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Ubiquitin C-terminal hydrolase-L3-knockout mice are resistant to diet-induced obesity and show increased activation of AMP-activated protein kinase in skeletal muscle

Rieko Setsuie^*, Mari Suzuki^*, Tomohiro Kabuta^*, Hiromi Fujita^*, Shinji Miura, Nobutsune Ichihara, Daisuke Yamada^*,, Yu-Lai Wang^*, Osamu Ezaki, Yasuyuki Suzuki^* and Keiji Wada^*,,1

^* Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan;

Nutritional Science Program, National Institute of Health and Nutrition, Tokyo, Japan;

School of Veterinary Medicine, Azabu University, Kanagawa, Japan; and

Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan

¹ Correspondence: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan. E-mail: wada{at}ncnp.go.jp

Obesity results from the dysregulation of energy balance throughout the entire body. Although the ubiquitin system participates in many cellular processes, its contribution to the balance of energy in the body remains poorly understood. Here, we show that ubiquitin C-terminal hydrolase (UCH)-L3, one of the deubiquitinating enzymes, contributes to the regulation of metabolism. Uchl3^–/– mice displayed a reduction of adipose tissue mass and were protected against high-fat diet (HFD)-induced obesity and insulin resistance. Uchl3^–/– mice given both a normal chow and an HFD had an increased whole-body energy expenditure accounting for the reduction of adipose tissue mass. Activation of AMP-activated protein kinase (AMPK) in skeletal muscle has been reported to increase fatty acid β-oxidation, leading to the elevation of the whole-body energy expenditure. Consistently, increased activation of AMPK and fatty acid β-oxidation was observed in skeletal muscle of Uchl3^–/– mice. Mouse embryonic fibroblasts derived from Uchl3^–/– mice also showed increased activation of AMPK, indicating that UCH-L3 is involved in a cell-autonomous down-regulation of AMPK. These results suggest a role for UCH-L3 in the regulation of AMPK activity and whole-body energy metabolism.—Setsuie, R., Suzuki, M., Kabuta, T., Fujita, H., Miura, S., Ichihara, N., Yamada, D., Wang, Y.-L., Ezaki, O., Suzuki, Y., Wada, K. Ubiquitin C-terminal hydrolase-L3-knockout mice are resistant to diet-induced obesity and show increased activation of AMP-activated protein kinase in skeletal muscle.

Key Words: energy balance • energy expenditure • deubiquitinating enzyme