Overexpression of glucose-6-phosphate dehydrogenase is associated with lipid dysregulation and insulin resistance in obesity.
Glucose-6-phosphate dehydrogenase (G6PD) produces cellular NADPH, which is required for the biosynthesis of fatty acids and cholesterol. Although G6PD is required for lipogenesis, it is poorly understood whether G6PD in adipocytes is involved in energy homeostasis, such as lipid and glucose metabolism. We report here that G6PD plays a role in adipogenesis and that its increase is tightly associated with the dysregulation of lipid metabolism and insulin resistance in obesity. We observed that the enzymatic activity and expression levels of G6PD were significantly elevated in white adipose tissues of obese models, including db/db, ob/ob, and diet-induced obesity mice. In 3T3-L1 cells, G6PD overexpression stimulated the expression of most adipocyte marker genes and elevated the levels of cellular free fatty acids, triglyceride, and FFA release. Consistently, G6PD knockdown via small interfering RNA attenuated adipocyte differentiation with less lipid droplet accumulation. Surprisingly, the expression of certain adipocytokines such as tumor necrosis factor alpha and resistin was increased, whereas that of adiponectin was decreased in G6PD overexpressed adipocytes. In accordance with these results, overexpression of G6PD impaired insulin signaling and suppressed insulin-dependent glucose uptake in adipocytes. Taken together, these data strongly suggest that aberrant increase of G6PD in obese and/or diabetic subjects would alter lipid metabolism and adipocytokine expression, thereby resulting in failure of lipid homeostasis and insulin resistance in adipocytes.
Park
Jiyoung
J
School of Biological Sciences, Seoul National University, San 56-1, Sillim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Rho
Ho Kyung
HK
Kim
Kang Ho
KH
Choe
Sung Sik
SS
Lee
Yun Sok
YS
Kim
Jae Bum
JB
D041721:3T3-L1 Cells; D052242:Adiponectin; D000273:Adipose Tissue / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation; D015971:Gene Expression Regulation, Enzymologic; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006729:Hormones, Ectopic / Q000378:metabolism; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D016297:Mutagenesis, Site-Directed; D009765:Obesity / Q000201:enzymology / Q000503:physiopathology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D052243:Resistin; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D052242:Adiponectin; D015415:Biomarkers; D006729:Hormones, Ectopic; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D052243:Resistin; C499623:Retn protein, mouse; D014409:Tumor Necrosis Factor-alpha; D005954:Glucosephosphate Dehydrogenase