Induction and reversibility of an obesity syndrome by intracerebroventricular neuropeptide Y administration to normal rats
Diabetologia
Induction and reversibility of an obesity syndrome by intracerebroventricular neuropeptide Y administration to normal rats
R. Vettor 0
N. Zarjevski 0
. Cusin 0
E Rohner-Jeanrenaud 0
B. Jeanrenaud 0
0 Laboratoires de Recherches M~taboliques,Faculty and Department of Medicine, University of Geneva , Geneva , Switzerland
Summary Intracerebroventricular neuropeptide Y (NPY) administration to normal rats for 7 days produced a sustained, threefold increase in food intake, resulting in a body weight gain of m o r e than 40 g. Basal plasma insulin and triglyceride levels were increased in NPY-treated compared to vehicle-infused rats by about four- and two-fold, respectively. The glucose utilization index of white adipose tissue, measured by the labelled 2-deoxy-D-glucose technique was four times higher in NPY-treated rats compared to controls. This change was accompanied by an increase in the insulin responsive glucose transporter protein ( G L U T 4). In marked contrast, muscle glucose utilization was decreased in NPY-treated compared to vehicle-infused animals. This change was accompanied by an increase in triglyceride content. When NPY-treated rats were prevented from overeating, there was no decrease in muscle glucose up-
Intracerebroventricular (i; c; v; ); neuropeptide Y (NPY); food intake; body weight gain; in vivo glucose uptake; muscle insulin resistance
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9 Springer-Verlag1994
Obesity is a pathological condition characterized by
an imbalance between caloric intake and total
energy expenditure. Hyperinsulinaemia and insulin
resistance are the most prominent facets of this
syndrome. The initial cause(s) that ultimately lead to
obesity are yet to be determined. In man,
cross-sectional studies suggested the existence of a
progressive evolution of the obese subjects to
hyperinsulinAbbreviations: NPY, Neuropeptide Y;
icv,intracerebroventricular; GLUT 4, glucose transporter 4.
take, nor was there an increase in muscle triglyceride
content. This suggests that muscle insulin resistance
of ad libitum-fed NPY-treated rats is due to a
glucose-fatty acid (Randle) cycle. When
intracerebroventricular NPY administration was stopped and rats
kept without any treatment for 7 additional days, all
the abnormalities brought about by the neuropeptide
were normalized. A tonic central effect of NPY is
therefore n e e d e d to elicit and maintain most of the
hormonal and metabolic abnormalities observed in
the present study. Such abnormalities are analogous
to those seen in the dynamic phase of obesity
syndromes in which high hypothalamic NPY levels have
been reported. [Diabetologia (1994) 37: 1202-1208]
aemia, subsequent glucose intolerance and diabetes
due to pancreatic decompensation. Such studies
failed, however, to pin-point any initial cause(s) in
such series of events [
1, 2
].
Investigation carried out in animal models
potentially allows for an understanding of the aetiology of
obesity syndromes. In this respect, it is noteworthy
that chronic intracerebroventricular (i.c.v.)
neuropeptide Y (NPY) administration to normal rats
produced several of the behavioral, hormonal, and
metabolic changes observed in the dynamic phase of the
genetic or hypothalamic obesity syndromes [
3-8
].
Thus, as in young genetically obese animals, chronic
i. c. v. NPY administration to normal rats for 7 days
resulted in increased food intake, body weight, liver
and adipose tissue lipogenic activity, together with a
state of muscle insulin resistance [
9, 10
].
These considerations, together with the reports
showing that hypothalamic NPY m R N A and protein
expression were both increased during the dynamic
phase of these syndromes [
11-13
] lead to the
proposal that N P Y could play a role in the establishment
and maintenance of obesity syndromes. To further
substantiate this viewpoint, N P Y was administered
i. c.v. to normal rats for 7 days, then the
administration of the peptide was stopped and the
hormonalmetabolic consequences of such cessation of N P Y
infusion were determined. To try to distinguish
between the effects of NPY per se and those due to
NPY-induced hyperphagia, metabolic parameters
were d e t e r m i n e d in NPY-treated rats prevented
from overeating (pair-feeding).
Materials and methods
Twelve-week-old lean female rats of the Zucker (FA/?) strain
were used throughout the study. The animals were initially
purchased from the "Centre de S61ection et d'Elevage d'Animaux
de Laboratoire" (Orldans, France). They were bred and
housed in our animal quarter, submitted to a 12-h light cycle
(lights on from 07.00-19.00 hours) and kept at a constant
temperature (23 ~ They were fed a standard laboratory chow
(carbohydrate 57.7 %; fat 2.5 %; protein 20.6 %; ash 7.5 %;
water 11.7 %, Provimi Lacta, Cossonay, Switzerland). Three days
before the implantation of the intracerebroventricular (i. c. v.)
guiding cannulas, the rats were placed into individual cages.
Body weight and food intake were then measured daily until (...truncated)