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Adipose tissue dysfunction in humans: a potential role for the transmembrane protein ENPP1
Manisha Chandalia1, Himara Davila, Wentong Pan
1Department of Medicine, Division of Endocrinology, University of Texas Medical Branch at Galveston, Texas 77555-1060, USA.
The Journal of Clinical Endocrinology and Metabolism
|September 27, 2012
Summary
Increased adipose tissue ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) is linked to metabolic dysfunction and insulin resistance in men. These findings in humans mirror a mouse model, suggesting ENPP1 as a therapeutic target for related diseases.
Area of Science:
- Metabolic research
- Endocrinology
- Molecular biology
Background:
- Adipose tissue (AT) regulates systemic lipid and glucose metabolism.
- Previous studies identified lipid/glucose abnormalities in mice overexpressing ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) in AT.
- This mouse model exhibited increased liver triglyceride content.
Purpose of the Study:
- To investigate the association between AT-ENPP1 overexpression and AT dysfunction in humans.
- To determine if AT-ENPP1 overexpression correlates with liver triglyceride deposition and systemic insulin resistance.
- To test the translational hypothesis from a mouse model to human physiology.
Main Methods:
- 134 young, normoglycemic men and women underwent body composition analysis, hyperinsulinemic-euglycemic clamps, and AT needle biopsy.
- Liver and muscle triglyceride content were measured using nuclear magnetic resonance spectroscopy in 20 men.
- Gene expression of ENPP1, lipid metabolism, and inflammation markers in AT were analyzed, alongside plasma adipokines and nonesterified fatty acid (NEFA) levels.
Main Results:
- In men, higher AT-ENPP1 correlated with increased expression of NEFA metabolism and inflammation genes, elevated NEFA levels, reduced adiponectin, higher liver triglycerides, and insulin resistance.
- In women, despite increased AT gene expression for lipid metabolism and inflammation, no significant changes in adiponectin, NEFAs, or glucose disposal were observed in relation to AT-ENPP1 levels.
- Statistical adjustments for body fat content were applied to the analyses.
Conclusions:
- Elevated AT-ENPP1 is associated with adipose tissue dysfunction, hepatic steatosis, and insulin resistance in young, normoglycemic men.
- These human findings align with the previously observed phenotype in the AdiposeENPP1-Tg mouse model.
- Targeting AT-ENPP1 may offer a therapeutic strategy for metabolic disorders like type 2 diabetes and cardiovascular disease.
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