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Experimental Biology and Medicine 228:1146-1155 (2003)
© 2003 Society for Experimental Biology and Medicine

OBESITY AND DIABETES: PATHOPHYSIOLOGICAL MECHANISMS AND THERAPEUTIC APPROACHES

Physiological Significance of 2-Buten-4-Olide (2-B4O), an Endogenous Satiety Substance Increased in the Fasted State

Yutaka Oomura*,1, Shuji Aou{dagger}, Ikuo Matsumoto{ddagger} and Toshiie Sakata§

* Department of Integrated Physiology, Faculty of Medicine, Kyushyu University, Fukuoka, Japan;
{dagger} Department of Brain Science, Life Science Technology, Kyushyu Institute of Technology, Kita-Kyushyu, Japan;
{ddagger} Department of Physiology, Faculty of Medicine, Nagasaki University, Nagasaki; And
§ Department of Internal Medicine, Oita Medical University, Oita, Japan

Abstract

A sugar acid, 2-B4O, has been found to increase from 3.5 to 13 µM in rat serum at 36 h after food deprivation. Injections of 2-B4O (2.5 µM) into the rat III cerebral ventricle (III ICV) suppress food intake and single neuronal activity in the lateral hypothalamic area (LHA). 2-B4O is effective even in 72 h food-deprived rats. 2-B4O hyperpolarizes glucose-sensitive neurons in the LHA via Na+-K+ pump activation, but depolarizes glucoreceptor neurons in the ventromedial nucleus (VMH) via closure of ATP-sensitive K channels. The plasma levels of glucose, corticosterone, and catecholamines, and the firing rate in both parvocellular neurons in the paraventricular nucleus (PVN) and sympathetic efferent nerves, all increase 2-B4O intravenous (iv) injection, indicating activation of the hypothalamo-pituitary-adrenal axis. A 2-B4O iv injection facilitates emotional and spatial learning and memory, and pretreatment with anti-acidic fibroblast growth factor (aFGF) antibody ICV eliminates these effects. aFGF is released from ependymal cells in the III cerebral ventricle in response to the glucose increase in CSF induced by 2-B4O iv injection. 2-B4O also suppresses the clinical symptoms of experimental allergic encephalomyelitis (EAE) in Lewis rats [induced by immunization with a myelin basic protein (MBP)], a model for human multiple sclerosis. After immunization with MBP, the delayed-type hypersensitivity response to MBP is also reduced in 2-B4O-treated rats. 2-B4O thus suppresses autoimmune responses. These results indicate that 2-B4O is not only a powerful satiety substance, but also effective as an activator of the hypothalamo-pituitary-adrenal axis and sympathetic efferent outflow, and as a memory facilitation and a modulator of immune functions.

Key Words: 3,4-dihydroxybutanoic acid{gamma}-lacton • 2-buten-4-olide • satiety substance • learning and memory facilitation • sympathetic activity • corticotropin-releasing factor • immune modulation






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