A nexus of lipid and O- Glcnac metabolism in physiology and disease

Abstract

Although traditionally considered a glucose metabolism-associated modification, the O-linked β-N-Acetylglucosamine (O-GlcNAc) regulatory system interacts extensively with lipids and is required to maintain lipid homeostasis. The enzymes of O-GlcNAc cycling have molecular properties consistent with those expected of broad-spectrum environmental sensors. By direct protein-protein interactions and catalytic modification, O-GlcNAc cycling enzymes may provide both acute and long-term adaptation to stress and other environmental stimuli such as nutrient availability. Depending on the cell type, hyperlipidemia potentiates or depresses O-GlcNAc levels, sometimes biphasically, through a diversity of unique mechanisms that target UDP-GlcNAc synthesis and the availability, activity and substrate selectivity of the glycosylation enzymes, O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA). At the same time, OGT activity in multiple tissues has been implicated in the homeostatic regulation of systemic lipid uptake, storage and release. Hyperlipidemic patterns of O-GlcNAcylation in these cells are consistent with both transient physiological adaptation and feedback uninhibited obesogenic and metabolic dysregulation. In this review, we summarize the numerous interconnections between lipid and O-GlcNAc metabolism. These links provide insights into how the O-GlcNAc regulatory system may contribute to lipid-associated diseases including obesity and metabolic syndrome.

Keywords: O-GlcNAc; fatty acid; glycosylation; hexosamine biosynthetic pathway; homeostasis; lipid; metabolism; obesity.

Figure 1

Lipid Control Over the O-GlcNAc Regulatory System. Protein O-GlcNAcylation (blue) is regulated by the activity or localization of the glycoslylation enzymes, O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA) through direct binding to lipid species (e.g. PIP3) or downstream of lipid sensitive proteins and miRNAs. The substrate for OGT is UDP-GlcNAc, which is synthesized through an offshoot of glycolysis (green) called the hexosamine biosynthetic pathway (HBP, purple). Lipid regulation of the HBP seems particularly focused on expression of the rate limiting enzyme GFAT and control over the metabolic fate of fructose-6-phosphate (P), which represents the divergence point between glycolysis and the HBP. Proteins (or microRNA) with an altered expression profile in obesity are indicated by asterisk (see main text for details). Orange dashed lines indicate agonistic (➔) or inhibitory (–|) relationships between lipid metabolites (e.g. Acyl-CoA) or lipid regulated species (e.g. Fatty Acid Synthase, FAS). It is important to note that UDP-GlcNAc has multiple utilizations in the cell, which might also be influenced by the regulatory relationship indicated. Post-translational modifications are not included for the sake of visual clarity. Created with BioRender.com.

Figure 2

OGT supports neural activity in hypothalamic nuclei that regulate homeostatic eating drives including hunger-stimulating AgRP neurons and satiety-promoting neurons in the ARC and PVN. OGT in β-cells and adipocytes is important for the production of insulin and leptin hormones, which promote satiety and inhibit mesolimbic dopamine circuits that control hedonic eating motivation towards high fat foods. OGT activity facilitates transient lipid hyperphagia through the stabilization of adipocyte endocannabinoid AEA but may also contribute to counter-balancing feedback through oral fat sensitivity and orexigenic intestinal hormone secretion (i.e. OEA, GLP-1). The O-GlcNAc potentiated and lipid binding proteins CD36 and PLIN2 are promising candidates for regulating systemic lipid uptake through lingual fat detection and/or enterocyte extraction of dietary fatty acids into circulatory particles of chylomicron TAG. These mechanisms support a physiological eating pattern driven by homeostatic motivations punctuated by transient hedonic overconsumption of high palatability foods. However, OGT is also implicated in mechanisms underlying obesogenic pathophysiology. Prolonged hyperlipidemia decreases macrophage O-GlcNAcylation to disinhibit TL4-mediated pro-inflammatory cytokine secretion that can blunt insulin and leptin receptor sensitivity as could OGT targeting of receptor signaling modulators PTP1B and STAT3 in multiple cell types. Persistent high fat exposure decreases O-GlcNAcylation in β-cells but potentiates it in adipocytes and intestinal epithelial cells, potentially contributing to the high basal but impaired nutrient regulation of mature insulin and leptin secretion, elevated AEA levels and increased dietary lipid extraction that characterize a shift in obesity away from homeostasis and towards the chronic overconsumption of fat. OGT in this diagram represents the output of OGT activity (e.g. O-GlcNAcylation or protein interactions), whether driven by UDP-GlcNAc synthesis, OGA or OGT itself. “?” indicates a regulatory mechanism that has been demonstrated in other cell types but only hypothesized in the current setting. Dashed arrows show movement and solid arrows show effect, whether potentiating (–>) or inhibitory (–|). A double arrow combination (1 up, 1 down) indicates an increase in tonic tone with a depression in nutrient-responsive potentiation. Created with BioRender.com. Abbreviations: Agouti-related protein (AgRP) expressing, Arcuate Nucleus (ARC), Paraventricular Nucleus (PVN), O-GlcNAc Transferase (OGT), Dopamine (DA), N-arachidonoylethanolamine (AEA), Oleoylethanolamide (OEA), Cluster of Differentiation 36 (CD36), Triacylglycerol (TAG), Protein Tyrosine Phosphatase 1B (PTP1B), short-isoform O-GlcNAcase (sOGA), Perilipin 2 (PLIN2), Toll-Like Receptor 4 (TLR4).

Figure 3

Model for O-GlcNAc Regulation of Adipogenesis. Adipocyte terminal differentiation is characterized by a progressive increase in O-GlcNAcylation but the precise rationale for this is not fully elucidated. One possibility is that a high OGA/OGT ratio at the start of differentiation (1) permits C/EBPβ kinase activation by keeping O-GlcNAcylation off of nearby inhibitory residues (2). Activated C/EBPβ can then act at the Pparɣ and Ogt promoters (3). Both C/EBPβ and PPARɣ stimulate expression of C/EBPα (4), which marks the transition from the 1^st to the 2^nd transcriptional wave (—–) on ~ day 3 of a standard 8-day 3T3L1 differentiation protocol [see (272, 280, 282)]. Building OGT levels, with static OGA expression, could then provide negative feedback on C/EBPβ activity and simultaneously potentiate PPARɣ through their respective O-GlcNAcylations (5). In the final phase of differentiation, C/EBPα and PPARɣ act as transcription factors for each other and for adipogenic and adipokinic genes that characterize a mature adipocyte (6). The left side graph shows the approximate relative activity of each protein (x-axis) over an 8-day time course (y-axis). On the right, solid arrows represent positive (green, –>) and negative (red, –|) effects. Dashed arrows indicate translocation. Phosphorylation is shown as an encircled pink P and O-GlcNAcylation as a blue square with a G. Created with BioRender.com