Key result
Mice lacking the Ron receptor tyrosine kinase signaling domain gained 50% less weight and exhibited improved insulin sensitivity and reduced hepatic steatosis compared to wild-type mice when fed a high-fat diet.
Why the study?
Does deletion of the Ron receptor tyrosine kinase signaling domain reduce obesity and metabolic dysregulation in mice fed a high-fat diet?
Does deletion of the Ron receptor tyrosine kinase signaling domain reduce obesity and metabolic dysregulation in mice fed a high-fat diet?
Effect estimate: 50% less weight gain
p-value: p=<0.05
Deletion of the Ron receptor tyrosine kinase signaling domain protects mice from high-fat diet-induced obesity, hepatic steatosis, and insulin resistance, identifying Ron as a potential therapeutic target for metabolic syndrome.
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.
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Stuart et al. (2015) studied Diet-induced obesity and metabolic syndrome. Global deletion of Ron tyrosine kinase signaling domain (TK-/-) vs. Wild-type (TK+/+) mice was evaluated on Weight gain on high-fat diet (50% less weight gain, p=<0.05). Mice lacking the Ron receptor tyrosine kinase signaling domain gained 50% less weight and exhibited improved insulin sensitivity and reduced hepatic steatosis compared to wild-type mice when fed a high-fat diet.
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