The Fabp4-Cre-Model is Insufficient to Study Hoxc9 Function in Adipose Tissue.

Sebastian Dommel,Matthias Blüher,Anne Kunath,Martin Gericke,Peter Kovacs,Claudia Berger,Matthias Kern,Nora Klöting,Esther Guiu-Jurado

doi:10.3390/biomedicines8070184

Abstract

Developmental genes are important regulators of fat distribution and adipose tissue (AT) function. In humans, the expression of homeobox c9 (HOXC9) is significantly higher in subcutaneous compared to omental AT and correlates with body fat mass. To gain more mechanistic insights into the role of Hoxc9 in AT, we generated Fabp4-Cre-mediated Hoxc9 knockout mice (ATHoxc9-/-). Male and female ATHoxc9-/- mice were studied together with littermate controls both under chow diet (CD) and high-fat diet (HFD) conditions. Under HFD, only male ATHoxc9-/- mice gained less body weight and exhibited improved glucose tolerance. In both male and female mice, body weight, as well as the parameters of glucose metabolism and AT function were not significantly different between ATHoxc9-/- and littermate control CD fed mice. We found that crossing Hoxc9 floxed mice with Fabp4-Cre mice did not produce a biologically relevant ablation of Hoxc9 in AT. However, we hypothesized that even subtle reductions of the generally low AT Hoxc9 expression may cause the leaner and metabolically healthier phenotype of male HFD-challenged ATHoxc9-/- mice. Different models of in vitro adipogenesis revealed that Hoxc9 expression precedes the expression of Fabp4, suggesting that ablation of Hoxc9 expression in AT needs to be achieved by targeting earlier stages of AT development.

Highlights

An important breakthrough in developmental biology was the discovery that there are common genes that control early embryonic development in organisms ranging from the fruit fly to humans.Edward B
Thereby, we detected twelve genes being differentially expressed between both depots, with seven of them showing higher expression levels in epididymal white AT (eWAT) and five genes more expressed in scWAT [6]. Among those adipose tissue (AT)-expressed developmental genes (Tbx15, Shox2, En1, Sfrp2), we found significantly higher homeobox c9 (HOXC9) expression in human subcutaneous compared to visceral AT correlating with body fat mass and adipocyte size [6,7]
ATHoxc9-/- mice were generated by crossing mice carrying the loxP-flanked Hoxc9 allele with transgenic mice expressing Cre recombinase under the control of the adipocyte-specific fatty acid-binding protein 4 (Fabp4) promoter

Summary

Introduction

An important breakthrough in developmental biology was the discovery that there are common genes that control early embryonic development in organisms ranging from the fruit fly to humans.Edward B. Lewis demonstrated that homeotic genes are of central importance for segmentation in Drosophila melanogaster [1]. Homeotic genes are lined up on the DNA in exactly the same order as they are expressed along the body axis during embryogenesis. As a subset of homeotic genes, Hox genes are considered as master regulators for segmentation patterning during embryogenesis. Humans and mice possess thirty-nine Hox genes organized into four clusters (A to D) on four chromosomes (Hoxa 7p15, Hoxb 7q21.2, Hoxc 12q13, and Hoxd 2q31). Each cluster consists of thirteen paralog groups with nine to eleven members [2]. The Hox clusters are organized in 30 to 50 orientation with paralogous lower number group members (e.g., Hoxa, Hoxb, Hoxd1) at the 30

Results

Discussion

Conclusion