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Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue.

Houde VP, Brûlé S, Festuccia WT, Blanchard PG, Bellmann K, Deshaies Y, Marette A - Diabetes (2010)

Bottom Line: Chronic rapamycin treatment reduced adiposity and fat cell number, which was associated with a coordinated downregulation of genes involved in both lipid uptake and output.The latter was associated with elevated expression of hepatic gluconeogenic master genes, PEPCK and G6Pase, and increased expression of the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) as well as enhanced nuclear recruitment of FoxO1, CRTC2, and CREB.These findings unravel a novel mechanism by which mTORC1/S6K1 controls gluconeogenesis through modulation of several key transcriptional factors.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Faculty of Medicine, Cardiology Axis of the Quebec Heart and Lung Institute, and the Metabolism, Vascular and Renal Health Axis, Laval University Hospital Research Center, Laval University, Quebec, Canada.

ABSTRACT

Objective: The mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) pathway is a critical signaling component in the development of obesity-linked insulin resistance and operates a nutrient-sensing negative feedback loop toward the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Whereas acute treatment of insulin target cells with the mTOR complex 1 (mTORC1) inhibitor rapamycin prevents nutrient-induced insulin resistance, the chronic effect of rapamycin on insulin sensitivity and glucose metabolism in vivo remains elusive.

Research design and methods: To assess the metabolic effects of chronic inhibition of the mTORC1/S6K1 pathway, rats were treated with rapamycin (2 mg/kg/day) or vehicle for 15 days before metabolic phenotyping.

Results: Chronic rapamycin treatment reduced adiposity and fat cell number, which was associated with a coordinated downregulation of genes involved in both lipid uptake and output. Rapamycin treatment also promoted insulin resistance, severe glucose intolerance, and increased gluconeogenesis. The latter was associated with elevated expression of hepatic gluconeogenic master genes, PEPCK and G6Pase, and increased expression of the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) as well as enhanced nuclear recruitment of FoxO1, CRTC2, and CREB. These changes were observed despite normal activation of the insulin receptor substrate/PI 3-kinase/Akt axis in liver of rapamycin-treated rats, as expected from the blockade of the mTORC1/S6K1 negative feedback loop.

Conclusions: These findings unravel a novel mechanism by which mTORC1/S6K1 controls gluconeogenesis through modulation of several key transcriptional factors. The robust induction of the gluconeogenic program in liver of rapamycin-treated rats underlies the development of severe glucose intolerance even in the face of preserved hepatic insulin signaling to Akt and despite a modest reduction in adiposity.

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Chronic rapamycin treatment coordinately downregulates genes required for triglyceride hydrolysis, fatty acid transport, and esterification in adipose tissue. Rats were treated with rapamycin as described in the legend to Fig. 1, and adipose tissue was sampled and processed as described in the research design and methods section for determinations of LPL, FATP1, FAT/CD36, Lipin1, PEPCK, MGL, HSL, ATGL, PPARγ1, and PPARγ2 mRNA expression. The graphs depict mRNA expression in the adipose tissue of target genes corrected for the expression of 36B4 as a control gene. n = 12 for each group. *P ≤ 0.05, **P ≤ 0.01.
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Figure 2: Chronic rapamycin treatment coordinately downregulates genes required for triglyceride hydrolysis, fatty acid transport, and esterification in adipose tissue. Rats were treated with rapamycin as described in the legend to Fig. 1, and adipose tissue was sampled and processed as described in the research design and methods section for determinations of LPL, FATP1, FAT/CD36, Lipin1, PEPCK, MGL, HSL, ATGL, PPARγ1, and PPARγ2 mRNA expression. The graphs depict mRNA expression in the adipose tissue of target genes corrected for the expression of 36B4 as a control gene. n = 12 for each group. *P ≤ 0.05, **P ≤ 0.01.

Mentions: To better understand the mechanism by which chronic rapamycin treatment impairs adipogenesis and causes hyperlipidemia, we next measured the mRNA levels of several genes involved in the clearance of lipids from the circulation and their deposition in adipose tissue as triglycerides. Retroperitoneal adipose tissue expression of lipoprotein lipase (LPL), which catalyzes the hydrolysis of lipoprotein-bound triglycerides supplying fatty acids and glycerol for adipose depot uptake (20), along with the fatty acid transporters (FATP1 and FAT/CD36) were all downregulated by rapamycin treatment (Fig. 2). In addition, phosphoenolpyruvate carboxykinase (PEPCK), which generates the glycerol 3-phosphate backbone for fatty acid esterification (21), and lipin 1, an important enzyme involved in triglyceride synthesis (22), were also significantly reduced by rapamycin treatment. We also evaluated the mRNA levels of the enzymes adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacyglycerol lipase (MGL), which catalyze the sequential hydrolysis of triglycerides to fatty acids and glycerol (23). Chronic rapamycin treatment markedly reduced the expression of ATGL and MGL without affecting those of HSL, excluding possible participation of increased lipolysis to the adipose tissue phenotype and hyperlipidemia. Interestingly, the reduced expression of genes involved in lipid uptake and storage and lipolysis was associated with a significant decrease in the mRNA levels of peroxisome proliferator-activated receptor-γ2 (PPARγ2), a master regulator of adipogenesis, lipogenesis, and lipolysis (Fig. 2) (13,20,24).


Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue.

