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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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Adipose tissue characteristics of HFD-fed Foxo1+/− mice. A and B: Average cell size of adipocytes from epididymal fat (wild type n = 6; Foxo1+/− n = 8). Representative photomicrographs are represented. Scale bars represent 100 μm. C: Epididymal adipose fat pads were isolated and weighed in HFD-fed wild-type and Foxo1+/− mice. Each bar represents individual means ± SE. *P < 0.03. D–G: Gene expression studies were performed on white adipose tissue of HFD-fed animals using real-time PCR to measure relative amounts of PPARγ and PPARγ target genes. Data represent means ± SE of RNA samples (n = 5 mice per genotype). *P < 0.05. AU, arbitrary units. ■, wild type; □, Foxo1+/−.
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Figure 4: Adipose tissue characteristics of HFD-fed Foxo1+/− mice. A and B: Average cell size of adipocytes from epididymal fat (wild type n = 6; Foxo1+/− n = 8). Representative photomicrographs are represented. Scale bars represent 100 μm. C: Epididymal adipose fat pads were isolated and weighed in HFD-fed wild-type and Foxo1+/− mice. Each bar represents individual means ± SE. *P < 0.03. D–G: Gene expression studies were performed on white adipose tissue of HFD-fed animals using real-time PCR to measure relative amounts of PPARγ and PPARγ target genes. Data represent means ± SE of RNA samples (n = 5 mice per genotype). *P < 0.05. AU, arbitrary units. ■, wild type; □, Foxo1+/−.

Mentions: FoxO1 is highly expressed in preadipoctyes and is known to regulate adipocyte differentiation. Of note, dominant-negative FoxO1 expression promotes adipogenesis in insulin-receptor–deficient cells (2). FoxO1 has also been reported to regulate target genes involved in apoptosis, cell cycle regulation, stress resistance, and DNA repair. Histological analysis of epididymal fat revealed that adipocyte cell size was significantly smaller in Foxo1+/− mice (Fig. 4A and B and supplementaryFig. 2, available in an online appendix), similar to previous reports (2). However, epididymal fat pad weights were 31% higher in the knockout mice (Fig. 4C) despite similar body weights of HFD-fed Foxo1+/− and wild-type mice, suggesting a role for FoxO1 in the development of this adipose depot. FoxO1 has been shown to upregulate mouse adiponectin gene expression by forming a transcriptional complex with CCAAT/enhancer-binding protein α and binding to the adiponectin promoter in differentiated adipocytes (15). Interestingly, plasma adiponectin levels were 22% lower in FoxO1 haploinsufficient mice (Table 1), perhaps due to reduced FoxO1 binding at the adiponectin promoter. Plasma leptin and free fatty acid levels were unchanged (data not shown). Plasma interleukin (IL)-6 levels were 35% lower in Foxo1+/− mice (Table 1), but macrophage content did not differ based on F4/80 staining of histological sections of adipose tissue (data not shown).


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)

Adipose tissue characteristics of HFD-fed Foxo1+/− mice. A and B: Average cell size of adipocytes from epididymal fat (wild type n = 6; Foxo1+/− n = 8). Representative photomicrographs are represented. Scale bars represent 100 μm. C: Epididymal adipose fat pads were isolated and weighed in HFD-fed wild-type and Foxo1+/− mice. Each bar represents individual means ± SE. *P < 0.03. D–G: Gene expression studies were performed on white adipose tissue of HFD-fed animals using real-time PCR to measure relative amounts of PPARγ and PPARγ target genes. Data represent means ± SE of RNA samples (n = 5 mice per genotype). *P < 0.05. AU, arbitrary units. ■, wild type; □, Foxo1+/−.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2682681&req=5

Figure 4: Adipose tissue characteristics of HFD-fed Foxo1+/− mice. A and B: Average cell size of adipocytes from epididymal fat (wild type n = 6; Foxo1+/− n = 8). Representative photomicrographs are represented. Scale bars represent 100 μm. C: Epididymal adipose fat pads were isolated and weighed in HFD-fed wild-type and Foxo1+/− mice. Each bar represents individual means ± SE. *P < 0.03. D–G: Gene expression studies were performed on white adipose tissue of HFD-fed animals using real-time PCR to measure relative amounts of PPARγ and PPARγ target genes. Data represent means ± SE of RNA samples (n = 5 mice per genotype). *P < 0.05. AU, arbitrary units. ■, wild type; □, Foxo1+/−.
Mentions: FoxO1 is highly expressed in preadipoctyes and is known to regulate adipocyte differentiation. Of note, dominant-negative FoxO1 expression promotes adipogenesis in insulin-receptor–deficient cells (2). FoxO1 has also been reported to regulate target genes involved in apoptosis, cell cycle regulation, stress resistance, and DNA repair. Histological analysis of epididymal fat revealed that adipocyte cell size was significantly smaller in Foxo1+/− mice (Fig. 4A and B and supplementaryFig. 2, available in an online appendix), similar to previous reports (2). However, epididymal fat pad weights were 31% higher in the knockout mice (Fig. 4C) despite similar body weights of HFD-fed Foxo1+/− and wild-type mice, suggesting a role for FoxO1 in the development of this adipose depot. FoxO1 has been shown to upregulate mouse adiponectin gene expression by forming a transcriptional complex with CCAAT/enhancer-binding protein α and binding to the adiponectin promoter in differentiated adipocytes (15). Interestingly, plasma adiponectin levels were 22% lower in FoxO1 haploinsufficient mice (Table 1), perhaps due to reduced FoxO1 binding at the adiponectin promoter. Plasma leptin and free fatty acid levels were unchanged (data not shown). Plasma interleukin (IL)-6 levels were 35% lower in Foxo1+/− mice (Table 1), but macrophage content did not differ based on F4/80 staining of histological sections of adipose tissue (data not shown).

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