Metabolic consequences of ENPP1 overexpression in adipose tissue

Wentong Pan, Ester Ciociola, Manish Saraf, Batbayar Tumurbaatar, Demidmaa Tuvdendorj, Sneha Prasad, Manisha Chandalia, Nicola Abate

Research output: Contribution to journalArticle

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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 AThave 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume301
Issue number5
DOIs
StatePublished - Nov 2011

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Adipose Tissue
Insulin Resistance
Adipocytes
Insulin
Glucose
Insulin Receptor
High Fat Diet
Fatty Liver
Glucose Tolerance Test
Lipid Metabolism
Fats
Diet
Body Fat Distribution
Liver
Phosphoric Diester Hydrolases
Hyperlipidemias
Transgenes
Transgenic Mice
Siblings
Skeletal Muscle

Keywords

  • Ectonucleotide pyrophosphate phosphodiesterase
  • Fatty liver
  • Transgenic mice

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

Metabolic consequences of ENPP1 overexpression in adipose tissue. / Pan, Wentong; Ciociola, Ester; Saraf, Manish; Tumurbaatar, Batbayar; Tuvdendorj, Demidmaa; Prasad, Sneha; Chandalia, Manisha; Abate, Nicola.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 301, No. 5, 11.2011.

Research output: Contribution to journalArticle

Pan, Wentong ; Ciociola, Ester ; Saraf, Manish ; Tumurbaatar, Batbayar ; Tuvdendorj, Demidmaa ; Prasad, Sneha ; Chandalia, Manisha ; Abate, Nicola. / Metabolic consequences of ENPP1 overexpression in adipose tissue. In: American Journal of Physiology - Endocrinology and Metabolism. 2011 ; Vol. 301, No. 5.
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AB - 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 AThave 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.

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