SFEBES2021 Oral Communications Metabolism, Obesity and Diabetes (6 abstracts)
Hepatic choline deficiency underpins amelioration of visceral obesity and diabetes in ectonucleotide pyrophosphatase (Enpp)-6–/– mice
Rongling Wang 1 , Katharina Schraut 1 , Roderick Carter 1 , Katherine Kentistou 1 , James Wilson 2 , Zoi Michailidou 1 , Scott Webster 1 & Nicholas Morton 1
1Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom; 2Usher Institute and MRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom
The global prevalence of obesity continues to rise, creating a growing need for new effective medicines. Selective targeting of visceral obesity (fat around the internal organs) would be particularly advantageous because it carries a greater risk for cardiometabolic diseases. The ectonucleotide pyrophosphatase (ENPP) enzyme family participates in several pathological conditions including diabetes (ENPP1, and ENPP2, also known as autotaxin) and vascular dysfunction (ENPP3-4). Of these, ENPP6 is a lysophospholipase-C-type enzyme recently linked to regulation of local phosphocholine availability. The role of ENPP6 in fat distribution and metabolism in the context of obesity is unknown. Here we investigated the metabolic profile of mice lacking the Enpp6 gene (Enpp6–/–) when exposed to an obesogenic high-fat-diet (HFD) and tested whether choline deficiency (CD) represented an underlying mechanism contributing to their phenotype. HFD-fedEnpp6–/– mice exhibited selectively reduced visceral adiposity with higher white adipose expression of “beigeing” markers (indicative of enhanced lipid burning), improved glucose tolerance and resistance to fatty liver compared to Enpp6+/+ mice. HFD-fed Enpp6–/– mice also exhibited significantly decreased hepatic choline levels and evidence for impaired de novo phosphatidylcholine biosynthesis through reduced hepatic phosphatidylethanolamine N-Methyltransferase (Pemt) expression. Dietary choline supplementation reversed the improved metabolic phenotype of Enpp6–/– mice in parallel with restored hepatic Pemt mRNA levels. Dietary choline deficiency (CD) did not augment the improved phenotype of HFD-fed Enpp6–/– mice. Instead, CD-HFD increased liver fat accumulation to a greater extent in Enpp6–/– mice. This suggests ENPP6-regulated endogenous choline production plays a novel role in body-fat distribution distinct to dietary choline. ENPP6 is a novel anti-visceral obesity target through its effects on endogenous hepatic choline production.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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