Houde VP, Brûlé S, Festuccia WT, Blanchard PG, Bellmann K, Deshaies Y, Marette A - Diabetes (2010)

Chronic rapamycin treatment coordinately downregulates genes required for triglyceride hydrolysis, fatty acid transport, and esterification in adipose tissue. Rats were treated with rapamycin as described in the legend to Fig. 1, and adipose tissue was sampled and processed as described in the research design and methods section for determinations of LPL, FATP1, FAT/CD36, Lipin1, PEPCK, MGL, HSL, ATGL, PPARγ1, and PPARγ2 mRNA expression. The graphs depict mRNA expression in the adipose tissue of target genes corrected for the expression of 36B4 as a control gene. n = 12 for each group. *P ≤ 0.05, **P ≤ 0.01.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874694&req=5

Figure 2: Chronic rapamycin treatment coordinately downregulates genes required for triglyceride hydrolysis, fatty acid transport, and esterification in adipose tissue. Rats were treated with rapamycin as described in the legend to Fig. 1, and adipose tissue was sampled and processed as described in the research design and methods section for determinations of LPL, FATP1, FAT/CD36, Lipin1, PEPCK, MGL, HSL, ATGL, PPARγ1, and PPARγ2 mRNA expression. The graphs depict mRNA expression in the adipose tissue of target genes corrected for the expression of 36B4 as a control gene. n = 12 for each group. *P ≤ 0.05, **P ≤ 0.01.
Mentions: To better understand the mechanism by which chronic rapamycin treatment impairs adipogenesis and causes hyperlipidemia, we next measured the mRNA levels of several genes involved in the clearance of lipids from the circulation and their deposition in adipose tissue as triglycerides. Retroperitoneal adipose tissue expression of lipoprotein lipase (LPL), which catalyzes the hydrolysis of lipoprotein-bound triglycerides supplying fatty acids and glycerol for adipose depot uptake (20), along with the fatty acid transporters (FATP1 and FAT/CD36) were all downregulated by rapamycin treatment (Fig. 2). In addition, phosphoenolpyruvate carboxykinase (PEPCK), which generates the glycerol 3-phosphate backbone for fatty acid esterification (21), and lipin 1, an important enzyme involved in triglyceride synthesis (22), were also significantly reduced by rapamycin treatment. We also evaluated the mRNA levels of the enzymes adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacyglycerol lipase (MGL), which catalyze the sequential hydrolysis of triglycerides to fatty acids and glycerol (23). Chronic rapamycin treatment markedly reduced the expression of ATGL and MGL without affecting those of HSL, excluding possible participation of increased lipolysis to the adipose tissue phenotype and hyperlipidemia. Interestingly, the reduced expression of genes involved in lipid uptake and storage and lipolysis was associated with a significant decrease in the mRNA levels of peroxisome proliferator-activated receptor-γ2 (PPARγ2), a master regulator of adipogenesis, lipogenesis, and lipolysis (Fig. 2) (13,20,24).

Bottom Line: Chronic rapamycin treatment reduced adiposity and fat cell number, which was associated with a coordinated downregulation of genes involved in both lipid uptake and output.The latter was associated with elevated expression of hepatic gluconeogenic master genes, PEPCK and G6Pase, and increased expression of the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) as well as enhanced nuclear recruitment of FoxO1, CRTC2, and CREB.These findings unravel a novel mechanism by which mTORC1/S6K1 controls gluconeogenesis through modulation of several key transcriptional factors.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Faculty of Medicine, Cardiology Axis of the Quebec Heart and Lung Institute, and the Metabolism, Vascular and Renal Health Axis, Laval University Hospital Research Center, Laval University, Quebec, Canada.

ABSTRACT

Objective: The mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) pathway is a critical signaling component in the development of obesity-linked insulin resistance and operates a nutrient-sensing negative feedback loop toward the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Whereas acute treatment of insulin target cells with the mTOR complex 1 (mTORC1) inhibitor rapamycin prevents nutrient-induced insulin resistance, the chronic effect of rapamycin on insulin sensitivity and glucose metabolism in vivo remains elusive.

Research design and methods: To assess the metabolic effects of chronic inhibition of the mTORC1/S6K1 pathway, rats were treated with rapamycin (2 mg/kg/day) or vehicle for 15 days before metabolic phenotyping.

Results: Chronic rapamycin treatment reduced adiposity and fat cell number, which was associated with a coordinated downregulation of genes involved in both lipid uptake and output. Rapamycin treatment also promoted insulin resistance, severe glucose intolerance, and increased gluconeogenesis. The latter was associated with elevated expression of hepatic gluconeogenic master genes, PEPCK and G6Pase, and increased expression of the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) as well as enhanced nuclear recruitment of FoxO1, CRTC2, and CREB. These changes were observed despite normal activation of the insulin receptor substrate/PI 3-kinase/Akt axis in liver of rapamycin-treated rats, as expected from the blockade of the mTORC1/S6K1 negative feedback loop.

Conclusions: These findings unravel a novel mechanism by which mTORC1/S6K1 controls gluconeogenesis through modulation of several key transcriptional factors. The robust induction of the gluconeogenic program in liver of rapamycin-treated rats underlies the development of severe glucose intolerance even in the face of preserved hepatic insulin signaling to Akt and despite a modest reduction in adiposity.

Show MeSH
Related in: MedlinePlus