Role of GALNT2 on Insulin Sensitivity, Lipid Metabolism and Fat Homeostasis

Abstract

O-linked glycosylation, the greatest form of post-translational modifications, plays a key role in regulating the majority of physiological processes. It is, therefore, not surprising that abnormal O-linked glycosylation has been related to several human diseases. Recently, GALNT2, which encodes the GalNAc-transferase 2 involved in the first step of O-linked glycosylation, has attracted great attention as a possible player in many highly prevalent human metabolic diseases, including atherogenic dyslipidemia, type 2 diabetes and obesity, all clustered on the common ground of insulin resistance. Data available both in human and animal models point to GALNT2 as a molecule that shapes the risk of the aforementioned abnormalities affecting diverse protein functions, which eventually cause clinically distinct phenotypes (a typical example of pleiotropism). Pathways linking GALNT2 to dyslipidemia and insulin resistance have been partly identified, while those for type 2 diabetes and obesity are yet to be understood. Here, we will provide a brief overview on the present knowledge on GALNT2 function and dysfunction and propose novel insights on the complex pathogenesis of the aforementioned metabolic diseases, which all impose a heavy burden for patients, their families and the entire society.

Keywords: O-linked glycosylation; atherogenic dyslipidemia; hyperglycemia; insulin resistance; metabolic abnormalities; obesity; ppGalNAc-T2.

Figure 1

Changes in GALNT2 expression and/or function and insulin resistance, atherogenic dyslipidemia and obesity. Notes: GALNT2 promotes insulin action by down-regulating ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) [83], a negative modulator of insulin signaling [41,42,43,44,45,46] (orange arrow). Whether ENPP1 is a primary ppGalNAc-T2 target or its down-regulation is secondary to upstream O-glycosylation events is unknown (dashed box). The role of GALNT2 down-regulation in atherogenic dyslipidemia (low HDL-Cholesterol and/or high triglycerides) is best understood. This effect is mediated by the O-glycosylation of three established targets of ppGalNAc-T2 [9] (the product of GALNT2) (blue arrow). Although no data are currently available, it cannot be excluded that some of the deleterious effects of GALNT2 down-regulation on dyslipidemia are mediated by the concurrent deleterious effect on insulin signaling which, in turn, causes insulin resistance and low HDL-cholesterol/high-triglyceride levels [19]. Experimental data suggest that the effect of GALNT2 on adipocyte maturation, adipogenesis and eventually obesity is at least partly due to its positive modulation of insulin signaling [84]. Whether GALNT2 also affects adipogenesis through other mechanisms, possibly mediating coordinated changes in key genes affecting adipocyte maturation [84], is an alternative possibility that deserves further studies to be addressed (purple dashed arrow). Finally, a high glucose concentration decreases GALNT2 expression and this may play a role in hyperglycemia-induced insulin resistance (glucose toxicity) [15]. The mechanisms through which this down-regulation occurs are not known (green arrow, dashed box).