Loss of intestinal GATA4 prevents diet-induced obesity and promotes insulin sensitivity in mice

Jay V Patankar, Prakash G Chandak, Sascha Obrowsky, Thomas Pfeifer, Clemens Diwoky, Andreas Uellen, Wolfgang Sattler, Rudolf Stollberger, Gerald Hoefler, Akos Heinemann, Michele Battle, Stephen Duncan, Dagmar Kratky, Sanja Levak-Frank

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Abstract

Transcriptional regulation of small intestinal gene expression controls plasma total cholesterol (TC) and triglyceride (TG) levels, which are major determinants of metabolic diseases. GATA4, a zinc finger domain transcription factor, is critical for jejunal identity, and intestinal GATA4 deficiency leads to a jejunoileal transition. Although intestinal GATA4 ablation is known to misregulate jejunal gene expression, its pathophysiological impact on various components of metabolic syndrome remains unknown. Here, we used intestine-specific GATA4 knockout (GATA4iKO) mice to dissect the contribution of GATA4 on obesity development. We challenged adult GATA4iKO mice and control littermates with a Western-type diet (WTD) for 20 wk. Our findings show that WTD-fed GATA4iKO mice are resistant to diet-induced obesity. Accordingly, plasma TG and TC levels are markedly decreased. Intestinal lipid absorption in GATA4iKO mice was strongly reduced, whereas luminal lipolysis was unaffected. GATA4iKO mice displayed a greater glucagon-like peptide-1 (GLP-1) release on normal chow and even after long-term challenge with WTD remained glucose sensitive. In summary, our findings show that the absence of intestinal GATA4 has a beneficial effect on decreasing intestinal lipid absorption causing resistance to hyperlipidemia and obesity. In addition, we show that increased GLP-1 release in GATA4iKO mice decreases the risk for development of insulin resistance.

Original languageEnglish
Pages (from-to)E478-88
JournalAmerican Journal of Physiology / Endocrinology and Metabolism
Volume300
Issue number3
DOIs
Publication statusPublished - Mar 2011

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Fields of Expertise

  • Human- & Biotechnology

Cite this

Patankar, J. V., Chandak, P. G., Obrowsky, S., Pfeifer, T., Diwoky, C., Uellen, A., ... Levak-Frank, S. (2011). Loss of intestinal GATA4 prevents diet-induced obesity and promotes insulin sensitivity in mice. American Journal of Physiology / Endocrinology and Metabolism, 300(3), E478-88. https://doi.org/10.1152/ajpendo.00457.2010