SUMMARY A major cause of hyperglycemia in diabetic patients is inappropriate hepatic gluconeogenesis. PGC-1α is a master regulator of gluconeogenesis, and its activity is controlled by various post-translational modifications. A small portion of glucose metabolizes through the hexosamine biosynthetic pathway, which leads to O-linked β-N-acetylglucosamine (O-GlcNAc) modification of cytoplasmic and nuclear proteins. Using a proteomic approach, we identified a broad variety of proteins associated with O-GlcNAc transferase (OGT), among which host cell factor C1 (HCF-1) is highly abundant. HCF-1 recruits OGT to O-GlcNAcylate PGC-1α and O-GlcNAcylation facilitates the binding of the deubiquitinase BAP1, thus protecting PGC-1α from degradation and promoting gluconeogenesis. Glucose availability modulates gluconeogenesis through the regulation of PGC-1α O-GlcNAcylation and stability by the OGT/HCF1 complex. Hepatic knockdown of OGT and HCF-1 improves glucose homeostasis in diabetic mice. These findings define the OGT/HCF-1 complex as a glucose sensor and key regulator of gluconeogenesis, shedding light on new strategies for treating diabetes.
SUMMARY Induction of beige cells causes the browning of white fat and improves energy metabolism. However, the central mechanism that controls adipose tissue browning and its physiological relevance are largely unknown. Here we demonstrate that fasting and chemical-genetic activation of orexigenic AgRP neurons in the hypothalamus suppress the browning of white fat. O-linked β-N-acetylglucosamine (O-GlcNAc) modification of cytoplasmic and nuclear proteins regulates fundamental cellular processes. The levels of O-GlcNAc transferase (OGT) and O-GlcNAc modification are enriched in AgRP neurons and are elevated by fasting. Genetic ablation of OGT in AgRP neurons inhibits neuronal excitability through the voltage-dependent potassium channel, promotes white adipose tissue browning, and protects mice against diet-induced obesity and insulin resistance. These data reveal adipose tissue browning as a highly dynamic physiological process under central control, in which O-GlcNAc signaling in AgRP neurons is essential for suppressing thermogenesis to conserve energy in response to fasting.
Nuclear, cytoplasmic and mitochondrial proteins are extensively modified by an O-linked β-N-acetylglucosamine (O-GlcNAc) moiety. This sugar modification regulates fundamental cellular processes in response to diverse nutritional and hormonal cues. The enzymes O-GlcNAc transferase (OGT) and O-linked β-N-acetylglucosaminase (O-GlcNAcase) mediate the addition and removal of O-GlcNAc, respectively. Aberrant O-GlcNAcylation has been implicated in a plethora of human diseases, including diabetes, cancer, aging, cardiovascular disease and neurodegenerative disease. As metabolic dysregulation is a vital component of these diseases, unraveling the roles of O-GlcNAc in metabolism is of emerging importance. Here, we review the current understanding of the functions of O-GlcNAc in cell signaling and gene transcription involved in metabolism, and focus on its relevance to diabetes, cancer, circadian rhythm, and mitochondrial function.
SUMMARY Circadian clocks are coupled to metabolic oscillations through nutrient-sensing pathways. Nutrient flux into the hexosamine biosynthesis pathway triggers covalent protein modification by O-linked β-D-N-acetylglucosamine (O-GlcNAc). Here we show that the hexosamine/O-GlcNAc pathway modulates peripheral clock oscillation. O-GlcNAc transferase (OGT) promotes expression of BMAL1/CLOCK target genes and affects circadian oscillation of clock genes in vitro and in vivo. Both BMAL1 and CLOCK are rhythmically O-GlcNAcylated and this protein modification stabilizes BMAL1 and CLOCK by inhibiting their ubiquitination. In vivo analysis of genetically modified mice with perturbed hepatic OGT expression shows aberrant circadian rhythms of glucose homeostasis. These results establish the counteraction between O-GlcNAcylation and ubiquitination as a key mechanism that regulates the circadian clock and suggest a crucial role for O-GlcNAc signaling in transducing nutritional signals to the core circadian timing machinery.
The covalent attachment of β-D-N-acetylglucosamine monosaccharides (O-GlcNAc) to serine/threonine residues of nuclear and cytoplasmic proteins is a major regulatory mechanism in cell physiology. Aberrant O-GlcNAc modification of signaling proteins, metabolic enzymes, and transcriptional and epigenetic regulators has been implicated in cancer. Relentless growth of cancer cells requires metabolic reprogramming that is intertwined with changes in the epigenetic landscape. This review highlights the emerging role of protein O-GlcNAcylation at the interface of cancer metabolism and epigenetics.
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