Intraventricular GLP-1 reduces short- but not long-term food intake or body weight in lean and obese rats

Abstract

Glucagon-like-peptide-1 (7–36) amide (GLP-1), when infused into the third ventricle (IVT), reduces short-term food intake. In the present experiments, we assessed whether IVT administration of GLP-1 could influence long-term food intake and body weight of lean Long Evans rats and of fatty Zucker (fa/fa) rats. In Experiment 1, we replicated the observation that 10 μg GLP-1, given IVT, reduces one and 2 h food intake, and extended the observation to fatty Zucker rats. However, in both rat strains, 24 h food intake and body weight were unchanged by this acute treatment. In Experiment 2, GLP-1 (30 μg/day) was infused IVT continuously for 4 days via an osmotic mini-pump. This treatment also had no effect on food intake or body weight in either Long–Evans or fatty Zucker rats. A control experiment verified that the GLP-1 remained biologically active over the duration of the infusion period. In a final experiment, Long-Evans rats were restricted to two 2 h periods of access to food each day for 6 days. Prior to each of these access periods, rats received either 15 μg of GLP-1 IVT or a vehicle control injection. While GLP-1 significantly reduced food intake on the first day of treatment, this effect of GLP-1 rapidly disappeared such that it was reduced on the second day and absent on the third day; and there was no effect on body weight at any time. Collectively, the present experiments do not support the hypothesis that GLP-1, acting in the CNS, is an important regulator of long-term food intake and body weight.

Introduction

The accurate regulation of food intake and body weight depends on the complex interaction of several regulatory systems. Some of these systems appear to act primarily at the level of individual bouts of ingestion or meals. The prototypical compound for such a short-term satiety signal is the gut peptide cholecystokinin (CCK) which is secreted in response to food in the upper intestine. When administered intraperitoneally or directly into the central nervous system (CNS), CCK causes a potent reduction in the size of the subsequent meal [16]. After such treatment, however, total daily food intake is not different from that of controls [22]. This implies that the effect of CCK is short-lived, and that animals eat more in subsequent meals in order to compensate for the lost calories from the reduced first meal in order to maintain daily caloric intake and body weight constant [22]. When CCK is administered at the onset of each spontaneous meal in non-deprived and freely feeding rats, it reliably reduces the size of each meal compared to the meal size of control animals, but daily caloric intake and body weight are unchanged because animals receiving CCK compensate by increasing the number of individual meals they take [22]. Hence, satiety factors such as CCK, if given alone, are unlikely to provide effective therapeutic tools for obesity.

A second category of peptides, including insulin and leptin, act in a fundamentally different manner. When administered continuously into the CNS over days, insulin or leptin produces persistent reductions in daily caloric intake and body weight at doses that have no effect when administered into the periphery 15, 23suggesting that the CNS is the likely target for this action. Since both insulin and leptin are secreted in proportion to body adiposity, each has been considered a likely factor that interacts with meal-generated satiety factors in the long-term control of body adiposity 13, 24. Consistent with this, there is evidence that the administration of small amounts of insulin (and possibly leptin) potentiates the action of meal-generated satiety factors such as CCK [14]. Hence, when an animal loses weight, it secretes less insulin and leptin, and satiety factors such as CCK are rendered less effective. One result is larger meals until weight is restored. The opposite occurs if an animal gains weight. In this way adiposity factors act in concert with satiety factors to coordinate food intake with the maintenance of total body adiposity.

Turton and colleagues have proposed that glucagon-like-peptide-1 (7–36) amide (GLP-1), acting at receptors in the CNS, is an endogenous factor important in the regulation of food intake 17, 19. GLP-1 is secreted from the distal gut in response to the presence of mixed nutrients in the gastrointestinal tract 3, 8. In the periphery, GLP-1 influences glucose homeostasis after ingestion of carbohydrate meals via modulation of gastric emptying and alteration of the secretion of insulin and glucagon from the pancreas [2]. The precursor for GLP-1 (preproglucagon) is also synthesized in the CNS in the nucleus of the solitary tract (NTS) 4, 7, 10. Receptors for GLP-1 are concentrated in the paraventricular nucleus of the hypothalamus (PVN), the amygdala, and several regions of the brainstem including the area postrema and the NTS [5]. In their report, Turton et al. [19]observed that bolus administration of GLP-1 into the third ventricle of lean rats produced a potent and dose-dependent reduction of 2 h food intake, and they further reported that this reduction could be blocked by pretreatment with the specific GLP-1 receptor antagonist, exendin. Based on these findings, they proposed GLP-1 as a natural regulator of food intake and possibly adiposity as well. The purpose of the present experiments was to determine whether central administration of GLP-1 alters long-term food intake and body weight in lean Long–Evans rats and in genetically obese (fa/fa) Zucker rats. We therefore sought to determine whether GLP-1 acts in the CNS as a short-term regulator of food intake, as occurs with CCK, or as a long-term adiposity-type signal such as leptin or insulin.