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IER3 – A New Target in the War against Obesity?

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Review of “IER3 Promotes Expansion of Adipose Progenitor Cells in Response to Changes in Distinct Microenvironmental Effectors” from Stem Cells by Stuart P. Atkinson

Adipocyte progenitor cell (APCs) differentiation into adipocytes in order to meet the energy requirements required for normal homeostasis. However, APC expansion and differentiation is also enhanced in obese patients [1], and so a better understanding of the processes which control APC self-renewal and differentiation may allow us to design new therapies aimed at reducing adipocyte production in vivo. Microenvironmental factors are vitally important to stem cell regulation, and this led researchers from the laboratory of Annie Ladoux (INSERM, Nice, France) to study how APCs react to the milieu of signal inputs generated in the stressful obese stem cell niche. To this end, they have identified that the immediate early response gene IER3, a stress-inducible gene which aids cell survival under stress conditions [2], is a pro-survival gene in APCs regulated by the inflammation-inducing factor Activin A and low oxygen concentrations (hypoxia). Interestingly, they also found IER3 upregulation in APCs of obese patients, altogether suggesting that changes in the stem cell niche can significantly alter APC function [3].

The researchers initially demonstrated IER3 expression in APCs and a decrease in this expression during differentiation towards adipocytes in vivo and in vitro. In the search for factors which modulated IER3 expression and boosted APC proliferation, the group identified Activin A (a crucial regulator of hAPC self-renewal [4] up-regulated in the adipose tissue of obese patients where it mediates an inflammatory response [5]) and hypoxia (a key characteristic of the obese microenvironment) via HIF1. Activin A activated the SMAD and ERK pathways in APCs through the phosphorylation of ERK1/2 and SMAD2, with both pathways linked to adipose stem cell (ASC) self-renewal. IER3 expression was also induced in APCs treated with adipose tissue macrophage-conditioned medium [6], agreeing with a previous study which demonstrated that pro-inflammatory populations of M1 macrophages, which secrete Activin A [7], accumulate in the adipose tissue of rodents with diet-induced obesity. To confirm all these findings, the group downregulated IER3 expression in APCs via siRNA and this led to a reduction in the proliferation of APCs, the acceleration of their differentiation towards adipocytes, the nullification of the pro-proliferative effects of Activin A and hypoxia, and the inhibition of SMAD and ERK pathway activation.

The study ended with an assessment of IER3 expression in adipose tissue derived from obese patients in comparison with those derived from lean patients. This demonstrated no differences in the adipocytes, but they did find a significantly higher amount of IER3 expression in APCs in obese patients.

This data supports a model in which Activin A release by macrophages and the hypoxic microenvironment of adipose tissue in obese patients lead to an increase in IER3 expression and this mediates the enhanced proliferation and expansion of APCs (See attached figure). Not only does this give us insight into the molecular underpinnings of APC/adipocyte biology under situations of both normal and obese environments, it also provides us with potentially druggable targets to reduce or inhibit the expansion of adipose tissue.

References

  1. Maumus M, Sengenes C, Decaunes P, et al. Evidence of in situ proliferation of adult adipose tissue-derived progenitor cells: influence of fat mass microenvironment and growth. J Clin Endocrinol Metab 2008;93:4098-4106.
  2. Shen L, Guo J, Santos-Berrios C, et al. Distinct domains for anti- and pro-apoptotic activities of IEX-1. J Biol Chem 2006;281:15304-15311.
  3. Ravaud C, Esteve D, Villageois P, et al. IER3 Promotes Expansion of Adipose Progenitor Cells in Response to Changes in Distinct Microenvironmental Effectors. Stem Cells 2015;33:2564-2573.
  4. Rodriguez AM, Pisani D, Dechesne CA, et al. Transplantation of a multipotent cell population from human adipose tissue induces dystrophin expression in the immunocompetent mdx mouse. J Exp Med 2005;201:1397-1405.
  5. Zaragosi LE, Wdziekonski B, Villageois P, et al. Activin a plays a critical role in proliferation and differentiation of human adipose progenitors. Diabetes 2010;59:2513-2521.
  6. Olefsky JM and Glass CK Macrophages, inflammation, and insulin resistance. Annual review of physiology 2010;72:219-246.
  7. Bourlier V, Sengenes C, Zakaroff-Girard A, et al. TGFbeta family members are key mediators in the induction of myofibroblast phenotype of human adipose tissue progenitor cells by macrophages. PLoS One 2012;7:e31274.

(See attached figure).