A Conserved Role for Syndecan Family Members in the Regulation of Whole-Body Energy Metabolism

Abstract

Syndecans are a family of type-I transmembrane proteins that are involved in cell-matrix adhesion, migration, neuronal development, and inflammation. Previous quantitative genetic studies pinpointed Drosophila Syndecan (dSdc) as a positional candidate gene affecting variation in fat storage between two Drosophila melanogaster strains. Here, we first used quantitative complementation tests with dSdc mutants to confirm that natural variation in this gene affects variability in Drosophila fat storage. Next, we examined the effects of a viable dSdc mutant on Drosophila whole-body energy metabolism and associated traits. We observed that young flies homozygous for the dSdc mutation had reduced fat storage and slept longer than homozygous wild-type flies. They also displayed significantly reduced metabolic rate, lower expression of spargel (the Drosophila homologue of PGC-1), and reduced mitochondrial respiration. Compared to control flies, dSdc mutants had lower expression of brain insulin-like peptides, were less fecund, more sensitive to starvation, and had reduced life span. Finally, we tested for association between single nucleotide polymorphisms (SNPs) in the human SDC4 gene and variation in body composition, metabolism, glucose homeostasis, and sleep traits in a cohort of healthy early pubertal children. We found that SNP rs4599 was significantly associated with resting energy expenditure (P = 0.001 after Bonferroni correction) and nominally associated with fasting glucose levels (P = 0.01) and sleep duration (P = 0.044). On average, children homozygous for the minor allele had lower levels of glucose, higher resting energy expenditure, and slept shorter than children homozygous for the common allele. We also observed that SNP rs1981429 was nominally associated with lean tissue mass (P = 0.035) and intra-abdominal fat (P = 0.049), and SNP rs2267871 with insulin sensitivity (P = 0.037). Collectively, our results in Drosophila and humans argue that syndecan family members play a key role in the regulation of body metabolism.

Metabolism and successful aging: Polymorphic variation of syndecan-4 (SDC4) gene associate with longevity and lipid profile in healthy elderly Italian subjects

“…interactions and matrix-mediated cellular signaling cascades impacts the decline of age-dependent physiological performance and thereby life span (Goddeeris et al, 2003;Hansen et al, 2005;Wolfson et al, 2009;De Luca et al, 2010;De Luca et al, 2011;Wilson et al, 2013;Nishimura et al, 2014). Consistently, here we report that common genetic variants in the SDC4 gene affect human longevity.…”

“…Furthermore, G allele carriers had higher levels of TG. This is particularly intriguing since we previously showed that American children (age 7 to 12 years)homozygous for the minor G-allele of rs1981429 had more intra-abdominal fat and less lean tissue mass (De Luca et al, 2010). Data on visceral fat were not available in the Italian cohort so we could not test for association between this trait and rs1981429.…”

“…Three of them, SDC1, SDC2, and SDC3, are expressed in a tissue-specific manner, whereas the fourth, SDC4, is expressed in a variety of cell types (Xianet al, 2010). Previously, common genetic variants in the human SDC4 gene were significantly associated with adiposity, fasting glucose, and energy expenditure in American children (De Luca et al, 2010). Association analysis in a cohort of middle-aged Finnish subjects also reported associations between SDC4 rs1981429 and hypertension, body mass index (BMI), and coronary heart disease (CHD) (Kunnas and Nikkari, 2014).…”

“…To this end, De Luca et al (2010) and Wilson et al (2013) recently reported that hypomorphic mutations in the Drosophila Sdc gene reduce life span in flies. Notably, Sdc mutant flies also display less fat and glycogen reserves and lower metabolic activity than control flies (De Luca et al, 2010), suggesting that Sdc might influence life span through a role in metabolism.…”

Dermal white adipose tissue: a new component of the thermogenic response

“…deduced to be under separate control, because they are targeted by different genetic drivers and respond to different cues. So far, there are no direct data that describe insulator activity in Drosophila ; however, the metabolic phenotypes described for the syndecan Sdc1 Ϫ / Ϫ insulation-defective mouse model (described in the following paragraph) are remarkably coincident with Sdc mutant Drosophila ( 33 ). Evidence points toward dWAT having a simple insulator function, with the support of hair covering as a relatively newer evolutionary innovation for this group of cells.…”