Deficiency of the tumor promoter gene wip1 induces insulin resistance.
Diabetes is a growing health care issue, and prediabetes has been established as a risk factor for type 2 diabetes. Prediabetes is characterized by deregulated glucose control, and elucidating pathways which govern this process is critical. We have identified the wild-type (WT) p53-inducible phosphatase (WIP1) phosphatase as a regulator of glucose homeostasis. Initial characterization of insulin signaling in WIP1 knockout (WIP1(KO)) murine embryo fibroblasts demonstrated reduced insulin-mediated Ak mouse transforming activation. In order to assess the role of WIP1 in glucose homeostasis, we performed metabolic analysis on mice on a low-fat chow diet (LFD) and high fat diet (HFD). We observed increased expression of proinflammatory cytokines in WIP1(KO) murine embryo fibroblasts, and WIP1(KO) mice fed a LFD and a HFD. WIP1(KO) mice exhibited glucose intolerance and insulin intolerance on a LFD and HFD. However, the effects of WIP1 deficiency cause different metabolic defects in mice on a LFD and a HFD. WIP1(KO) mice on a LFD develop hepatic insulin resistance, whereas this is not observed in HFD-fed mice. Mouse body weights and food consumption increase slightly over time in LFD-fed WT and WIP1(KO) mice. Leptin levels are increased in LFD-fed WIP1(KO) mice, compared with WT. In contrast, HFD-fed WIP1(KO) mice are resistant to HFD-induced obesity, have decreased levels of food consumption, and decreased leptin levels compared with HFD-WT mice. WIP1 has been shown to regulate the nuclear factor kappa-light-chain-enhancer of activated B cells pathway, loss of which leads to increased inflammation. We propose that this increased inflammation triggers insulin resistance in WIP1(KO) mice on LFD and HFD.
Department of Medicine (H.L.A., S.C., L.W., H.K.S.), Division of Endocrinology, Metabolism, and Diabetes (H.L.A., S.C., L.W., J.K.K., H.K.S.), and Program in Molecular Medicine (H.J.K., Y.L., D.Y.J., J.K.K.), University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Heather L
HL
Armata
Sally
S
Chamberland
Lauren
L
Watts
Hwi Jin
HJ
Ko
Yongjin
Y
Lee
Dae Young
DY
Jung
Jason K
JK
Kim
Hayla K
HK
Sluss
D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D004041:Dietary Fats; D005347:Fibroblasts / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000378:metabolism; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000096:biosynthesis / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D015850:Interleukin-6 / Q000096:biosynthesis; D020738:Leptin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D011236:Prediabetic State / Q000235:genetics*; D061251:Primary Cell Culture; D000071636:Protein Phosphatase 2C; D015398:Signal Transduction / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D004041:Dietary Fats; D007328:Insulin; D015850:Interleukin-6; D020738:Leptin; D014409:Tumor Necrosis Factor-alpha; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C; D005947:Glucose