Obesity has become a global pandemic that poses massive economic and public health burdens worldwide. Adipose tissue has an enormous plasticity in response to nutrient availability. Nutrient flux into the hexosamine biosynthetic pathway leads to the posttranslational modification of nuclear, cytoplasmic, and mitochondrial proteins by O-linked ?-N-acetylglucosamine (O-GlcNAc) moieties. O-GlcNAc transferase (OGT) is responsible for the addition of GlcNAc moieties to target proteins. Our preliminary results show that deletion of OGT in mature adipocytes results in lipodystrophy and transgenic overexpression of OGT promotes diet-induced obesity. Additionally, conditioned medium from OGT-deficient adipocytes modulates preadipocyte proliferation and differentiation in vitro. To illustrate how nutrient-sensing OGT impacts adipose tissue homeostasis, we hypothesize that OGT in mature adipocytes controls adipogenesis through paracrine regulation of preadipocyte proliferation and differentiation.
Aim 1 will assess in vivo adipogenesis in adipose-specific OGT knockout and knockin mice.
Aim 2 will determine the effects of adipose OGT on dietary regulation of adipogenesis and whole-body metabolism.
Aim 3 will identify how OGT in mature adipocytes regulates preadipocyte proliferation and differentiation in a paracrine manner. Completion of the proposed studies will define adipocyte OGT as a nutrient sensor that mediates the paracrine regulation of adipogenesis and controls the development of obesity and co-morbidities.

Public Health Relevance

The adult obesity rate in the United States is above 35% and is still rapidly increasing. Obesity-related health problems, such as diabetes and cardiovascular disease, continue to rise at an alarming rate. Results from the proposed studies will provide novel insight into how diets regulate body fat mass, which may lead to novel approaches to treat obesity and related diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Veterinary Sciences
Schools of Medicine
New Haven
United States
Zip Code
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
Zhao, Lin; Feng, Zhihui; Yang, Xiaoyong et al. (2016) The regulatory roles of O-GlcNAcylation in mitochondrial homeostasis and metabolic syndrome. Free Radic Res 50:1080-1088
Jiang, Mingzuo; Qiu, Zhaoyan; Zhang, Song et al. (2016) Elevated O-GlcNAcylation promotes gastric cancer cells proliferation by modulating cell cycle related proteins and ERK 1/2 signaling. Oncotarget 7:61390-61402
Xie, Zhongyu; Zhang, Di; Chung, Dongjun et al. (2016) Metabolic Regulation of Gene Expression by Histone Lysine ?-Hydroxybutyrylation. Mol Cell 62:194-206
Perry, Rachel J; Camporez, João-Paulo G; Kursawe, Romy et al. (2015) Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160:745-758
Singh, Jay Prakash; Zhang, Kaisi; Wu, Jing et al. (2015) O-GlcNAc signaling in cancer metabolism and epigenetics. Cancer Lett 356:244-50
Zhang, Kaisi; Yin, Ruonan; Yang, Xiaoyong (2014) O-GlcNAc: A Bittersweet Switch in Liver. Front Endocrinol (Lausanne) 5:221

Showing the most recent 10 out of 20 publications