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FoxO1 haploinsufficiency protects against high-fat diet-induced insulin resistance with enhanced peroxisome proliferator-activated receptor gamma activation in adipose tissue.

Kim JJ, Li P, Huntley J, Chang JP, Arden KC, Olefsky JM - Diabetes (2009)

Bottom Line: Although the FoxO1 isoform is known to play a key role in adipogenesis, its physiological role in differentiated adipose tissue remains unclear.FoxO1 haploinsufficiency also resulted in increased peroxisome proliferator-activated receptor (PPAR)gamma gene expression in adipose tissue, with enhanced expression of PPARgamma target genes known to influence metabolism.Moreover, treatment of mice with the PPARgamma agonist rosiglitazone caused a greater improvement in in vivo insulin sensitivity in FoxO1 haploinsufficient animals, including reductions in circulating proinflammatory cytokines.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of California at San Diego, La Jolla, California, USA. janekim@ucsd.edu

ABSTRACT

Objective: Forkhead box O (FoxO) transcription factors represent evolutionarily conserved targets of insulin signaling, regulating metabolism and cellular differentiation in response to changes in nutrient availability. Although the FoxO1 isoform is known to play a key role in adipogenesis, its physiological role in differentiated adipose tissue remains unclear.

Research design and methods: In this study, we analyzed the phenotype of FoxO1 haploinsufficient mice to investigate the role of FoxO1 in high-fat diet-induced obesity and adipose tissue metabolism.

Results: We showed that reduced FoxO1 expression protects mice against obesity-related insulin resistance with marked improvement not only in hepatic insulin sensitivity but also in skeletal muscle insulin action. FoxO1 haploinsufficiency also resulted in increased peroxisome proliferator-activated receptor (PPAR)gamma gene expression in adipose tissue, with enhanced expression of PPARgamma target genes known to influence metabolism. Moreover, treatment of mice with the PPARgamma agonist rosiglitazone caused a greater improvement in in vivo insulin sensitivity in FoxO1 haploinsufficient animals, including reductions in circulating proinflammatory cytokines.

Conclusions: These findings indicate that FoxO1 proteins negatively regulate insulin action and that their effect may be explained, at least in part, by inhibition of PPARgamma function.

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Effect of TZD treatment on in vivo glucose homeostasis and insulin sensitivity in Foxo1+/− mice. A: Body weights of male mice were measured at initiation of rosiglitazone treatment and every 4 weeks up to 8 weeks of age (wild-type HFD + TZD n = 8; Foxo1+/− HFD + TZD n = 10). B: Glucose tolerance testing (1 g/kg dextrose i.p.) was performed on mice after 5 weeks of combined HFD and TZD (wild-type HFD + TZD n = 8; Foxo1+/− HFD + TZD n = 10) and compared with GTT results from mice after 5 weeks of the HFD alone (wild-type HFD n = 10; Foxo1+/− HFD n = 14). Values represent mean glucose ± SE. C and D: Insulin tolerance testing (0.35 unit/kg insulin i.p.) was conducted on mice after 5 weeks of combined HFD and TZD (HFD + TZD wild type n = 8; HFD Foxo1+/− + TZD n = 10) and compared with GTT results from mice after 5 weeks of the HFD alone (HFD wild type n = 10; HFD Foxo1+/− n = 14). Results are represented as both absolute glucose values and percent glucose decrease from basal. Glucose curves from both GTT and ITT were significantly different between TZD-treated Foxo1+/− and wild-type mice (P < 0.04) and between TZD-treated Foxo1+/− mice compared with mice fed a HFD alone (P < 0.001). ○, HFD Foxo1+/−; ■, HFD wild type; ○, HFD + TZD Foxo1+/−; ■, HFD + TZD wild type. E and F: Liver gene expression studies conducted in TZD-treated Foxo1+/− mice used a programmed microarray technique to measure genes that influence both hepatic glucose production and fatty acid synthesis. Relative mRNA values are reported as means ± SE. *P < 0.05. AU, arbitrary units. ■, FD + TZD wild type; ▨, HFD + TZD Foxo1+/−.
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Figure 5: Effect of TZD treatment on in vivo glucose homeostasis and insulin sensitivity in Foxo1+/− mice. A: Body weights of male mice were measured at initiation of rosiglitazone treatment and every 4 weeks up to 8 weeks of age (wild-type HFD + TZD n = 8; Foxo1+/− HFD + TZD n = 10). B: Glucose tolerance testing (1 g/kg dextrose i.p.) was performed on mice after 5 weeks of combined HFD and TZD (wild-type HFD + TZD n = 8; Foxo1+/− HFD + TZD n = 10) and compared with GTT results from mice after 5 weeks of the HFD alone (wild-type HFD n = 10; Foxo1+/− HFD n = 14). Values represent mean glucose ± SE. C and D: Insulin tolerance testing (0.35 unit/kg insulin i.p.) was conducted on mice after 5 weeks of combined HFD and TZD (HFD + TZD wild type n = 8; HFD Foxo1+/− + TZD n = 10) and compared with GTT results from mice after 5 weeks of the HFD alone (HFD wild type n = 10; HFD Foxo1+/− n = 14). Results are represented as both absolute glucose values and percent glucose decrease from basal. Glucose curves from both GTT and ITT were significantly different between TZD-treated Foxo1+/− and wild-type mice (P < 0.04) and between TZD-treated Foxo1+/− mice compared with mice fed a HFD alone (P < 0.001). ○, HFD Foxo1+/−; ■, HFD wild type; ○, HFD + TZD Foxo1+/−; ■, HFD + TZD wild type. E and F: Liver gene expression studies conducted in TZD-treated Foxo1+/− mice used a programmed microarray technique to measure genes that influence both hepatic glucose production and fatty acid synthesis. Relative mRNA values are reported as means ± SE. *P < 0.05. AU, arbitrary units. ■, FD + TZD wild type; ▨, HFD + TZD Foxo1+/−.

