title: Loss of Ron receptor signaling leads to reduced obesity, diabetic phenotypes and hepatic steatosis in response to high-fat diet in mice.
abstract: The Ron receptor tyrosine kinase is a heterodimeric, membrane-spanning glycoprotein that participates in divergent processes, including proliferation, motility, and modulation of inflammatory responses. We observed male C57BL/6 mice with a global deletion of the Ron tyrosine kinase signaling domain (TK(-/-)) to be leaner compared with control (TK(+/+)) mice under a standard diet. When fed a high-fat diet (HFD), TK(-/-) mice gained 50% less weight and were more insulin sensitive and glucose tolerant than controls. Livers from HFD TK(-/-) mice were considerably less steatotic and weighed significantly less than TK(+/+) livers. Serum cytokine levels of HFD TK(-/-) mice were also significantly altered compared with TK(+/+) mice. Fewer and smaller adipocytes were present in the TK(-/-) mice on both control and HFD and were accompanied by diminished adiponectin and peroxisome proliferator-activated receptor-γ expression. In vitro adipogenesis experiments suggested reduced differentiation in TK(-/-) embryonic fibroblasts (MEFs) that was rescued by Ron reconstitution. Likewise, signal transducer and activator of transcription (STAT)-3 phosphorylation was diminished in TK(-/-) MEFs but was increased after Ron reconstitution. The adipogenic inhibitors, preadipocyte factor 1 and Sox9, were elevated in TK(-/-) MEFs and increased in both groups after STAT3 silencing. In total, these studies document a previously unknown function for the Ron receptor in mediating HFD-induced obesity and metabolic dysregulation.
authors: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and.
authors: William D
authors: WD
authors: Stuart
authors: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and.
authors: Nicholas E
authors: NE
authors: Brown
authors: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and.
authors: Andrew M
authors: AM
authors: Paluch
authors: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and Department of Research, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio susan.waltz@uc.edu.
authors: Susan E
authors: SE
authors: Waltz
mesh_terms: D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004622:Embryo, Mammalian; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D011505:Protein-Tyrosine Kinases; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
keywords: Ron tyrosine kinase; receptor tyrosine kinase; signal transducer and activator of transcription 3
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