A novel role for GalNAc-T2 dependent glycosylation in energy homeostasis

Leveraging Genetics to Address the Role of GALNT2 on Atherogenic Dyslipidemia

“…The correlation between GALNT2 genetic variability and HOMA IR observed in our cohort reinforces previous evidences deriving from human, animal and cellular models pointing GALNT2 as a positive modulator of insulin signaling and action in vitro [16,17,32] and of insulin sensitivity in vivo. [18,19] Indeed, GALNT2 expression in cultured cells is inversely correlated with that of ENPP1, a well-established negative modulator of insulin signaling, [33][34][35][36][37][38] thus making possible to hypothesize that ENPP1 downregulation partly mediates the insulin sensitizing effect of GALNT2. Even more importantly, insulin receptor has been very recently reported as a novel target of GALNT2 glycosylation activity, [19] with insulin signaling being impaired in visceral white adipose tissue from Galnt2 −/mice.…”

“…[18,19] Indeed, GALNT2 expression in cultured cells is inversely correlated with that of ENPP1, a well-established negative modulator of insulin signaling, [33][34][35][36][37][38] thus making possible to hypothesize that ENPP1 downregulation partly mediates the insulin sensitizing effect of GALNT2. Even more importantly, insulin receptor has been very recently reported as a novel target of GALNT2 glycosylation activity, [19] with insulin signaling being impaired in visceral white adipose tissue from Galnt2 −/mice. [19] No matter how GALNT2 affects insulin action, our present data suggesting that the effect of GALNT2 on lipid levels is in part mediated by changes in insulin sensitivity, reinforce the hypothesis that GALNT2 exerts pleiotropic effects (i.e., via different mechanisms) on several pathophysiological metabolic pathways.…”

“…Even more importantly, insulin receptor has been very recently reported as a novel target of GALNT2 glycosylation activity, [19] with insulin signaling being impaired in visceral white adipose tissue from Galnt2 −/mice. [19] No matter how GALNT2 affects insulin action, our present data suggesting that the effect of GALNT2 on lipid levels is in part mediated by changes in insulin sensitivity, reinforce the hypothesis that GALNT2 exerts pleiotropic effects (i.e., via different mechanisms) on several pathophysiological metabolic pathways. [23,39] All this said, we do acknowledge that in contrast to our present finding, data from GWAs showed no significant association between rs4846914 and HOMA IR in more than 45 000 individuals from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), [40] while the lack of association with serum adiponectin resembles those previously reported from GWAs.…”

“…In addition, GALNT2 positively affects insulin signaling and action in vitro [16,17] and insulin sensitivity in vivo. [18][19][20] Since insulin sensitivity modulates serum HDL-C and triglycerides levels, [1,21,22] it can be hypothesized that in addition to the direct effects on the key lipid metabolism enzymes mentioned above, [3,[6][7][8][9]12] GALNT2 also indirectly affects serum lipids through its effect on insulin sensitivity. [23] Moreover, we have recently shown that in mouse 3T3L1 cells GALNT2 over-expression strongly upregulates Adipoq, the gene which encodes adiponectin, [24,25] during the entire period of adipogenesis.…”

Loss of the glycosyltransferase Galnt11 affects vitamin D homeostasis and bone composition

“…Enzymatic studies have demonstrated that members of this family have overlapping, yet unique substrate specificities as well as unique patterns of expression ( 1 , 2 , 3 , 4 , 5 , 6 , 7 ). Studies in model organisms have shown that certain family members are essential for viability and others are involved in diverse biological processes including cell adhesion, protein processing, secretion, and organ development and function ( 2 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ). Mutations in human GALNT3 are responsible for the disease hyperphosphatemic familial tumoral calcinosis ( 16 ), and a recent study has identified mutations in GALNT2 that result in a novel congenital disorder of glycosylation ( 17 ).…”