Mentions: The PPARγ nuclear receptor is a well-known molecular target in the treatment of insulin resistance. To further investigate the interaction of FoxO1 and PPARγ in vivo, we treated Foxo1+/− and wild-type mice with the PPARγ agonist rosiglitazone. Both groups (4 months old) were fed a 45% HFD with and without rosiglitazone treatment for 4 weeks. Weight gain was identical between genotypes (Fig. 5A).


FoxO1 haploinsufficiency protects against high-fat diet-induced insulin resistance with enhanced peroxisome proliferator-activated receptor gamma activation in adipose tissue.

Kim JJ, Li P, Huntley J, Chang JP, Arden KC, Olefsky JM - Diabetes (2009)

Effect of TZD treatment on in vivo glucose homeostasis and insulin sensitivity in Foxo1+/− mice. A: Body weights of male mice were measured at initiation of rosiglitazone treatment and every 4 weeks up to 8 weeks of age (wild-type HFD + TZD n = 8; Foxo1+/− HFD + TZD n = 10). B: Glucose tolerance testing (1 g/kg dextrose i.p.) was performed on mice after 5 weeks of combined HFD and TZD (wild-type HFD + TZD n = 8; Foxo1+/− HFD + TZD n = 10) and compared with GTT results from mice after 5 weeks of the HFD alone (wild-type HFD n = 10; Foxo1+/− HFD n = 14). Values represent mean glucose ± SE. C and D: Insulin tolerance testing (0.35 unit/kg insulin i.p.) was conducted on mice after 5 weeks of combined HFD and TZD (HFD + TZD wild type n = 8; HFD Foxo1+/− + TZD n = 10) and compared with GTT results from mice after 5 weeks of the HFD alone (HFD wild type n = 10; HFD Foxo1+/− n = 14). Results are represented as both absolute glucose values and percent glucose decrease from basal. Glucose curves from both GTT and ITT were significantly different between TZD-treated Foxo1+/− and wild-type mice (P < 0.04) and between TZD-treated Foxo1+/− mice compared with mice fed a HFD alone (P < 0.001). ○, HFD Foxo1+/−; ■, HFD wild type; ○, HFD + TZD Foxo1+/−; ■, HFD + TZD wild type. E and F: Liver gene expression studies conducted in TZD-treated Foxo1+/− mice used a programmed microarray technique to measure genes that influence both hepatic glucose production and fatty acid synthesis. Relative mRNA values are reported as means ± SE. *P < 0.05. AU, arbitrary units. ■, FD + TZD wild type; ▨, HFD + TZD Foxo1+/−.
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Related In: Results  -  Collection

