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Comparative proteome analysis of brown adipose tissue in obese C57BL/6J mice using iTRAQ-coupled 2D LC-MS/MS.

Li J, Zhao WG, Shen ZF, Yuan T, Liu SN, Liu Q, Fu Y, Sun W - PLoS ONE (2015)

Bottom Line: As compared HFD with ND, we obtained 727 differentially expressed proteins.Functional analysis found that those proteins were mainly assigned to the pathway of mitochondrial function.The results indicated that HFD might induce the apoptosis of brown adipocytes via the up-regulated AIF1.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

ABSTRACT
High-fat diet (HFD) leads to the development of obesity accompanied by insulin resistance, which increases the risk of type 2 diabetes mellitus and cardiovascular disease. Brown adipose tissue (BAT) plays an essential role in energy metabolism, thus it will give us promising treatment targets through elucidating underlying mechanisms of BAT in obesity. In this study, female C57BL/6J mice were fed HFD or normal diet (ND) for 22 weeks. Hyperinsulinemic-euglycemic clamp was performed to evaluate insulin sensitivity, which was independently correlated with obesity. Using isobaric tag for relative and absolute quantification (iTRAQ) coupled with 2D LC-MS/MS, we quantitated 3048 proteins in BAT. As compared HFD with ND, we obtained 727 differentially expressed proteins. Functional analysis found that those proteins were mainly assigned to the pathway of mitochondrial function. In this pathway, carnitine O-palmitoyltransferase 2 (CPT2), uncoupling protein 1 (UCP1) and apoptosis-inducing factor 1 (AIF1) were up-regulated significantly by HFD, and they were confirmed by western blotting. The results indicated that HFD might induce the apoptosis of brown adipocytes via the up-regulated AIF1. Meanwhile, HFD also stimulated fatty acid β-oxidation and raised compensatory energy consuming through the increases of CPT2 and UCP1, respectively. However, the apoptosis of brown adipocytes might weaken the compensatory energy expenditure, and finally contribute to overweight/obesity. So, preventing the apoptosis of brown adipocytes may be the key target to treat obesity.

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Proposed schematic diagram of BAT in obesity and impaired insulin sensitivity induced by HFD.It is likely that HFD activates the catabolism of fatty acid and the compensatory energy expenditure for anti-obesity through the up regulation of CPT2 and UCP1 in BAT, respectively. In addition, HFD also induces the apoptosis of brown adipocytes via the up regulation of AIF1, to weaken its anti-obesity effect. Attenuating compensatory action of BAT might cause imbalance of energy metabolism in BAT and WAT, and contribute to the development of obesity and impaired insulin resistance.
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pone.0119350.g007: Proposed schematic diagram of BAT in obesity and impaired insulin sensitivity induced by HFD.It is likely that HFD activates the catabolism of fatty acid and the compensatory energy expenditure for anti-obesity through the up regulation of CPT2 and UCP1 in BAT, respectively. In addition, HFD also induces the apoptosis of brown adipocytes via the up regulation of AIF1, to weaken its anti-obesity effect. Attenuating compensatory action of BAT might cause imbalance of energy metabolism in BAT and WAT, and contribute to the development of obesity and impaired insulin resistance.

Mentions: In summary, female C57BL/6J mice were successfully induced to obesity and decreased insulin sensitivity by HFD for 22 weeks. We applied comparative proteomics to analyze the differential expression proteins in BAT of C57BL/6J mice fed HFD and ND. With iTRAQ-coupled 2D LC-MS/MS, we found that HFD not only inhibited glucose metabolism and the synthesis of fatty acid, but also activated the catabolism of fatty acid in BAT through the up-regulation of CPT2. Besides, HFD also activated the compensatory energy-consuming process for anti-obesity through the up-regulation of UCP1 in BAT. Above all, HFD might increase the apoptosis of brown adipocytes via a non-classical apoptotic pathway, including AIF1, to weaken its anti-obesity effect. Thus, attenuating the compensatory action of BAT might led to the proliferation of WAT and the reduction of BAT, thereby contributing to the development of obesity and impaired insulin sensitivity (Fig. 7). Further research on AIF1 and upstream mechanisms would illuminate the way of preservation, regeneration and activation of BAT. Moreover, study with multi-period and different degrees of obesity would be more helpful to reveal the targets which can resist the development of obesity and related complications. Thus, preventing the apoptosis of brown adipocytes might be an important clue to treat obesity.


