Homeodomain interacting protein kinase 2 is downregulated through the peroxisome proliferator-activated receptor gamma signaling pathway in an insulin-resistant population.

Abstract

Homeodomain interacting protein kinase 2 (HIPK2), the highly conserved nuclear serine/threonine kinase, is known to act as a co-repressor through interacting with a number of transcription factors. Notably, HIPK2 inhibits cell growth through the activation of p53. However, its in vivo function in insulin resistance is still unknown. Recently, the discovery by Sjolund et al.1 has implicated HIPK2 as a central modulator of adipogenesis. They found that deletion of HIPK2 in mice gave rise to decreased adipogenesis and increased insulin-sensitivity independence of the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway. According to their result, we hypothesize that the expression of HIPK2 in the insulin-resistant population might be upregulated. To testify our supposition, we analyzed the publicly available expression data from two human insulin-resistant expression data in GEO datasets that use the same platform. Contrary to our deduction, the HIPK2 gene was downregulated in the insulin-resistant population (Figure ​(Figure11a,b). Figure 1 Decreased expression of homeodomain interacting protein kinase 2 (HIPK2) in an insulin resistant population was associated with the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway. (a,b) Expression of HIPK2 detected ... PPARγ is the key transcription factor in adipogenesis, as well as glucose and fatty acid metabolism, and alterations in the pathway lead to insulin resistance and type 2 diabetes mellitus2. According to the report by Sjolund et al.1, the function of HIPK2 was not mediated by a PPARγ-dependent mechanism1. However, we identified that some downstream targets of PPARγ, which Sjolund et al. mentioned, were downregulated in adipocytes in insulin-resistant people, which is synchronously expressed with HIPK2 messenger ribonucleic acid expression (Figure ​(Figure1c).1c). Some transcription cofactors of PPARγ shown by GeneMANIA (http://www.genemania.org/) were also downregulated in the adipocytes of the insulin-resistant population (Figure ​(Figure11d). Rosiglitazone (Rosi), a member of the thiazolidinediones and an agonist of PPARγ, works as an insulin sensitizer in type 2 diabetes mellitus3. The present results showed that HIPK2 messenger ribonucleic acid expression was significantly increased in the presence of both Rosi and overexpressed PPARγ in murine marrow-derived U-33 cells, indicating a tendency of increased HIPK2 expression after administration of insulin sensitizer (Figure ​(Figure1e).1e). In agreement with this, several other articles published the same results that HIPK2 expression was elevated after administration of insulin sensitizer, rosiglitazone and troglitazone (Table S1), suggested by The Comparative Toxicogenomics Database (http://ctdbase.org/). Taken together, despite of Sjolund et al. discovery that HIPK2 deletion in mice induces increased insulin sensitivity and was not mediated by the PPARγ pathway, our data suggest that downexpression of HIPK2 was discovered in a population that suffered from decreased insulin sensitivity (insulin resistance) through the PPARγ-dependent pathway. This discrepancy might be caused by the following reasons: (i) metabolic differences between humans and murine; (ii) the discovery by Sjolund et al. was carried out on skeletal muscle, where the present results were shown in adipocytes; and (iii) our discovery was the result of a subset of humans, accordingly, the discovery by Sjolund et al. was based on a few HIPK2 knockout mice, the two studies all await further verification. Furthermore, we also showed that administration of insulin sensitizer could promote the elevated expression of HIPK2, thus providing a benefit for treatment of insulin resistance.