Leslie J. Stein

Peptides and the control of meal size

SummaryThere are now a large number of experiments demonstrating that peripheral administration of exogenous cholecystokinin or its synthetic analogue, CCK-8, reduces meal size in a number of species. The peptide interacts with other factors which influence satiety, and treatments thought to be effective in eliciting secretion of cholecystokinin have predictable effects on meal size. Cholecystokinin is effective in the genetically obese Zucker rat, obese rats with lesions of the ventromedial hypothalamus, and subdiaphragmatically vagotomized rats. Somatostatin and bombesin are also reasonable candidates for satiety factors. Intraperitoneal naloxone reduces meal size in rats, and beta-endorphin injected intraventricularly causes an increase in meal size of 50% over 30 minutes. We conclude that cholecystokinin and bombesin may interact in weight regulation and control of meal time food intake.

Genetically obese zucker rats have abnormally low brain insulin content

The concentration of immunoreactive insulin (IRI) extracted from the olfactory bulb, hypothalamus, hippocampus, cerebral cortex, amygdala, midbrain, and hindbrain was significantly lower in obese (fa/fa) and heterozygous (Fa/fa) Zucker rats in comparison to lean (Fa/Fa) Zucker rats. This deficit in brain IRI content was most severe in the hypothalamus and olfactory bulb and was independent of severe obesity since the marked reduction of brain IRI content was also found in heterozygous rats which possessed only one copy of the fa allele. These results demonstrate that in the 2-3 month-old female Zucker rat, the fa allele is associated with defective regulation of insulin in the brain.

Gastrin releasing peptide reduces meal size in rats

The satiety-eliciting effect of gastrin-releasing peptide (GRP), a putative mammalian counterpart of bombesin (BBS), was examined in mildly food-deprived rats. Intraperitoneal injections of GRP resulted in a significant decrease of 30-minute food intake at 2, 4, 8 and 16 micrograms/kg, while 1 microgram/kg had no reliable effect. Intraperitoneal GRP at 4 and 8 micrograms/kg did not suppress 30-minute water consumption by thirsty rats. When the dose-effect curves of GRP and BBS are compared on a molar scale, GRP is approximately 30% less potent than BBS in suppressing food intake. The two dose-effect curves are similar in shape and their regression lines have parallel slopes. These data lend further support to the hypothesis that GRP is a mammalian counterpart of BBS and strengthen the argument that they may function as endogenous satiety factors.

Bombesin stimulates insulin secretion and reduces food intake in the baboon

Baboons received a 5-minute intravenous infusion of either saline or bombesin (BBS; 1-4 micrograms/kg) following 3 1/2 or 16 1/2 hours of food deprivation and were then allowed to eat for 30 minutes. Plasma insulin was significantly elevated following five minutes of BBS infusion, but there was no change of plasma glucose over the same interval. Bombesin infusion resulted in a dose-dependent decrease of food intake that was independent of deprivation time. Plasma insulin levels following the 30-minute meal were significantly depressed after BBS infusions such that there was essentially no change of plasma insulin over the duration of the meal, even though the baboons did not totally suppress their food intake. Following 3 1/2 hours food deprivation, BBS suppressed the post-prandial rise of plasma glucose in a dose-dependent manner. The results provide further evidence that BBS and/or structurally-related peptides are involved in the regulation of feeding and metabolism.

Cholecystokinin and bombesin act independently to decrease food intake in the rat

The satiating effects of cholecystokinin-octapeptide (CCK-8) and bombesin (BBS) when injected alone and in combination were compared in intact rats. When injected alone, both CCK-8 and BBS elicited a dose-related decrease of 30-minute food intake. Injections of BBS were less potent than the equivalent doses of CCK-8 in producing satiety. BBS reached an asymptotic level of suppression of approximately 40 percent at a dose of 2 micrograms/kg, whereas injections of 4 micrograms/kg of CCK-8 resulted in a 72 percent suppression of food intake. When the two peptides were administered in a single injection, the resulting suppression of food intake was equivalent to that which would be predicted if their effects were completely additive. These results support the hypothesis that CCK-8 and BBS act via independent mechanisms to induce satiety. A preliminary model of peptidergic satiety, based on this hypothesis, is proposed.

Neuroendocrine regulation of food intake and body weight

Abstract This paper reviews the effects of peptide hormones upon food intake. These effects are seen as falling into one of two categories depending upon whether the hormone in question is affected by the degree of adiposity. Many gut peptides, such as CCK and somatostatin, influence the size of individual meals and presumably reflect only the calories involved with that meal. Other peptides, especially insulin as it acts at the CNS, influence the size of all meals by indicating the current degree of adiposity. Such signals reflect not only single meal calories but also calories stored in the adipose beds and are therefore often called “long-term” signals.

Insulin in the Central Nervous System: A Regulator of Appetite and Body Weight

Although numerous potentially physiologic actions of insulin in the central nervous system (CNS) have been identified at the cellular level, the consequences of these actions at the level of the organism have not been defined. In this chapter we advance the hypothesis that insulin may act as a regulator of body weight. In 1979, Woods and Porte suggested that insulin levels in the cerebrospinal fluid (CSF) may act as an indicator of body adiposity and provide a negative feedback signal to regulate body weight on a long term basis.1,2 This hypothesis was based upon three lines of experimental evidence: First, basal plasma insulin levels are correlated with body adiposity. Second, CSF insulin levels represent a slow integral over time of plasma levels, with rapid fluctuations in plasma insulin levels being damped. Third, direct infusion of insulin into the CSF and into certain brain sites can result in a decrease of food intake and body weight. These three lines of evidence will be reviewed. Additionally, this chapter will provide some discussion of the possible regulation involved in generating and sensing this signal, as well as possible defects in the brain insulin system in a genetically obese rat model. Readers who wish specific discussion of issues surrounding the brain insulin system are referred to the chapters in this text by LeRoith, Heidenreich, and Raizada, and to a recent review.3