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• Role of Hypoxia Inducible Factor 2 and NFKB in lipodystrophy and Obesity
  Atif A Baig
  Published on: 27 April 2016

• Published on: 27 April 2016

  Role of Hypoxia Inducible Factor 2 and NFKB in lipodystrophy and Obesity

  • Atif A Baig, Medical Lecturer & Researcher

  I have read all the respective article and I agreed to most of the findings. Recently, our group has been working with metabolomics towards lipodystropy and we did found similar findings. Recently it has been reported (Abael et al., 2010) that the changes in local thyroid hormone (TH) metabolism may occur in areas with lipoatrophy. These changes could be because of different molecular mechanisms (for example; levels of...

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  I have read all the respective article and I agreed to most of the findings. Recently, our group has been working with metabolomics towards lipodystropy and we did found similar findings. Recently it has been reported (Abael et al., 2010) that the changes in local thyroid hormone (TH) metabolism may occur in areas with lipoatrophy. These changes could be because of different molecular mechanisms (for example; levels of monocarboxylate transporter 8 and iodothyronine deiodinases). Recently, it has been reported that the prelamin A accumulating mesenchymal stem cells (hMSCs) have a premature aging phenotype which affects their functional competence in vivo. The combination of prelamin A accumulation and stress conditions enhance the aging phenotype by dysregulating the activity of the octamer binding protein Oct-1(Infante et al., 2014). There is a need to evaluate Oct-1 in type 2 familial partial lipodystrophy. Stress could be in the form of hypoxia and oxygen concentration and PO2 is documented to be involved in the activity of nucleoside reverse transcriptase inhibitors (NRTIs) to characterised the metabolic effect on the targeted adipose tissues (Gentil et al., 2006). There could be a relation between hypoxia inducible factors (HIF1 & HIF2) to be defined for lipodystrophy.

  Hypoxia Inducible Factor 1 (HIF-1) was firstly identified to be a nuclear factor involved in activation of gene expression under the response of reduced cellular O2 during Erythropoietin expression and regulation (Semenza & Wang, 1992). Following this invention, HIF-1 was reported to be involved in expression and regulation of Vascular Endothelial Growth Factor (VEGF), glycolytic enzymes, nitric oxide synthetase and glucose transporter 1 (Glut 1) (Wenger & Gassmann. 1997; Semenza, 1998). Structurally, HIF-1 is a heterodimer composed of two basic helix-loop-helix PAS domains (bHLH-PAS) protein, called HIF-1? and HIF-1? subunits (Wang et al., 1995).

  Tian and colleagues (Tian et al., 1997) identified a novel bHLH-PAS protein called Endothelial PAS domain protein (EPAS1) with 48% sequence similarity with HIF-1 ?. Further studies termed it as HIF-like factor (HLF) (Ema et al., 1997) followed by HIF-related factor (HRF) (Flamme et al., 1997) followed by current name given to this factor to be HIF-2 (Wenger & Gassmann, 1997). Recently, it has been shown that HIF-2 ? forms a functional heterodimer with HIF-1?, resulting in the HIF-2 complex and this complex has been found to bind the same hypoxia response element (HRE) of Epo and VEGF gene to which HIF-1 complex binds. Both of these HRE and bindings (binding of HIF-1 and HIF-2 complex) are activated under hypoxic conditions (Tian et al., 1997, Ema et al., 1997).

  The role of HIF-2 as compared to HIF-1 has been much less studied. Patel and colleagues (Patel et al., 2008) reported HIF-2 complex to be more tissue specific than HIF-1 by suggesting its response to different levels of O2 and this justified strongly the role of HIF-2 on expression of genes in obesity and inflammation. Hyperplasia and hypertrophy in adipocytes can lead to many morphological and molecular changes in adipocytes resulting in hypoxia, metabolic dysregulation and increased expression and secretion of cytokines (Hosogai et al., 2007, Ye et al., 2007). Different vital genes involved in metabolic and diet induced obesity have been reported to be expressed under the action of HIF-1. Recently, NF-KB has been reported to be induced through hypoxia (Culver et al., 2010). It has been suggested that the role of HIF-2 and NF-?B can be considered because of a strong evidence of former (HIF-2) been reported to be linked with hypoxia inducible inhibition of insulin signaling (Regazzetti et al., 2009). There is a strong evidence of hypoxia in obesity (Ye et al., 1997), with a reported finding of HIF-2 to be tissue specific rather than HIF-1 (Patel et al., 2008).

  The potential role of HIF-2 and NF-KB in pathways involving vital genes and proteins in response of adipocytes to hypoxia needs to be explored at molecular level to get a better picture and role of hypoxia in inducing obesity genes expression in this respective report beside inflammation as per induced.

  References:

  Culver C, Sundqvist A, Mudie S, Melvin A, Xirodimas D, Rocha S. Mechanism of hypoxia-induced NF-kappaB. Mol Cell Biol. 2010 Oct;30(20):4901-21. doi: 10.1128/MCB.00409-10.

  Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, and Fujii-Kuriyama Y (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia- inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 94: 4273 -4278.

  Gentil C, Le Jan S, Philippe J, Leibowitch J, Sonigo P, Germain S, Pi?tri-Rouxel F. Is oxygen a key factor in the lipodystrophy phenotype? Lipids Health Dis. 2006 Oct 18;5:27.

  Hosogai, N., Fukuhara, A., Oshima, K., Miyata, Y., Tanaka, S., Segawa, K., Furukawa, S., Tochino, Y., Komuro, R., Matsuda, M., and Shimomura, I. (2007) Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56, 901-911.

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  Lado-Abeal J, Calvo RM, Victoria B, Castro I, Obregon MJ, Araujo- Vilar D.Regional decrease of subcutaneous adipose tissue in patients with type 2 familial partial lipodystrophy is associated with changes in thyroid hormone metabolism. Thyroid. 2010 Apr;20(4):419-24. doi: 10.1089/thy.2009.0267.

  Patel SA, Simon MC. Biology of hypoxia-inducible factor-2alpha in development and disease. Cell Death Differ. 2008 Apr;15(4):628-34. doi: 10.1038/cdd.2008.17. Epub 2008 Feb 15. Review. PubMed PMID: 18259197; PubMed Central PMCID:PMC2882207.

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  Tian H, McKnight SL, and Russell DW (1997) Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 11: 72-82.

  Semenza, G. L. and Wang, G. L. (1992). A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Molec. cell. Biol. 12, 5447-5454.

  Semenza, G. L. (1998). Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr. Opin. Genet. Dev. 8, 588-594.

  Wang, G.L., Jiang, B.H., Rue, E.A., Semenza, G.L., 1995. Hypoxia?inducible factor?1 is a basic? helix?loop?helix?pas heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92, 5510?5514.

  Wenger, R. H. and Gassmann, M. (1997). Oxygen(es) and the hypoxia- inducible factor-1. Biol. Chem. 378, 609-616.

  Ye, J., Gao, Z., Yin, J., and He, Q. (2007) Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293, E1118-1128.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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