired glucose and insulin tolerance [6, 17, 18, 23, 24]. At least some of these effects seem to be dependent on genetic strain of the model system, means of administration and length of treatment [6, 17, 18, 23, 24]. Here, we found that chronic treatment with enteric rapamycin (eRAPA) significantly impairs glucose intolerance and promotes insulin resistance in C57BL/6 mice when given in combination with either a low fat or a high fat diet (Figure 1). The same group of mice were tested longitudinally, first after 2 months and then after 4 months of eRAPA treatment. Both high fat diet and eRAPA impaired glucose and insulin tolerance at each time points, but we found no significant interaction effect suggesting that eRAPA promoted metabolic dysfunction equally in both low fat and high fat diets (Figure 1B, D). Moreover, time on diet had no significant effect on either markers suggesting that the effects of eRAPA occur quickly but do not become progressively worse at least in the time frame at which we studied. Fasting blood glucose levels were unaffected by eRAPA at both time points on both diets, though high fat diet did significantly increase these levels (Figure 2A). We also measured glucose-stimulated insulin secretion to determine if this might explain the impaired glucose tolerance. While high fat diet significantly increased blood insulin levels in both fasted and glucose-stimulated mice, these levels were unaffected by treatment with eRAPA on both diets (Figure 2B).


Rapamycin-induced metabolic defects are reversible in both lean and obese mice.

Liu Y, Diaz V, Fernandez E, Strong R, Ye L, Baur JA, Lamming DW, Richardson A, Salmon AB - Aging (Albany NY) (2014)

(A) Fasting blood glucose levels after feeding indicated diets for 2 and 4 months. (B) Fasting and glucose stimulated insulin levels in whole blood. For all, symbols represent average (± SEM) values for n=6 mice treated with (solid) or without (open) encapsulated rapamycin (eRAPA) for the indicated diet. F and p values are given for either 2 way (A) or 3 way (B) ANOVA testing indicated variables.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4221917&req=5

Figure 2: (A) Fasting blood glucose levels after feeding indicated diets for 2 and 4 months. (B) Fasting and glucose stimulated insulin levels in whole blood. For all, symbols represent average (± SEM) values for n=6 mice treated with (solid) or without (open) encapsulated rapamycin (eRAPA) for the indicated diet. F and p values are given for either 2 way (A) or 3 way (B) ANOVA testing indicated variables.
Mentions: Chronic rapamycin treatment has been shown to impair several measurements of glucose metabolism including increased circulating levels of glucose and insulin and impaired glucose and insulin tolerance [6, 17, 18, 23, 24]. At least some of these effects seem to be dependent on genetic strain of the model system, means of administration and length of treatment [6, 17, 18, 23, 24]. Here, we found that chronic treatment with enteric rapamycin (eRAPA) significantly impairs glucose intolerance and promotes insulin resistance in C57BL/6 mice when given in combination with either a low fat or a high fat diet (Figure 1). The same group of mice were tested longitudinally, first after 2 months and then after 4 months of eRAPA treatment. Both high fat diet and eRAPA impaired glucose and insulin tolerance at each time points, but we found no significant interaction effect suggesting that eRAPA promoted metabolic dysfunction equally in both low fat and high fat diets (Figure 1B, D). Moreover, time on diet had no significant effect on either markers suggesting that the effects of eRAPA occur quickly but do not become progressively worse at least in the time frame at which we studied. Fasting blood glucose levels were unaffected by eRAPA at both time points on both diets, though high fat diet did significantly increase these levels (Figure 2A). We also measured glucose-stimulated insulin secretion to determine if this might explain the impaired glucose tolerance. While high fat diet significantly increased blood insulin levels in both fasted and glucose-stimulated mice, these levels were unaffected by treatment with eRAPA on both diets (Figure 2B).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus