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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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Metabolic characterization of HFD-fed Foxo1+/− mice. Metabolic features of 10-month-old male mice after 24 weeks of a HFD (wild type n = 10; Foxo1+/− n = 14). A and B: Whole-blood glucose and plasma insulin during intraperitoneal glucose tolerance testing. C and D: Insulin tolerance testing. Animals were fasted for 6 and 4 h before GTTs and ITTs, respectively. Results are represented as both absolute glucose values and percent glucose decrease from basal. Values represent mean glucose ± SE. *P < 0.05 for Foxo1+/− versus wild-type. E: Mice were weighed at the initiation of the HFD and then at 4-week intervals up to 28 weeks of HFD duration. Values represent mean body weight of at least 15 mice per genotype ± SE. ■, wild type; ○, Foxo1+/−.
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Figure 1: Metabolic characterization of HFD-fed Foxo1+/− mice. Metabolic features of 10-month-old male mice after 24 weeks of a HFD (wild type n = 10; Foxo1+/− n = 14). A and B: Whole-blood glucose and plasma insulin during intraperitoneal glucose tolerance testing. C and D: Insulin tolerance testing. Animals were fasted for 6 and 4 h before GTTs and ITTs, respectively. Results are represented as both absolute glucose values and percent glucose decrease from basal. Values represent mean glucose ± SE. *P < 0.05 for Foxo1+/− versus wild-type. E: Mice were weighed at the initiation of the HFD and then at 4-week intervals up to 28 weeks of HFD duration. Values represent mean body weight of at least 15 mice per genotype ± SE. ■, wild type; ○, Foxo1+/−.

Mentions: FoxO1 haploinsufficient mice exhibited a striking age-related phenotype, developing enhanced insulin sensitivity after 24 weeks of the HFD. Although we performed intraperitoneal glucose and insulin tolerance tests every 4 weeks after initiation of the HFD, no significant differences between genotypes emerged until 24 weeks. At this point, Foxo1+/− mice demonstrated lower fasting blood glucose (Foxo1+/− 160 ± 5.2 mg/dl vs. wild type 193 ± 9.6 mg/dl, P < 0.01) and plasma insulin levels (Foxo1+/− 4.27 ± 0.6 vs. wild type 8.11 ± 1.7 mg/dl, P < 0.05). Accordingly, improved insulin sensitivity was observed in Foxo1+/− mice in glucose tolerance tests, as evident by reduced postabsorptive glucose and insulin values (Fig. 1A and B). Consistent with these results, the glucose-lowering effects of insulin were significantly enhanced in HFD-fed Foxo1+/− mice during insulin tolerance tests (Fig. 1C and D). No differences in body weight were detected between the two groups (Fig. 1E). Together, these data indicate an age-dependent protection from HFD-induced insulin resistance in Foxo1+/− mice, similar to previous published reports (2).


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)

Metabolic characterization of HFD-fed Foxo1+/− mice. Metabolic features of 10-month-old male mice after 24 weeks of a HFD (wild type n = 10; Foxo1+/− n = 14). A and B: Whole-blood glucose and plasma insulin during intraperitoneal glucose tolerance testing. C and D: Insulin tolerance testing. Animals were fasted for 6 and 4 h before GTTs and ITTs, respectively. Results are represented as both absolute glucose values and percent glucose decrease from basal. Values represent mean glucose ± SE. *P < 0.05 for Foxo1+/− versus wild-type. E: Mice were weighed at the initiation of the HFD and then at 4-week intervals up to 28 weeks of HFD duration. Values represent mean body weight of at least 15 mice per genotype ± SE. ■, wild type; ○, Foxo1+/−.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682681&req=5

Figure 1: Metabolic characterization of HFD-fed Foxo1+/− mice. Metabolic features of 10-month-old male mice after 24 weeks of a HFD (wild type n = 10; Foxo1+/− n = 14). A and B: Whole-blood glucose and plasma insulin during intraperitoneal glucose tolerance testing. C and D: Insulin tolerance testing. Animals were fasted for 6 and 4 h before GTTs and ITTs, respectively. Results are represented as both absolute glucose values and percent glucose decrease from basal. Values represent mean glucose ± SE. *P < 0.05 for Foxo1+/− versus wild-type. E: Mice were weighed at the initiation of the HFD and then at 4-week intervals up to 28 weeks of HFD duration. Values represent mean body weight of at least 15 mice per genotype ± SE. ■, wild type; ○, Foxo1+/−.
Mentions: FoxO1 haploinsufficient mice exhibited a striking age-related phenotype, developing enhanced insulin sensitivity after 24 weeks of the HFD. Although we performed intraperitoneal glucose and insulin tolerance tests every 4 weeks after initiation of the HFD, no significant differences between genotypes emerged until 24 weeks. At this point, Foxo1+/− mice demonstrated lower fasting blood glucose (Foxo1+/− 160 ± 5.2 mg/dl vs. wild type 193 ± 9.6 mg/dl, P < 0.01) and plasma insulin levels (Foxo1+/− 4.27 ± 0.6 vs. wild type 8.11 ± 1.7 mg/dl, P < 0.05). Accordingly, improved insulin sensitivity was observed in Foxo1+/− mice in glucose tolerance tests, as evident by reduced postabsorptive glucose and insulin values (Fig. 1A and B). Consistent with these results, the glucose-lowering effects of insulin were significantly enhanced in HFD-fed Foxo1+/− mice during insulin tolerance tests (Fig. 1C and D). No differences in body weight were detected between the two groups (Fig. 1E). Together, these data indicate an age-dependent protection from HFD-induced insulin resistance in Foxo1+/− mice, similar to previous published reports (2).

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