Chronic central neuropeptide Y infusion in normal rats: status of the hypothalamo-pituitary-adrenal axis, and vagal mediation of hyperinsulinaemia

Diabetologia, Nov 1997

Summary Neuropeptide Y in the hypothalamus is a potent physiological stimulator of feeding, and may contribute to the characteristic metabolic defects of obesity when hypothalamic levels remain chronically elevated. Since corticosterone and insulin are important regulators of fuel metabolism, the longitudinal effects of chronic (6 days) intracerebroventricular infusion of neuropeptide Y in normal rats on the hypothalamo-pituitary-adrenal axis and on insulin secretion were studied. Neuropeptide Y-infused rats were either allowed to eat ad libitum, or were pair-fed with normophagic control rats. Neuropeptide Y increased the basal plasma concentrations of adrenocorticotropic hormone and corticosterone during the first 2 days of its intracerebroventricular infusion and increased cold stress-induced plasma adrenocorticotropic hormone concentrations. After 4-6 days of central neuropeptide Y infusion, however, basal plasma adrenocorticotropic hormone and corticosterone concentrations were no different from control values (except in ad libitum-fed rats in which corticosteronaemia remained elevated), they were unaffected by the stress of cold exposure, and the hypothalamic content of corticotropin-releasing factor immunoreactivity was significantly decreased. A state of hyperinsulinaemia was present throughout the 6 days of intracerebroventricular neuropeptide Y infusion, being more marked in the ad libitum-fed than in the pair-fed group. The proportions of insulin, proinsulin, and conversion intermediates in plasma and pancreas were unchanged. Hyperinsulinaemia of the pair-fed neuropeptide Y-infused rats was accompanied by muscle insulin resistance and white adipose tissue insulin hyperresponsiveness, as assessed by the in vivo uptake of 2-deoxyglucose. Finally, bilateral subdiaphragmatic vagotomy prevented both the basal and the marked glucose-induced hyperinsulinaemia of animals chronically infused with neuropeptide Y, demonstrating that central neuropeptide Y-induced hyperinsulinaemia is mediated by the parasympathetic nervous system.

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Chronic central neuropeptide Y infusion in normal rats: status of the hypothalamo-pituitary-adrenal axis, and vagal mediation of hyperinsulinaemia

