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Brainstem Thyrotropin-Releasing Hormone Regulates Food Intake through Vagal-Dependent Cholinergic Stimulation of Ghrelin Secretion

Center for Ulcer Research and Education: Digestive Diseases Research Center (Y.A., V.L.W.G., N.T., J.R.R., H.Y.), Division of Digestive Diseases, Department of Medicine (Y.A., V.L.W.G., N.T., T.L., Y.W., M.K.S., J.R.R., Y.L., H.Y.), and Brain Research Institute (Y.A., N.T., H.Y.), University of California, Los Angeles, and Department of Veterans Affairs Greater Los Angeles Healthcare System (Y.A., V.L.W.G., N.T., Y.W., M.K.S., J.R.R., Y.L., H.Y.), Los Angeles, California 90073

Address all correspondence and requests for reprints to: Hong Yang, M.D., Ph.D., CURE: Digestive Diseases Research Center, Veterans Affairs Greater Los Angeles Healthcare System, Building 115, Room 203, 11301 Wilshire Boulevard, Los Angeles, California 90073. E-mail: hoyang{at}ucla.edu.

The brainstem is essential for mediating energetic response to starvation. Brain stem TRH is synthesized in caudal raphe nuclei innervating brainstem and spinal vagal and sympathetic motor neurons. Intracisternal injection (ic) of a stable TRH analog RX77368 (7.5–25 ng) dose-dependently stimulated solid food intake by 2.4- to 3-fold in freely fed rats, an effect that lasted for 3 h. By contrast, RX77368 at 25 ng injected into the lateral ventricle induced a delayed and insignificant orexigenic effect only in the first hour. In pentobarbital-anesthetized rats, RX77368 (50 ng) ic induced a significant bipeak increase in serum total ghrelin levels from the basal of 8.7 ± 1.7 ng/ml to 13.4 ± 2.4 ng/ml at 30 min and 14.5 ± 2.0 ng/ml at 90 min, which was prevented by either bilateral vagotomy (–60 min) or atropine pretreatment (2 mg/kg, –30 min) but magnified by bilateral adrenalectomy (–60 min). TRH analog ic-induced food intake in freely fed rats was abolished by either peripheral atropine or ghrelin receptor antagonist (D-Lys-3)-GHRP-6 (10 µmol/kg) or ic Y1 receptor antagonist 122PU91 (10 nmol/5 µl). Brain stem TRH mRNA and TRH receptor 1 mRNA increased by 57–58 and 33–35% in 24- and 48-h fasted rats and returned to the fed levels after a 3-h refeeding. Natural food intake in overnight fasted rats was significantly reduced by ic TRH antibody, ic Y1 antagonist, and peripheral atropine. These data establish a physiological role of brainstem TRH in vagal-ghrelin-mediated stimulation of food intake, which involves interaction with brainstem Y1 receptors.