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Figure 5: Effect of TZD treatment on in vivo glucose homeostasis and insulin sensitivity in Foxo1+/− mice. A: Body weights of male mice were measured at initiation of rosiglitazone treatment and every 4 weeks up to 8 weeks of age (wild-type HFD + TZD n = 8; Foxo1+/− HFD + TZD n = 10). B: Glucose tolerance testing (1 g/kg dextrose i.p.) was performed on mice after 5 weeks of combined HFD and TZD (wild-type HFD + TZD n = 8; Foxo1+/− HFD + TZD n = 10) and compared with GTT results from mice after 5 weeks of the HFD alone (wild-type HFD n = 10; Foxo1+/− HFD n = 14). Values represent mean glucose ± SE. C and D: Insulin tolerance testing (0.35 unit/kg insulin i.p.) was conducted on mice after 5 weeks of combined HFD and TZD (HFD + TZD wild type n = 8; HFD Foxo1+/− + TZD n = 10) and compared with GTT results from mice after 5 weeks of the HFD alone (HFD wild type n = 10; HFD Foxo1+/− n = 14). Results are represented as both absolute glucose values and percent glucose decrease from basal. Glucose curves from both GTT and ITT were significantly different between TZD-treated Foxo1+/− and wild-type mice (P < 0.04) and between TZD-treated Foxo1+/− mice compared with mice fed a HFD alone (P < 0.001). ○, HFD Foxo1+/−; ■, HFD wild type; ○, HFD + TZD Foxo1+/−; ■, HFD + TZD wild type. E and F: Liver gene expression studies conducted in TZD-treated Foxo1+/− mice used a programmed microarray technique to measure genes that influence both hepatic glucose production and fatty acid synthesis. Relative mRNA values are reported as means ± SE. *P < 0.05. AU, arbitrary units. ■, FD + TZD wild type; ▨, HFD + TZD Foxo1+/−.
Mentions: The PPARγ nuclear receptor is a well-known molecular target in the treatment of insulin resistance. To further investigate the interaction of FoxO1 and PPARγ in vivo, we treated Foxo1+/− and wild-type mice with the PPARγ agonist rosiglitazone. Both groups (4 months old) were fed a 45% HFD with and without rosiglitazone treatment for 4 weeks. Weight gain was identical between genotypes (Fig. 5A).

Bottom Line: Although the FoxO1 isoform is known to play a key role in adipogenesis, its physiological role in differentiated adipose tissue remains unclear.FoxO1 haploinsufficiency also resulted in increased peroxisome proliferator-activated receptor (PPAR)gamma gene expression in adipose tissue, with enhanced expression of PPARgamma target genes known to influence metabolism.Moreover, treatment of mice with the PPARgamma agonist rosiglitazone caused a greater improvement in in vivo insulin sensitivity in FoxO1 haploinsufficient animals, including reductions in circulating proinflammatory cytokines.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of California at San Diego, La Jolla, California, USA. janekim@ucsd.edu

ABSTRACT

Objective: Forkhead box O (FoxO) transcription factors represent evolutionarily conserved targets of insulin signaling, regulating metabolism and cellular differentiation in response to changes in nutrient availability. Although the FoxO1 isoform is known to play a key role in adipogenesis, its physiological role in differentiated adipose tissue remains unclear.

Research design and methods: In this study, we analyzed the phenotype of FoxO1 haploinsufficient mice to investigate the role of FoxO1 in high-fat diet-induced obesity and adipose tissue metabolism.

Results: We showed that reduced FoxO1 expression protects mice against obesity-related insulin resistance with marked improvement not only in hepatic insulin sensitivity but also in skeletal muscle insulin action. FoxO1 haploinsufficiency also resulted in increased peroxisome proliferator-activated receptor (PPAR)gamma gene expression in adipose tissue, with enhanced expression of PPARgamma target genes known to influence metabolism. Moreover, treatment of mice with the PPARgamma agonist rosiglitazone caused a greater improvement in in vivo insulin sensitivity in FoxO1 haploinsufficient animals, including reductions in circulating proinflammatory cytokines.

Conclusions: These findings indicate that FoxO1 proteins negatively regulate insulin action and that their effect may be explained, at least in part, by inhibition of PPARgamma function.

Show MeSH
Related in: MedlinePlus