title: Loss of intestinal GATA4 prevents diet-induced obesity and promotes insulin sensitivity in mice.
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.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/3, Graz, Austria.
authors.forename: Jay V
authors.initials: JV
authors.lastname: Patankar
authors.forename: Prakash G
authors.initials: PG
authors.lastname: Chandak
authors.forename: Sascha
authors.initials: S
authors.lastname: Obrowsky
authors.forename: Thomas
authors.initials: T
authors.lastname: Pfeifer
authors.forename: Clemens
authors.initials: C
authors.lastname: Diwoky
authors.forename: Andreas
authors.initials: A
authors.lastname: Uellen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sattler
authors.forename: Rudolf
authors.initials: R
authors.lastname: Stollberger
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.forename: Akos
authors.initials: A
authors.lastname: Heinemann
authors.forename: Michele
authors.initials: M
authors.lastname: Battle
authors.forename: Stephen
authors.initials: S
authors.lastname: Duncan
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
authors.forename: Sanja
authors.initials: S
authors.lastname: Levak-Frank
mesh_terms: D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D004032:Diet; D004041:Dietary Fats / Q000493:pharmacokinetics; D004797:Enzyme-Linked Immunosorbent Assay; D005243:Feces / Q000737:chemistry; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000502:physiology*; D005746:Gastric Emptying / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000502:physiology; D005951:Glucose Tolerance Test; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology*; D007408:Intestinal Absorption / Q000235:genetics / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D008066:Lipolysis / Q000502:physiology; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000378:metabolism*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution
chemical_list: D004041:Dietary Fats; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D012313:RNA; D052216:Glucagon-Like Peptide 1