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A. Nagasaka
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H. Hidaka
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H. Itoh
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H. Nakagawa
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K. Kataoka
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A. Yamaguchi
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K. Iwase
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A. Nakai
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T. Ohyama
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T. Aono
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S. Miyakawa
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K. Kawase
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K. Miura
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ABSTRACT

Adenylate cyclase and cyclic AMP phosphodiesterase activities in the thyroid gland were significantly reduced after hypophysectomy, followed by a gradual restoration of the enzyme activities to the levels seen in sham-operated rats whereas a slight and persistent reduction was evident in guanylate cyclase and cyclic GMP phosphodiesterase activities in the same tissue. These changes in enzyme activities were restored by TSH administration but not by ACTH. The recovery of activity produced by TSH administration was inhibited by cycloheximide. Hypophysectomy, or TSH and cycloheximide administration, did not produce any significant changes in the concentrations of calmodulin, suggesting that the alteration of these enzyme activities is not induced by a decrease in the concentration of calmodulin. Since forskolin activation of adenylate cyclase did not restore the reduced activity in the hypophysectomized rat thyroid to the level found in the sham-operated control rat thyroid, we conclude that there is a reduction of the amount of enzyme after hypophysectomy rather than a change of the active site on adenylate cyclase. The spontaneous restoration of adenylate cyclase and cyclic AMP phosphodiesterase activities after hypophysectomy implies that cyclic AMP-metabolizing enzymes are responsive to an autoregulatory mechanism in thyroid follicular cells.

J. Endocr. (1985) 105, 363–369

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T Ishizuka
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A Miura
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K Kajita
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K Yamada
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H Wada
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S Itaya
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Y Kanoh
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M Ishizawa
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M Kimura
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K Yasuda
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The Otsuka Long-Evans Tokushima fatty (OLETF) rat is a new spontaneous non-insulin-dependent diabetes mellitus (NIDDM) model rat strain developed in Tokushima, Japan. After 18 weeks of age, decreases of 45% and 40% respectively in insulin- and phorbol ester-stimulated [3H]2-deoxyglucose (DOG) uptake were observed, compared with those in Long-Evans Tokushima (LETO) rats (control). Insulin-specific binding and 95 kDa autophosphorylation of insulin receptor in OLETF rats were not different from those in LETO rats. Insulin-induced diacylglycerol (DG) production and Mono Q column-purified protein kinase C (PKC) translocation in adipocytes of OLETF rats were decreased compared with those of LETO rats. Insulin-induced PKC beta translocation from cytosol to membrane was also decreased in adipocytes of OLETF rats. Increases of the PKC beta I, beta II, epsilon and zeta isoforms in membranes of OLETF rats were markedly smaller than those of LETO rats. Analysis of mRNA levels of PKC isoforms in adipocytes of OLETF rats showed decreases of basal level and insulin-induced delayed responses of PKC beta I, beta II, epsilon and zeta mRNA in OLETF rats. On the other hand, insulin- or phorbol ester-induced phosphatidylinositol 3-kinase (PI 3-kinase) activation was decreased in adipocytes of OLETF rats compared with those of LETO rats. These results suggest that insulin resistance in OLETF rats, a spontaneous NIDDM model rat, may be associated with deterioration of insulin-induced DG-PKC signaling and subsequent decrease in PI 3-kinase activation.

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M Makino
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N Oda
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N Miura
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S Imamura
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K Yamamoto
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T Kato
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K Fujiwara
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Y Sawai
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K Iwase
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A Nagasaka
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M Itoh
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Thyroid hormones affect reactions in almost all pathways of lipid metabolism. It has been reported that plasma free fatty acid (FFA) concentration in hypothyroidism is generally within the normal range. In this study, however, we show that plasma FFA concentration in some hypothyroid patients is higher than the normal range. Symptoms of thyroid dysfunction in these individuals were less severe than those of patients with lower plasma FFA concentrations. From these findings we hypothesized that the change in FFA concentration must correlate with thyroid function. Using an animal model, we then examined the effect of highly purified eicosapentaenoic acid ethyl ester (EPA-E), a n-3 polyunsaturated fatty acid derived from fish oil, on thyroid function in 1-methyl-2-imidazolethiol (MMI)-induced hypothyroid rats. Oral administration of EPA-E inhibited reduction of thyroid hormone levels and the change of thyroid follicles in MMI-induced hypothyroid rats. These findings suggest that FFA may affect thyroid functions and EPA-E may prevent MMI-induced hypothyroidism.

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T Akamizu Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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T Murayama Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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S Teramukai Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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K Miura Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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I Bando Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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T Irako Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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H Iwakura Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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H Ariyasu Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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H Hosoda Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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H Tada Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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A Matsuyama Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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S Kojima Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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T Wada Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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Y Wakatsuki Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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K Matsubayashi Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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T Kawakita Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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A Shimizu Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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M Fukushima Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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M Yokode Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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K Kangawa Ghrelin Research Project and
Post-genome Project, Department of Experimental Therapeutics, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Clinical Innovative Medicine, and
Department of Clinical Trial Design and Management, Kyoto University Hospital, Kyoto 606-8507, Japan
Translational Research Center, Kyoto University Hospital, and Department of Geriatric Medicine, Kyoto University School of Medicine, Kyoto 606-8507, Japan
Center for Southeast Asian Studies, Kyoto University, Kyoto 606-8501, Japan
Kyoto Preventive Medical Centre, Kyoto 604-8491, Japan
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

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Aging is associated with a decrease in growth hormone (GH) secretion, appetite and energy intake. As ghrelin stimulates both GH secretion and appetite, reductions in ghrelin levels may be involved in the reductions in GH secretion and appetite observed in the elderly. However, only preliminary studies have been performed on the role of ghrelin in elderly subjects. In this study, we sought to clarify the physiologic implications of the age-related alterations in ghrelin secretion by determining plasma ghrelin levels and other clinical parameters in healthy elderly subjects. Subjects were ≥ 65 years old, corresponding to the SENIEUR protocol, had not had a resection of the upper gastrointestinal tract and had not been treated with hormones. One hundred and five volunteers (49 men and 56 women) were admitted to this study (73.4 ± 6.3 years old). Plasma levels of acylated ghrelin in elderly female subjects positively correlated with serum IGF-I levels and bowel movement frequency and negatively with systolic blood pressure. In elderly men, desacyl ghrelin levels correlated only weakly with bowel movement frequency. These findings suggest that the plasma levels of the acylated form of ghrelin may influence the age-related alterations in GH/IGF-I regulation, blood pressure and bowel motility. These observational associations warrant further experimental studies to clarify the physiologic significance of these effects.

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