Whole body ARHGAP21 reduction improves glucose homeostasis in high‐fat diet obese mice

Abstract

GTPase activating proteins (GAPs) are ubiquitously expressed, and their role in cellular adhesion and membrane traffic processes have been well described. TBC1D1, which is a Rab-GAP, is necessary for adequate glucose uptake by muscle cells, whereas increased TCGAP, which is a Rho-GAP, decreases GLUT4 translocation, and consequently glucose uptake in adipocytes. Here, we assessed the possible involvement of ARHGAP21, a Rho-GAP protein, in glucose homeostasis. For this purpose, wild type mice and ARHGAP21 transgenic whole-body gene-deficiency mice (heterozygous mice, expressing approximately 50% of ARHGAP21) were fed either chow (Ctl and Het) or high-fat diet (Ctl-HFD and Het-HFD). Het-HFD mice showed a reduction in white fat storage, reflected in a lower body weight gain. These mice also displayed an improvement in insulin sensitivity and glucose tolerance, which likely contributed to reduced insulin secretion and pancreatic beta cell area. The reduction of body weight was also observed in Het mice and this phenomenon was associated with an increase in brown adipose tissue and reduced muscle weight, without alteration in glucose-insulin homeostasis. In conclusion, the whole body ARHGAP21 reduction improved glucose homeostasis and protected against diet-induced obesity specifically in Het-HFD mice. However, the mechanism by which ARHGAP21 leads to these outcomes requires further investigation.

Effects of rosuvastatin on metabolic profile: Versatility of dose-dependent effect

“…Besides, high glucose level stimulates the adaptive response of β-cell through insulin overproduction to compensate the IR. [1718]…”

Whole-Body ARHGAP21-Deficiency Improves Energetic Homeostasis in Lean and Obese Mice

“…We previously showed that ARHGAP21 inhibition decreased body weight in mice (21), but the mechanisms involved remain unknown. It is well established that body weight and appetite control are complex and that central mechanistic disturbances can lead to hyperphagia or anorexia depending on the balance between the expression of anorexic and orexic genes in the hypothalamus (7, 28).…”

“…In our study, as expected, mice submitted to high-fat diet presented metabolic inflexibility. However, Het-HFD mice presented increased RER during the dark phase, suggesting an improvement in metabolic flexibility, which can be explained, at least in part, by increased insulin sensitivity (21) leading to efficient glucose uptake and oxidation. These data support the hypothesis that ARHGAP21 reduction is able to boost the nutrient handling, energetic homeostasis, and metabolic flexibility (42, 43).…”

“…Indeed, GAP TBC1 domain family member 1 (TBC1D1)-deficiency reduces body weight (16–20), decreases respiratory quotient (16–19) and increases energy expenditure (17–20) in addition to suppressing diet-induced obesity (16, 19). Recently, our group reported that reduction of ARHGAP21 (a Rho-GAP isoform) improved glucose tolerance and insulin sensitivity and reduced weight gain in mice fed on high-fat diet (21). However, the role of ARHGAP21 in hypothalamic appetite control and whole-body energy homeostasis remains unclear.…”

ARHGAP21 Acts as an Inhibitor of the Glucose-Stimulated Insulin Secretion Process

“…Thus, investigating proteins and process that can mitigate beta cell overload and dysfunction may reveal new targets for better management of this pathology. In this context, our group has explored the role of ARGHAP21 (a RhoGAP protein), that has been implicated in cancer due to its suppressor tumor function, (4,5), and in the glycemic and insulin homeostasis (6)(7)(8)(9).…”