Leptin-Adipocyte Project

Adipocyte-derived hormone, leptin has pleiotropic effects on the regulation of energy metabolism. We and others have revealed that hypoleptinemia caused by fat deficiency leads to various metabolic disorders in lipodystrophy. One of our goals is a new dug approval of the leptin-replacement therapy for lipodystrophy.
However, leptin does not improve lipodystrophy itself. We already succeeded to develop a method of adipocyte differentiation from human iPS cells. Another goal is a development of cell therapy for lipodystrophy with iPS cells.

Research and Education

An adipokine, leptin is known as an anti-obesity hormone, suppressing appetite and increasing energy expenditure mainly through the hypothalamus. In addition to the regulation of body weight, leptin has been shown to have pleiotropic effects on the regulation of energy metabolism. Lipodystrophy is a rare disease characterized by a paucity of adipose tissue that leads to leptin deficiency and often associated with metabolic disorders such as insulin-resistant diabetes, hypertriglyceridemia and fatty liver. We and others have shown that the main cause of metabolic complications in lipodystrophy is a lack of leptin using animal models. Furthermore, we and others have demonstrated that leptin effectively improved metabolic disorders in patients with lipodystrophy. Our project aims at a new drug approval of the leptin-replacement therapy in patients with lipodystrophy with the Investigator Initiated Trial (ITT) and the clinical trial under Evaluation System of Highly Medical Technology (ESHMT).
Leptin effectively improved metabolic disorders but does not improve lipodystrophy itself. We have already succeeded to develop a method of adipocyte differentiation from human iPS cells, for the first time in the world. Our project also aims at a development of cell therapy for lipodystrophy using iPS cells.
Furthermore, with its pleiotropic effects on metabolic regulation, we aims to expand the clinical application of leptin in the field of metabolic syndrome.

r-124-1Figure1:Leptin-replacement therapy in patients with lipodystrophy

r-124-2Figure2:Adipocyte differentiation from human iPS cells


Recent Publications

1.D. Aotani, K. Ebihara, N. Sawamoto, T. Kusakabe, M. Aizawa-Abe, S. Kataoka, T. Sakai, H. Iogawa, C. Ebihara, J. Fujikura, K. Hosoda, H. Fukuyama, K. Nakao. Functional Magnetic Resonance Imaging Analysis of Food-Related Brain Activity in Patients with Lipodystrophy Undergoing Leptin Replacement Therapy. J Clin Endocrinol Metab. 97: 3663- 3671, 2012.
2.T. Kusakabe, K. Ebihara, T. Sakai, L. Miyamoto, D. Aotani, Y. Yamamoto, S. Yamamoto-Kataoka, M. Aizawa-Abe, J. Fujikura, K. Hosoda, K. Nakao. Amylin improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese mice. Am J Physiol Endocrinol Metab. 302: E924-931, 2012.
3.D. Taura, M. Noguchi, M. Sone, K. Hosoda, E. Mori, Y. Okada, K. Takahashi, K. Homma, N. Oyamada, M. Inuzuka, T. Sonoyama, K. Ebihara, N. Tamura, H. Itoh, H. Suemori, N. Nakatsuji, H. Okano, S. Yamanaka, K. Nakao. Adipogenic differentiation of human induced pluripotent stem cells: comparison with that of human embryonic stem cells. FEBS Lett. 583: 1029-1033, 2009.
4.T. Kusakabe, H. Tanioka, K. Ebihara, M. Hirata, L. Miyamoto, F. Miyanaga, H. Hige, D. Aotani, T. Fujisawa, H. Masuzaki, K. Hosoda, K. Nakao. Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet. Diabetologia. 52: 675-683, 2009.
5.K. Ebihara, T. Kusakabe, M. Hirata, H. Masuzaki, F. Miyanaga, N. Kobayashi, T. Tanaka, H. Chusyo, T. Miyazawa, T. Hayashi, K. Hososda, Y. Ogawa, A M. Depaoli, M. Fukushima and K. Nakao. Efficacy and safety of leptin-replacement theraphy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J Clin Endocrinol Metab 92: 532- 541, 2007.

Laboratory

Associate Professor:Ken Ebihara
Assistant Professor:Megumi Abe, Daisuke Aotani
TEL:+81-75-751-4750
FAX:+81-75-771-9452
e-mail:kebihara@kuhp.kyoto-u.ac.jp