Glucose-6-Phosphate Dehydrogenase Deficiency Improves Insulin Resistance With Reduced Adipose Tissue Inflammation in Obesity.
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 (G6PD(mut)) 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 G6PD(mut) mice. In diet-induced obesity (DIO), the adipose tissue of G6PD(mut) mice decreased the expression of inflammatory cytokines, accompanied by downregulated proinflammatory macrophages. Accordingly, macrophages from G6PD(mut) mice greatly suppressed lipopolysaccharide-induced proinflammatory signaling cascades, leading to enhanced insulin sensitivity in adipocytes and hepatocytes. Furthermore, adoptive transfer of G6PD(mut) 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.
Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Initiatives Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Korea.
Mira
M
Ham
Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Initiatives Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Korea.
Sung Sik
SS
Choe
Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Initiatives Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Korea.
Kyung Cheul
KC
Shin
Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Initiatives Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Korea.
Goun
G
Choi
Department of Endocrinology and Metabolism, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Ji-Won
JW
Kim
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Korea.
Jung-Ran
JR
Noh
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Korea.
Yong-Hoon
YH
Kim
Department of Radiation Oncology, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Korea.
Je-Won
JW
Ryu
Department of Endocrinology and Metabolism, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Kun-Ho
KH
Yoon
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Korea.
Chul-Ho
CH
Lee
Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Initiatives Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Korea jaebkim@snu.ac.kr.
Jae Bum
JB
Kim
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D017077:Culture Media, Conditioned; D059305:Diet, High-Fat / Q000009:adverse effects; D005215:Fasting / Q000097:blood; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009765:Obesity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017077:Culture Media, Conditioned; D007328:Insulin; D017382:Reactive Oxygen Species