Syndecan-4 as a genetic determinant of the metabolic syndrome

Paolina Crocco; Denise Vecchie; Sreejit Gopalkrishna; Serena Dato; Giuseppe Passarino; Martin E Young; Prabhakara R Nagareddy; Giuseppina Rose; Maria De Luca

doi:10.1186/s13098-023-01132-8

Syndecan-4 as a genetic determinant of the metabolic syndrome

Diabetol Metab Syndr. 2023 Jul 17;15(1):156. doi: 10.1186/s13098-023-01132-8.

Authors

Affiliations

¹ Department of Biology, Ecology, and Earth Sciences, University of Calabria, Rende, 87036, Italy.
² Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
³ Department of Surgery, Division of Cardiac Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
⁴ Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
⁵ Department of Biology, Ecology, and Earth Sciences, University of Calabria, Rende, 87036, Italy. pina.rose@unical.it.
⁶ Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. mdeluca2@uab.edu.

^# Contributed equally.

Abstract

Background: Syndecan-4 (SDC4) is a member of the heparan sulfate proteoglycan family of cell-surface receptors. We and others previously reported that variation in the SDC4 gene was associated with several components of the metabolic syndrome, including intra-abdominal fat, fasting glucose and triglyceride levels, and hypertension, in human cohorts. Additionally, we demonstrated that high fat diet (HFD)-induced obese female mice with a Sdc4 genetic deletion had higher visceral adiposity and a worse metabolic profile than control mice. Here, we aimed to first investigate whether the mouse Sdc4 null mutation impacts metabolic phenotypes in a sex- and diet-dependent manner. We then tested whether SDC4 polymorphisms are related to the metabolic syndrome (MetS) in humans.

Methods: For the mouse experiment, Sdc4-deficient (Sdc4^-/-) and wild-type (WT) mice were treated with 14-weeks of low-fat diet (LFD). Body composition, energy balance, and selected metabolic phenotypes were assessed. For the human genetic study, we used logistic regression models to test 11 SDC4 SNPs for association with the MetS and its components in a cohort of 274 (113 with MetS) elderly subjects from southern Italy.

Results: Following the dietary intervention in mice, we observed that the effects of the Sdc4 null mutation on several phenotypes were different from those previously reported in the mice kept on an HFD. Nonetheless, LFD-fed female Sdc4^-/- mice, but not males, displayed higher levels of triglycerides and lower insulin sensitivity at fasting than WT mice, as seen earlier in the HFD conditions. In the parallel human study, we found that carriers of SDC4 rs2228384 allele C and rs2072785 allele T had reduced risk of MetS. The opposite was true for carriers of the SDC4 rs1981429 allele G. Additionally, the SNPs were found related to fasting triglyceride levels and triglyceride glucose (TyG) index, a reliable indicator of insulin resistance, with sex-stratified analysis detecting the association of rs1981429 with these phenotypes only in females.

Conclusions: Altogether, our results suggest that SDC4 is an evolutionary conserved genetic determinant of MetS and that its genetic variation is associated with fasting triglyceride levels in a female-specific manner.

Keywords: Heparan sulfate proteoglycans; Insulin resistance; Lipid profile; Metabolic syndrome; Obesity; Single nucleotide polymorphism.

Abstract

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