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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

Representative western blot of p-HSL, HSL, and ATGL in adipose tissue from mice fed indicated diets
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Figure 8: Representative western blot of p-HSL, HSL, and ATGL in adipose tissue from mice fed indicated diets

Mentions: These data suggest that the obesogenic effect of eRAPA in combination with high fat or high caloric intake may be through pathways of fat mobilization. In vitro, inhibition of mTOR blocks adipogenesis and stimulates lipolysis [26-28]. In adipose tissue, we found that chronic eRAPA in combination with low fat diet reduces the phosphorylation of hormone sensitive lipase (HSL), the rate limiting step in lipolysis (Figure 8). In high fat-fed mice, there was almost no measurable phosphorylation of HSL in both control and eRAPA treated mice. These data suggest that lipolysis then is inhibited in vivo by chronic eRAPA treatment in mice fed the low fat fed mice. However, we also saw that adipose triglyceride lipase (ATGL), was elevated by eRAPA in both low fat and high fat diets suggesting increased breakdown of adipose resources (Figure 8). ATGL catalyzes the initial step in triacylglyceride hydrolysis, whereas HSL may have more specificity to the diacylglyceride form. These data then suggests a potentially complex effect of chronic eRAPA treatment that contributes to the adipose gain of these mice when also exposed to a high fat diet.


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)

Representative western blot of p-HSL, HSL, and ATGL in adipose tissue from mice fed indicated diets
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Representative western blot of p-HSL, HSL, and ATGL in adipose tissue from mice fed indicated diets
Mentions: These data suggest that the obesogenic effect of eRAPA in combination with high fat or high caloric intake may be through pathways of fat mobilization. In vitro, inhibition of mTOR blocks adipogenesis and stimulates lipolysis [26-28]. In adipose tissue, we found that chronic eRAPA in combination with low fat diet reduces the phosphorylation of hormone sensitive lipase (HSL), the rate limiting step in lipolysis (Figure 8). In high fat-fed mice, there was almost no measurable phosphorylation of HSL in both control and eRAPA treated mice. These data suggest that lipolysis then is inhibited in vivo by chronic eRAPA treatment in mice fed the low fat fed mice. However, we also saw that adipose triglyceride lipase (ATGL), was elevated by eRAPA in both low fat and high fat diets suggesting increased breakdown of adipose resources (Figure 8). ATGL catalyzes the initial step in triacylglyceride hydrolysis, whereas HSL may have more specificity to the diacylglyceride form. These data then suggests a potentially complex effect of chronic eRAPA treatment that contributes to the adipose gain of these mice when also exposed to a high fat diet.

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