The Rho-guanine nucleotide exchange factor PDZ-RhoGEF governs susceptibility to diet-induced obesity and type 2 diabetes

Abstract

Adipose tissue is crucial for the maintenance of energy and metabolic homeostasis and its deregulation can lead to obesity and type II diabetes (T2D). Using gene disruption in the mouse, we discovered a function for a RhoA-specific guanine nucleotide exchange factor PDZ-RhoGEF (Arhgef11) in white adipose tissue biology. While PDZ-RhoGEF was dispensable for a number of RhoA signaling-mediated processes in mouse embryonic fibroblasts, including stress fiber formation and cell migration, it's deletion led to a reduction in their proliferative potential. On a whole organism level, PDZ-RhoGEF deletion resulted in an acute increase in energy expenditure, selectively impaired early adipose tissue development and decreased adiposity in adults. PDZ-RhoGEF-deficient mice were protected from diet-induced obesity and T2D. Mechanistically, PDZ-RhoGEF enhanced insulin/IGF-1 signaling in adipose tissue by controlling ROCK-dependent phosphorylation of the insulin receptor substrate-1 (IRS-1). Our results demonstrate that PDZ-RhoGEF acts as a key determinant of mammalian metabolism and obesity-associated pathologies.DOI: http://dx.doi.org/10.7554/eLife.06011.001

Genome-wide association study reveals putative role of gga-miR-15a in controlling feed conversion ratio in layer chickens

“…FARP2 (FERM, RhoGEF and pleckstrin domain-containing protein 2), a guanine nucleotide exchange factor in the Rho family of small GTPases, was a shared candidate gene for both FI and RFI. FARP2 was identified as a candidate gene in diabetes research [ 30 ], and is correlated with energy metabolism and obesity-associated pathologies [ 31 ]. Another promising candidate gene for RFI was cannabinoid receptor 1 ( CNR1 ), which is referred to in an energy homeostasis and metabolic process revealed by pharmacological studies [ 32 ].…”

FAK signalling controls insulin sensitivity through regulation of adipocyte survival

“…Lean body mass of HFD-fed mice was determined by magnetic resonance imaging (Biospec 70/30; Bruker, Ettlingen, Germany) and semi-automated and manual segmentation tools using MIPAV software 52 58 . Total body and fat mass were measured and used to calculate lean body mass.…”

Tight junctions as regulators of tissue remodelling

“…The third junctional RhoA GEF is ARHGEF11/PDZ-RhoGEF and is recruited to TJ by ZO-1 [33]. ARHGEF11 has recently been linked to insulin signalling in mice, suggesting that it may link TJ to regulation of metabolic pathways [34].…”