title: Metabolic consequences of ENPP1 overexpression in adipose tissue.
abstract: Ectonucleotide pyrophosphate phosphodiesterase (ENPP1) has been shown to negatively modulate insulin receptor and to induce cellular insulin resistance when overexpressed in various cell types. Systemic insulin resistance has also been observed when ENPP1 is overexpressed in multiple tissues of transgenic models and attributed largely to tissue insulin resistance induced in skeletal muscle and liver. Another key tissue in regulating glucose and lipid metabolism is adipose tissue (AT). Interestingly, obese patients with insulin resistance have been reported to have increased AT ENPP1 expression. However, the specific effects of ENPP1 in AT have not been studied. To better understand the specific role of AT ENPP1 on systemic metabolism, we have created a transgenic mouse model (C57/Bl6 background) with targeted overexpression of human ENPP1 in adipocytes, using aP2 promoter in the transgene construct (AdiposeENPP1-TG). Using either regular chow or pair-feeding protocol with 60% fat diet, we compared body fat content and distribution and insulin signaling in adipose, muscle, and liver tissues of AdiposeENPP1-TG and wild-type (WT) siblings. We also compared response to intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT). Our results show no changes in Adipose ENPP1-TG mice fed a regular chow diet. After high-fat diet with pair-feeding protocol, AdiposeENPP1-TG and WT mice had similar weights. However, AdiposeENPP1-TG mice developed fatty liver in association with changes in AT characterized by smaller adipocyte size and decreased phosphorylation of insulin receptor Tyr(1361) and Akt Ser(473). These changes in AT function and fat distribution were associated with systemic abnormalities of lipid and glucose metabolism, including increased plasma concentrations of fatty acid, triglyceride, plasma glucose, and insulin during IPGTT and decreased glucose suppression during ITT. Thus, our results show that, in the presence of a high-fat diet, ENPP1 overexpression in adipocytes induces fatty liver, hyperlipidemia, and dysglycemia, thus recapitulating key manifestations of the metabolic syndrome.
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Texas Medical Branch at Galveston, Galveston, Texas 77555-1060, USA.
authors.forename: Wentong
authors.initials: W
authors.lastname: Pan
authors.forename: Ester
authors.initials: E
authors.lastname: Ciociola
authors.forename: Manish
authors.initials: M
authors.lastname: Saraf
authors.forename: Batbayar
authors.initials: B
authors.lastname: Tumurbaatar
authors.forename: Demidmaa
authors.initials: D
authors.lastname: Tuvdendorj
authors.forename: Sneha
authors.initials: S
authors.lastname: Prasad
authors.forename: Manisha
authors.initials: M
authors.lastname: Chandalia
authors.forename: Nicola
authors.initials: N
authors.lastname: Abate
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism / Q000235:genetics* / Q000502:physiology; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics; D005260:Female; D044882:Glucose Metabolism Disorders / Q000209:etiology / Q000235:genetics; D006801:Humans; D006949:Hyperlipidemias / Q000209:etiology / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000209:etiology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
chemical_list: D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases