Yong Ryoul Yang1, Hyun-Jun Jang1,2, Sun-Sil Choi1, Yong Hwa Lee1, Gyun Hui Lee1, Young-Kyo Seo1, Jang Hyun Choi1, Dohyun Park2, Ara Koh2, Il Shin Kim1, Ho Lee3, Sung Ho Ryu2, Pann-Ghill Suh4. 1. School of Life Sciences, Ulsan National Institute of Science and Technology, Building 104, Room 705, UNIST-gil 50, Eonyang-eup, Ulju-gun, Ulsan, 689-798, Republic of Korea. 2. Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea. 3. Cancer Experimental Resources Branch, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea. 4. School of Life Sciences, Ulsan National Institute of Science and Technology, Building 104, Room 705, UNIST-gil 50, Eonyang-eup, Ulju-gun, Ulsan, 689-798, Republic of Korea. pgsuh@unist.ac.kr.
Abstract
AIMS/HYPOTHESIS: O-GlcNAcylation plays a role as a metabolic sensor regulating cellular signalling, transcription and metabolism. Transcription factors and signalling pathways related to metabolism are modulated by N-acetyl-glucosamine (O-GlcNAc) modification. Aberrant regulation of O-GlcNAcylation is closely linked to insulin resistance, type 2 diabetes and obesity. Current evidence shows that increased O-GlcNAcylation negatively regulates insulin signalling, which is associated with insulin resistance and type 2 diabetes. Here, we aimed to evaluate the effects of Oga (also known as Mgea5) haploinsufficiency, which causes hyper-O-GlcNAcylation, on metabolism. METHODS: We examined whether Oga(+/-) mice developed insulin resistance. Metabolic variables were determined including body weight, glucose and insulin tolerance, metabolic rate and thermogenesis. RESULTS: Oga deficiency does not affect insulin signalling even at hyper-O-GlcNAc levels. Oga(+/-) mice are lean with reduced fat mass and improved glucose tolerance. Furthermore, Oga(+/-) mice resist high-fat diet-induced obesity with ameliorated hepatic steatosis and improved glucose metabolism. Oga haploinsufficiency potentiates energy expenditure through the enhancement of brown adipocyte differentiation from the stromal vascular fraction of subcutaneous white adipose tissue (WAT). CONCLUSIONS/ INTERPRETATION: Our observations suggest that O-GlcNAcase (OGA) is essential for energy metabolism via regulation of the thermogenic WAT program.
AIMS/HYPOTHESIS: O-GlcNAcylation plays a role as a metabolic sensor regulating cellular signalling, transcription and metabolism. Transcription factors and signalling pathways related to metabolism are modulated by N-acetyl-glucosamine (O-GlcNAc) modification. Aberrant regulation of O-GlcNAcylation is closely linked to insulin resistance, type 2 diabetes and obesity. Current evidence shows that increased O-GlcNAcylation negatively regulates insulin signalling, which is associated with insulin resistance and type 2 diabetes. Here, we aimed to evaluate the effects of Oga (also known as Mgea5) haploinsufficiency, which causes hyper-O-GlcNAcylation, on metabolism. METHODS: We examined whether Oga(+/-) mice developed insulin resistance. Metabolic variables were determined including body weight, glucose and insulin tolerance, metabolic rate and thermogenesis. RESULTS:Oga deficiency does not affect insulin signalling even at hyper-O-GlcNAc levels. Oga(+/-) mice are lean with reduced fat mass and improved glucose tolerance. Furthermore, Oga(+/-) mice resist high-fat diet-induced obesity with ameliorated hepatic steatosis and improved glucose metabolism. Oga haploinsufficiency potentiates energy expenditure through the enhancement of brown adipocyte differentiation from the stromal vascular fraction of subcutaneous white adipose tissue (WAT). CONCLUSIONS/ INTERPRETATION: Our observations suggest that O-GlcNAcase (OGA) is essential for energy metabolism via regulation of the thermogenic WAT program.
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