Adipose Tissue Dysfunction in Humans: A Potential Role for the Transmembrane Protein ENPP1

Chandalia, Manisha; Davila, Himara; Pan, Wei‐Jian; Szuszkiewicz, Magdalena; Tuvdendorj, Demidmaa; Livingston, Edward H.; Abate, Nicola

doi:10.1210/jc.2012-2018

Cited by 19 publications

(16 citation statements)

References 33 publications

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“…Pan et al (2011) showed that the overexpression of ENPP1 in a human cell line resulted in adipocyte insulin resistance and demonstrated an association with fatty liver, hyperlipidemia and dysglycaemia. Accordingly, the study by Chandalia et al (2012) underlined increased ENPP1 expression in adipose tissue associated with defective adipocyte maturation leading to pathogenesis of insulin resistance and its associated complications for glucose and lipid metabolism in the absence of obesity. In addition, Meyre et al (2005) reported the presence of three ENPP1 SNPs in human genes associated with adult obesity and increased risk of glucose intolerance and type 2 diabetes.…”

Section: Genes Differentially Expressed Between Lean and Fat Animals mentioning

confidence: 99%

Transcriptional profiling of subcutaneous adipose tissue in Italian Large White pigs divergent for backfat thickness

Zambonelli¹,

Gaffo

Zappaterra³

et al. 2016

Animal Genetics

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Fat deposition is a widely studied trait in pigs because of its implications with animal growth efficiency, technological and nutritional characteristics of meat products, but the global framework of the biological and molecular processes regulating fat deposition in pigs is still incomplete. This study describes the backfat tissue transcription profile in Italian Large White pigs and reports genes differentially expressed between fat and lean animals according to RNA-seq data. The backfat transcription profile was characterised by the expression of 23 483 genes, of which 54.1% were represented by known genes. Of 63 418 expressed transcripts, about 80% were non-previously annotated isoforms. By comparing the expression level of fat vs. lean pigs, we detected 86 robust differentially expressed transcripts, 72 more highly expressed (e.g. ACP5, BCL2A1, CCR1, CD163, CD1A, EGR2, ENPP1, GPNMB, INHBB, LYZ, MSR1, OLR1, PIK3AP1, PLIN2, SPP1, SLC11A1, STC1) and 14 lower expressed (e.g. ADSSL1, CDO1, DNAJB1, HSPA1A, HSPA1B, HSPA2, HSPB8, IGFBP5, OLFML3) in fat pigs. The main functional categories enriched in differentially expressed genes were immune system process, response to stimulus, cell activation and skeletal system development, for the overexpressed genes, and unfolded protein binding and stress response, for the underexpressed genes, which included five heat shock proteins. Adipose tissue alterations and impaired stress response are linked to inflammation and, in turn, to adipose tissue secretory activity, similar to what is observed in human obesity. Our results provide the opportunity to identify biomarkers of carcass fat traits to improve the pig production chain and to identify genetic factors that regulate the observed differential expression.

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Section: Genes Differentially Expressed Between Lean and Fat Animals mentioning

confidence: 99%

Transcriptional profiling of subcutaneous adipose tissue in Italian Large White pigs divergent for backfat thickness

Zambonelli¹,

Gaffo

Zappaterra³

et al. 2016

Animal Genetics

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“…Although we have previously demonstrated that ENPP1 is linked to IR in men, and in the AtENNP1 Tg mice, 12,18 this is the first study to show a correlation between ENPP1 and IR in women. Future investigations could clarify the mechanisms regulating ENPP1 in AT and perhaps assess the potential role of this protein as a novel target of therapeutic intervention to prevent GDM and its associated complications for both mother and newborn health.…”

Section: Discussionmentioning

confidence: 60%

“…10 For example, AT expandability during pregnancy has been proposed to play a role in the etiology of GDM as supported by gene expression and histological properties of GDM subcutaneous AT. 23,24 According to this view, similarly to what is found in men with metabolic syndrome, 12 decreased ability to store energy in adipocytes plays a role in accentuating IR during pregnancy. Along these lines, our study proposes that ENPP1 upregulation could functionally mediate impairment in AT expandability just as previously shown in the AtENPP1 Tg mice.…”

Section: Discussionmentioning

confidence: 74%

Adipose Tissue Insulin Resistance in Gestational Diabetes

Tumurbaatar

Poole

Olson

et al. 2017

Metabolic Syndrome and Related Disorders

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Background: Gestational diabetes mellitus (GDM) is a metabolic disorder characterized by insulin resistance (IR) and altered glucose-lipid metabolism. We propose that ectonucleotide pyrophosphate phosphodiesterase-1 (ENPP1), a protein known to induce adipocyte IR, is a determinant of GDM. Our objective was to study ENPP1 expression in adipose tissue (AT) of obese pregnant women with or without GDM, as well as glucose tolerance in pregnant transgenic (Tg) mice with AT-specific overexpression of human ENPP1. Methods: AT biopsies and blood were collected from body mass index-matched obese pregnant women non-GDM (n = 6), GDM (n = 7), and nonpregnant controls (n = 6) undergoing cesarian section or elective surgeries, respectively. We measured the following: (1) Expression of key molecules involved in insulin signaling and glucose-lipid metabolism in AT; (2) Plasma glucose and insulin levels and calculation of homeostasis model assessment of IR (HOMA-IR); (3) Intraperitoneal glucose tolerance test in AtENPP1 Tg pregnant mice. Results: We found that: (1) Obese GDM patients have higher AT ENPP1 expression than obese non-GDM patients, or controls (P = 0.01-ANOVA). (2) ENPP1 expression level correlated negatively with glucose transporter 4 (GLUT4) and positively with insulin receptor substrate-1 (IRS-1) serine phosphorylation, and to other adipocyte functional proteins involved in glucose and lipid metabolism (P < 0.05 each), (3) AT ENPP1 expression levels were positively correlated with HOMA-IR (P = 0.01-ANOVA). (4) Pregnant AT ENPP1 Tg mice showed higher plasma glucose than wild type animals (P = 0.046-t test on area under curve [AUC] glucose ). Conclusions: Our results provide evidence of a causative link between ENPP1 and alterations in insulin signaling, glucose uptake, and lipid metabolism in subcutaneous abdominal AT of GDM, which may mediate IR and hyperglycemia in GDM.

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“…To better define the effect of ENPP1 in humans, we [18] recently conducted a study on the relationship of ENPP1 expression level and insulin resistance in 134 young normoglycemic volunteers. Body composition studies, hyperinsulinemic-euglycemic clamps and adipose tissue biopsy were obtained to test the overall hypothesis that ENPP1 over-expression contributes to AT dysfunction and systemic insulin resistance.…”

mentioning

confidence: 99%

“…However, we have described a significant interaction between the gene and BMI [17]. We have also described a gender difference in the association between ENPP1 expression and insulin resistance [18]. Therefore, the degree of functional impairment determined by the 121Q variant may not be sufficient to determine a measurable phenotype, unless interaction variables are taken into account.…”

mentioning

confidence: 99%