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]
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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)