Obesity is a major risk factor for type 2 diabetes, cardiovascular disease, and hypertension. Induction of beige or brite adipocytes in white adipose tissue, called the browning process, promotes energy expenditure. Nutrient flux into the hexosamine biosynthesis pathway leads to the post-translational modification of cytoplasmic and nuclear proteins by O-linked beta-N- acetylglucosamine (O-GlcNAc). It has been well established that O-GlcNAc modification of insulin signaling proteins and transcriptional regulators in peripheral tissues is important for glucose and lipid metabolism. However, little is known about the role of this sugar modification in central regulation of metabolism. Hypothalamic neurons that co-express agouti-related protein (AgRP) and neuropeptide Y (NPY) promote feeding behavior and glucose homeostasis. Our previous studies show that genetic ablation of O-GlcNAc transferase (OGT) in AgRP neurons impairs neuronal excitability, induces thermogenic gene expression in white adipose tissue, and protects mice from high fat diet-induced obesity. Our unpublished data show that OGT ablation in POMC neurons leads to decreased energy expenditure and increased adiposity. Based on these findings, we hypothesize that O-GlcNAc signaling in POMC neurons integrates nutritional and hormonal cues to regulate adipose tissue browning and energy homeostasis.
The specific aims are: 1) Determine the regulation of WAT browning by OGT in POMC neurons; 2) Determine whether calcium signaling regulates OGT function in POMC neurons; 3) Determine whether O-GlcNAc signaling mediates the response of POMC neurons to metabolic cues. Completion of this proposal will reveal the importance of O-GlcNAc signaling in POMC neurons to central control of adipose tissue browning.

Public Health Relevance

Obesity is becoming one of the principal threats to human health in the twenty-first century. Both brown and beige adipocytes are appealing targets to increase energy expenditure and thereby ameliorate obesity and related metabolic diseases. Results from the proposed studies will establish a functional link between central O-GlcNAc signaling and adipose tissue properties, and aid in designing new strategies to modulate adaptive thermogenesis to combat obesity and associated morbidity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Silva, Corinne M
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Yale University
Veterinary Sciences
Schools of Medicine
New Haven
United States
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Qian, Kevin; Wang, Simeng; Fu, Minnie et al. (2018) Transcriptional regulation of O-GlcNAc homeostasis is disrupted in pancreatic cancer. J Biol Chem 293:13989-14000
Ruan, Hai-Bin; Ma, Yina; Torres, Sara et al. (2017) Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation. Genes Dev 31:1655-1665
Wang, Simeng; Yang, Xiaoyong (2017) Inter-organ regulation of adipose tissue browning. Cell Mol Life Sci 74:1765-1776
Yang, Xiaoyong; Qian, Kevin (2017) Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol 18:452-465