A . Sainsbury 0 E Rohner-Jeanrenaud I 0 I. Cusin 0 K. E. Z a k r z e w s k a 0 P. A . H a l b a n 0 R. C. Gaillard 0 B. Jeanrenaud 0 0 1Laboratoires de Recherches M6taboliques,Faculty of Medicine, University of Geneva , Geneva , Switzerland 2Laboratoires de Recherche Louis Jeantet, University of Geneva Medical Centre , Geneva , Switzerland 3Division d'Endocrinologie et du M6tabolisme,Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois , Lausanne, Switzerland content of corticotropin-releasing factor immunoreactivity was significantly decreased. A state of hyperinsulinaemia was present throughout the 6 days of intracerebroventricular neuropeptide Y infusion, being more marked in the ad libitum-fed than in the pair-fed group. The proportions of insulin, proinsulin, and conversion intermediates in plasma and pancreas were unchanged. Hyperinsulinaemia of the pair-fed neuropeptide Y-infused rats was accompanied by muscle insulin resistance and white adipose tissue insulin hyperresponsiveness, as assessed by the in vivo uptake of 2-deoxyglucose. Finally, bilateral subdiaphragmatic vagotomy prevented both the basal and the marked glucose-induced hyperinsulinaemia of animals chronically infused with neuropeptide Y, demonstrating that central neuropeptide Y-induced hyperinsulinaemia is mediated by the parasympathetic nervous system. [Diabetologia (1997) 40: 1269-1277] - Summary Neuropeptide Y in the hypothalamus is a potent physiological stimulator of feeding, and may contribute to the characteristic metabolic defects of obesity when hypothalamic levels remain chronically elevated. Since corticosterone and insulin are importantJJregulators of fuel metabolism, the longitudinal effects of chronic (6 days) intracerebroventricular infusion of neuropeptide Y in normal rats on the hypothalamo-pituitary-adrenal axis and on insulin secretion were studied. Neuropeptide Y-infused rats were either allowed to eat ad libitum, o r were pair-fed with normophagic control rats. Neuropeptide Y increased t h e basal plasma concentrations of adrenocorticotropic hormone and corticosterone during the first 2 days of its intracerebroventricular infusion and increased cold stress-induced plasma adrenocorticotropic hormone concentrations. After 4-6 days of central neuropeptide Y infusion, however, basal plasma adrenocorticotropic hormone and corticosterone concentrations were no different from control values (except in ad libitum-fed rats in which corticosteronaemia remained elevated), they were unaffected by the stress of cold exposure, and the hypothalamic Neuropeptide Y (NPY) is a 36 amino acid peptide of the peripheral and central nervous system [1]. Centrally it is found in particularly high concentrations in the hypothalamus [1], where it is involved in the regulation of many neuroendocrine and autonomic functions [2, 3]. NPY is particularly well known for its role as a potent, physiological stimulator of feeding acting within discrete hypothalamic sites [4]. Defects in the activity of NPY-ergic neurones in the hypothalamus may contribute to the development of obesity, at least in rodents [5]. In support of this hypothesis, elevated levels of NPY and/or its t r a n s c r i p t h a v e b e e n o b s e r v e d in t h e h y p o t h a l a m i o f g e n e t i c a l l y o b e s e r o d e n t s such as fa/fa a n d cp/cp rats [6, 7] as well as o b / o b a n d d b / d b m i c e [8]. This inc r e a s e has b e e n d e t e c t e d e a r l y a f t e r w e a n i n g in faJfa rats, c o r r e s p o n d i n g with the t i m e w h e n t h e i r o b e s i t y s y n d r o m e first b e c o m e s a p p a r e n t [6]. F u r t h e r m o r e , c h r o n i c a d m i n i s t r a t i o n o f e x o g e n o u s N P Y to specific h y p o t h a l a m i c nuclei or i n t o t h e c e r e b r a l v e n t r i c l e s o f n o r m a l rats results in m a n y o f t h e d e f e c t s o f obesity, including a m a r k e d i n c r e a s e in f o o d i n t a k e , accelera t e d b o d y w e i g h t gain, h y p e r c o r t i c o s t e r o n a e m i a a n d h y p e r i n s u l i n a e m i a , l e a d i n g to m u s c l e insulin resist a n c e with r e s p e c t to glucose u p t a k e , a n d i n c r e a s e d t r i g l y c e r i d e s t o r a g e d u e to i n c r e a s e d insulin r e s p o n siveness in w h i t e a d i p o s e tissue [9-16]. It is o f n o t e t h a t h y p e r c o r t i c o s t e r o n a e m i a a n d hyp e r i n s u l i n a e m i a are c o m m o n f e a t u r e s o f m a n y states of o b e s i t y a s s o c i a t e d with insulin r e s i s t a n c e in rod e n t s a n d in m a n [17-20], a n d t h e s e h o r m o n a l p e r t u r bations are o f k e y i m p o r t a n c e in t h e N P Y - i n d u c e d o b e s i t y s y n d r o m e . A l t h o u g h p r e v i o u s studies h a v e inv e s t i g a t e d t h e e f f e c t s o f N P Y o n t h e h y p o t h a l a m o - p i t u i t a r y - a d r e n a l ( H P A ) axis a n d o n insuli (...truncated)


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A. Sainsbury, F. Rohner-Jeanrenaud, I. Cusin, K. E. Zakrzewska, P. A. Halban, R. C. Gaillard, B. Jeanrenaud. Chronic central neuropeptide Y infusion in normal rats: status of the hypothalamo-pituitary-adrenal axis, and vagal mediation of hyperinsulinaemia, Diabetologia, 1997, pp. 1269, Volume 40, Issue 11, DOI: 10.1007/s001250050820