Effects of X-chromosome Tenomodulin Genetic Variants on Obesity in a Children’s Cohort and Implications of the Gene in Adipocyte Metabolism

Abstract

Tenomodulin (TNMD) is a type II transmembrane glycoprotein that has been recently linked to obesity, and it is highly expressed in obese adipose tissue. Several sex-dependent associations have been observed between single-nucleotide polymorphisms (SNPs) of the TNMD gene, which is located in the X-chromosome, and obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome in adults. On the other hand, results are lacking for children. We aimed (i) to study the association between TNMD genetic variants and metabolic complications related to childhood obesity and (ii) to investigate the function of TNMD in human adipocytes. We conducted a case-control, multicenter study in 915 Spanish children and demonstrated significant positive associations between TNMD genetic variants and BMI z-score, waist circumference, fasting glucose, and insulin resistance in boys, highlighting the SNP rs4828038. Additionally, we showed a BMI-adjusted inverse association with waist circumference in girls. Second, in vitro experiments revealed that TNMD is involved in adipogenesis, along with glucose and lipid metabolism in differentiated adipocytes, and these effects may be mediated through AMPK activation. Hence, these results suggest that TNMD genetic variants could be potentially useful as early life risk indicators for obesity and T2DM. In addition, we support the fact that TNMD exhibits significant metabolic functions in adipocytes.

Anti‑glycolipid disorder effect of epigallocatechin‑3‑gallate on high‑fat diet and STZ‑induced T2DM in mice

“…The serum Tc, TG and ldl levels of the T2DM group were significantly higher compared with the normal group, showing that a hyperlipidemia T2dM mouse model had been successfully established. a previous clinical trial revealed that the serum levels of TG and ldl-r are significantly higher in T2dM patients with vascular lesions compared with T2dM patients without such complications (44). The HFd and STZ-induced diabetic mice also demonstrated dyslipidemia, as evidenced by elevated levels of Tc, ldl-r and TG, with a concomitant decrease in Hdl, as observed in human T2dM (45), which was consistent with the findings of the present study.…”

X chromosome genetic data in a Spanish children cohort, dataset description and analysis pipeline

“…Similarly, SNPs in the SLC6A14 gene, also located in the X chromosome, have shown evidence of association with obesity 14 . As a whole, these TNMD and SLC6A14 reports support the fact that X chromosome genetic variants may be not only useful early life risk indicators of obesity but also an interesting source of missing heritability 13 .…”

“…These methods are an expanded version of descriptions in our related work and general characteristics of the dataset have been previously described 13 . Briefly, in this case-control multicentre study, 915 Spanish children (438 males and 477 females) were recruited from three national health institutions: Lozano Blesa University Clinical Hospital, Santiago de Compostela University Clinical Hospital and Reina Sofía University Clinical Hospital.…”

“…Regarding children population, our research group found that TNMD expression was five fold-times up-regulated in visceral adipose tissue (VAT) of children with obesity, compared with their normal-weight counterparts (Gene Expression Omnibus GSE9624) 11,12 . Recently, we have reported new associations between TNMD SNPs and childhood obesity and metabolic alterations in a Spanish children population 13 . Interestingly, our study has been the first to analyse and detect associations between X chromosome TNMD genetic variants and obesity in a children cohort.…”

“…Given the lack of public available genetic datasets incorporating X chromosome genetic variants and the still prevalent statistical hurdles that make the X chromosome a difficult region to be tested in functional genetics, we here aimed: (1) to make public and describe a dataset incorporating X chromosome genotype data from a children cohort 13,15 , and (2) to outline a whole implementation of the special X chromosome analytic process in genetics. The presented research dataset includes X-chromosomal SNP data (mapping the genes TNMD and SLC6A14 ) from a children cohort composed of 915 normal-weight, overweight and obese subjects.…”