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.

Maternal diethylhexyl phthalate exposure affects adiposity and insulin tolerance in offspring in a PCNA-dependent manner

“…Through secretion of hormonal regulators, such as leptin, TNFα, IL-6, MCP-1, PAI-1, ASP, resistin, and adiponectin, modulation and regulation of metabolic functions of the pancreas, liver, and muscles are coordinated and balanced in normal tissue (Troiano, Briefel et al 2000, Tang, Otto et al 2003, Andrikopoulos, Blair et al 2008, Stuart, Brown et al 2015). Human obesity-related diseases, including metabolic syndrome, may be a consequence of unbalanced regulation in adipose tissue, such as observed in the insulin resistance phenotype of A-ZIP/F-1 mice (mutation inducing a severe form of lipoatrophic diabetes) which is reversed via surgical implantation of adipose tissue grafts (Gavrilova, Marcus-Samuels et al 2000, Kim, Gavrilova et al 2000).…”

“…Glucose tolerance testing (GTT) was performed using 1g/kg intra-peritoneal glucose injection (Andrikopoulos, Blair et al 2008, Stuart, Brown et al 2015); glucose levels were measured using Accu-Chek Aviva Plus meter and test strips (Roche) from blood collected via tail nicks. GTT statistics were performed using two-way ANOVA analyses of data at individual time points.…”

“…GTT statistics were performed using two-way ANOVA analyses of data at individual time points. Insulin tolerance testing (ITT) was performed using 0.5 U/kg as per published protocols (Feige, Gelman et al 2007, Stuart, Brown et al 2015). GTT and ITT were performed at 12 and 13 weeks of HFD feeding, respectively.…”

Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

“…HGF activates MET which induces glucose uptake in both adipocytes and myotubes (Bertola et al, 2007;Perdomo et al, 2008) decreases lipid accumulation in liver (Kosone et al, 2007), and increases glycogen synthesis and glucose uptake in hepatocytes (Fafalios et al, 2011). MSP binds to RON to inhibit lipid accumulation in the liver (Stuart et al, 2015;Chanda et al, 2016). GAS6 activates TAM receptor family members to decrease β-oxidation and increase inflammation in the liver (Fourcot et al, 2011).…”

“…However, the global Ron receptor knockout mice where the ligand-binding domain is deleted develop severe obesity and glucose intolerance under high-fat diet (Yu et al, 2016). On the other hand, studies on Ron knockout mice lacking the tyrosine kinase domain rendering the protein inactive demonstrated the opposing finding that ablation of Ron signaling protected the mice from highfat diet induced obesity and hepatic steatosis (Stuart et al, 2015). The reason for this discrepancy is unclear but might be related to the strain differences (FVB versus C57BL/6) or to the method of gene targeting in these mice.…”