Glucose-6-Phosphate Dehydrogenase Deficiency Improves Insulin Resistance With Reduced Adipose Tissue Inflammation in Obesity

Abstract

Glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway, plays important roles in redox regulation and de novo lipogenesis. It was recently demonstrated that aberrant upregulation of G6PD in obese adipose tissue mediates insulin resistance as a result of imbalanced energy metabolism and oxidative stress. It remains elusive, however, whether inhibition of G6PD in vivo may relieve obesity-induced insulin resistance. In this study we showed that a hematopoietic G6PD defect alleviates insulin resistance in obesity, accompanied by reduced adipose tissue inflammation. Compared with wild-type littermates, G6PD-deficient mutant (G6PDmut) mice were glucose tolerant upon high-fat-diet (HFD) feeding. Intriguingly, the expression of NADPH oxidase genes to produce reactive oxygen species was alleviated, whereas that of antioxidant genes was enhanced in the adipose tissue of HFD-fed G6PDmut mice. In diet-induced obesity (DIO), the adipose tissue of G6PDmut mice decreased the expression of inflammatory cytokines, accompanied by downregulated proinflammatory macrophages. Accordingly, macrophages from G6PDmut mice greatly suppressed lipopolysaccharide-induced proinflammatory signaling cascades, leading to enhanced insulin sensitivity in adipocytes and hepatocytes. Furthermore, adoptive transfer of G6PDmut bone marrow to wild-type mice attenuated adipose tissue inflammation and improved glucose tolerance in DIO. Collectively, these data suggest that inhibition of macrophage G6PD would ameliorate insulin resistance in obesity through suppression of proinflammatory responses.

The role of glucose-6-phosphate dehydrogenase in adipose tissue inflammation in obesity

“…12,39,40 Very recently, the importance of G6PD to adipose tissue dysfunction is substantiated in diet-induced obesity. 45 In agreement with cell culture and ex vivo data, G6PD-deficient mutant mice (G6PD mut ) display amelioration of adipose tissue inflammation with a concomitant improvement in dysfunction of adipose tissue in obesity. The expression of pro-inflammatory genes decreases whereas the expression of adiponectin, one of the beneficial adipokines, increases in adipose tissue of high fat diet fed G6PD mut mice.…”

“…The expression of pro-inflammatory genes decreases whereas the expression of adiponectin, one of the beneficial adipokines, increases in adipose tissue of high fat diet fed G6PD mut mice. 45 Additionally, ROS production and NADPH oxidase expression in adipose tissue are significantly decreased in G6PD mut mice. 45 Together, such changes in adipose tissue result in the improvement of whole body insulin sensitivity and glucose tolerance.…”

“…45 Additionally, ROS production and NADPH oxidase expression in adipose tissue are significantly decreased in G6PD mut mice. 45 Together, such changes in adipose tissue result in the improvement of whole body insulin sensitivity and glucose tolerance. 45 One of the distinct phenotypes of G6PD mut mice, which differs from other knockout mice lacking NADPH-producing enzymes, is that there are no significant changes in the lipid synthesis and bodyweight in diet-induced obesity.…”

“…45 Together, such changes in adipose tissue result in the improvement of whole body insulin sensitivity and glucose tolerance. 45 One of the distinct phenotypes of G6PD mut mice, which differs from other knockout mice lacking NADPH-producing enzymes, is that there are no significant changes in the lipid synthesis and bodyweight in diet-induced obesity. These phenotypes are of interest as they imply that a decrease in G6PD-derieved NADPH appears to selectively diminish ROS generation without having impacts on lipid synthesis.…”

“…These phenotypes are of interest as they imply that a decrease in G6PD-derieved NADPH appears to selectively diminish ROS generation without having impacts on lipid synthesis. 45 Molecular mechanisms involved in such selective effect are under investigation. Importantly, adoptive transfer of G6PD mut bone marrow mitigated obesity-induced ROS generation, adipose tissue inflammation, and systemic insulin resistance in Figure 2.…”