Induction and reversibility of an obesity syndrome by intracerebroventricular neuropeptide Y administration to normal rats

Diabetologia, Dec 1994

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 more 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 (GLUT 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 uptake, 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 intracerebro-ventricular 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 needed 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.

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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 - 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)


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R. Vettor, N. Zarjevski, I. Cusin, F. Rohner-Jeanrenaud, B. Jeanrenaud. Induction and reversibility of an obesity syndrome by intracerebroventricular neuropeptide Y administration to normal rats, Diabetologia, 1994, pp. 1202-1208, Volume 37, Issue 12, DOI: 10.1007/BF00399793