Comparative proteome analysis of brown adipose tissue in obese C57BL/6J mice using iTRAQ-coupled 2D LC-MS/MS.

Li J, Zhao WG, Shen ZF, Yuan T, Liu SN, Liu Q, Fu Y, Sun W - PLoS ONE (2015)

Proposed schematic diagram of BAT in obesity and impaired insulin sensitivity induced by HFD.It is likely that HFD activates the catabolism of fatty acid and the compensatory energy expenditure for anti-obesity through the up regulation of CPT2 and UCP1 in BAT, respectively. In addition, HFD also induces the apoptosis of brown adipocytes via the up regulation of AIF1, to weaken its anti-obesity effect. Attenuating compensatory action of BAT might cause imbalance of energy metabolism in BAT and WAT, and contribute to the development of obesity and impaired insulin resistance.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352050&req=5

pone.0119350.g007: Proposed schematic diagram of BAT in obesity and impaired insulin sensitivity induced by HFD.It is likely that HFD activates the catabolism of fatty acid and the compensatory energy expenditure for anti-obesity through the up regulation of CPT2 and UCP1 in BAT, respectively. In addition, HFD also induces the apoptosis of brown adipocytes via the up regulation of AIF1, to weaken its anti-obesity effect. Attenuating compensatory action of BAT might cause imbalance of energy metabolism in BAT and WAT, and contribute to the development of obesity and impaired insulin resistance.
Mentions: In summary, female C57BL/6J mice were successfully induced to obesity and decreased insulin sensitivity by HFD for 22 weeks. We applied comparative proteomics to analyze the differential expression proteins in BAT of C57BL/6J mice fed HFD and ND. With iTRAQ-coupled 2D LC-MS/MS, we found that HFD not only inhibited glucose metabolism and the synthesis of fatty acid, but also activated the catabolism of fatty acid in BAT through the up-regulation of CPT2. Besides, HFD also activated the compensatory energy-consuming process for anti-obesity through the up-regulation of UCP1 in BAT. Above all, HFD might increase the apoptosis of brown adipocytes via a non-classical apoptotic pathway, including AIF1, to weaken its anti-obesity effect. Thus, attenuating the compensatory action of BAT might led to the proliferation of WAT and the reduction of BAT, thereby contributing to the development of obesity and impaired insulin sensitivity (Fig. 7). Further research on AIF1 and upstream mechanisms would illuminate the way of preservation, regeneration and activation of BAT. Moreover, study with multi-period and different degrees of obesity would be more helpful to reveal the targets which can resist the development of obesity and related complications. Thus, preventing the apoptosis of brown adipocytes might be an important clue to treat obesity.

Bottom Line: As compared HFD with ND, we obtained 727 differentially expressed proteins.Functional analysis found that those proteins were mainly assigned to the pathway of mitochondrial function.The results indicated that HFD might induce the apoptosis of brown adipocytes via the up-regulated AIF1.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

ABSTRACT
High-fat diet (HFD) leads to the development of obesity accompanied by insulin resistance, which increases the risk of type 2 diabetes mellitus and cardiovascular disease. Brown adipose tissue (BAT) plays an essential role in energy metabolism, thus it will give us promising treatment targets through elucidating underlying mechanisms of BAT in obesity. In this study, female C57BL/6J mice were fed HFD or normal diet (ND) for 22 weeks. Hyperinsulinemic-euglycemic clamp was performed to evaluate insulin sensitivity, which was independently correlated with obesity. Using isobaric tag for relative and absolute quantification (iTRAQ) coupled with 2D LC-MS/MS, we quantitated 3048 proteins in BAT. As compared HFD with ND, we obtained 727 differentially expressed proteins. Functional analysis found that those proteins were mainly assigned to the pathway of mitochondrial function. In this pathway, carnitine O-palmitoyltransferase 2 (CPT2), uncoupling protein 1 (UCP1) and apoptosis-inducing factor 1 (AIF1) were up-regulated significantly by HFD, and they were confirmed by western blotting. The results indicated that HFD might induce the apoptosis of brown adipocytes via the up-regulated AIF1. Meanwhile, HFD also stimulated fatty acid β-oxidation and raised compensatory energy consuming through the increases of CPT2 and UCP1, respectively. However, the apoptosis of brown adipocytes might weaken the compensatory energy expenditure, and finally contribute to overweight/obesity. So, preventing the apoptosis of brown adipocytes may be the key target to treat obesity.

Show MeSH
Related in: MedlinePlus