Mary M. Hagan

Physiology: does gut hormone PYY3-36 decrease food intake in rodents?

Arising from: R. L. Batterham et al. 418, 650–654 (2002); Batterham et al. replyBatterham et al. report that the gut peptide hormone PYY3–36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3–36.

A new animal model of binge eating: Key synergistic role of past caloric restriction and stress

Dieting and stress are important in the etiology and maintenance of eating disorders, and dieting strongly predicts stress-induced overeating in humans. We hypothesized that caloric restriction and stress interact in a unique manner to promote binge eating. To test this hypothesis, a group of young female rats were cycled through a restriction period (4 days of 66% of control food intake) followed by 6 days of free feeding prior to being stressed by acute foot shock. After three of these cycles, the food intake of rats exposed only to restriction (R), or only to stress (S), did not differ from controls. However, R+S rats that were restricted and refed, despite normal body weight and food intake after free feeding, engaged in a powerful bout of hyperphagia when stressed (Experiment 1). The R + S effect was replicated in an older group of rats (Experiment 2). The hyperphagia was characteristically binge-like, it constituted a 40% selective increase in highly palatable (HP) food (P < .001) over a discrete period of time (within 24 h post-stress), and reflected feeding for reward (higher HP:chow ratio) over metabolic need as occurred after restriction (higher chow:HP ratio). Subsequent experiments revealed that binge eating did not occur if only chow was available (Experiment 3) or if restriction-refeeding (R-R) did not proximally precede stress (Experiment 4). Experiment 5 revealed that a history of R-R cycles followed by only one stress episode was sufficient to increase intake to 53% above controls as early as 2 h after stress (P < .001). This animal model of binge eating should facilitate investigations into the neurochemical changes induced by dieting and environmental stress to produce disordered eating and provide a preclinical tool to test preventive strategies and treatments more relevant to bulimia nervosa, multiple cases of binge eating disorder (BED) and binge-purge type anorexia nervosa.

Persistence of binge-eating patterns after a history of restriction with intermittent bouts of refeeding on palatable food in rats: Implications for bulimia nervosa

OBJECTIVE To test the hypothesis that experience with food restriction produces persistent binge eating. The Minnesota semistarvation experiment and studies of prisoners-of-war show that chronic food restriction produces dramatic changes in eating behavior (including binge eating) that endure decades after restriction has ceased. Bulimia nervosa patients who restrict also binge. Restriction may be a risk factor in the etiology of binge eating and bulimia. METHOD Animals were subjected to four different patterns of 12-week restriction-refeeding cycles. The rats were either food restricted (dieting) or not restricted and refed regular or palatable food (binging). RESULTS Thirty days after normalization (full feeding, no restriction cycling), rats with a history of cycles of restriction and hyperphagia continued to exhibit persistent binge eating. This effect was shown particularly with palatable food, in stated conditions, and in response to acute 24-hr deprivation. DISCUSSION Results from this animal model implicate restriction and overeating on palatable food as biological determinants of binge-eating behaviors, including bulimia nervosa.

Immediate and prolonged patterns of Agouti-related peptide-(83--132)-induced c-Fos activation in hypothalamic and extrahypothalamic sites.

Several lines of evidence substantiate the important role of the central nervous system melanocortin 3- and 4-receptor (MC3/4-R) system in the control of food intake and energy balance. Agouti-related peptide (AgRP), an endogenous antagonist of these receptors, produces a robust and unique pattern of increased food intake that lasts up to 7 days after a single injection. Little is known about brain regions that may mediate this powerful effect of AgRP on food intake. To this end we compared c-Fos-like immunoreactivity (c-FLI) in several brain sites of rats injected intracerebroventricularly with 1 nmol AgRP-(83--132) 2 and 24 h before death and compared c-FLI patterns to those induced by another potent orexigenic peptide, neuropeptide Y (NPY). Although both NPY and AgRP induced c-FLI in hypothalamic areas, AgRP also produced increased c-FLI in the accumbens shell and lateral septum. Although NPY elicited no changes in c-FLI 24 h after administration, AgRP induced c-FLI in the accumbens shell, nucleus of the solitary tract, central amygdala, and lateral hypothalamus. These results indicate that an NPY-like hypothalamic circuit mediates the short-term effects of AgRP, but that the unique sustained effect of AgRP on food intake involves a complex circuit of key extrahypothalamic reward and feeding regulatory nuclei.

Peptide YY: a key mediator of orexigenic behavior

Peptide YY (PYY) is the most potent orexigenic peptide or substance known. However, neither the underlying physiology of this hyperphagia nor PYYs natural role in brain are well understood. Thus, this review details the neuroanatomical sites, the neurochemical and systemic interactions, the food-related properties and the motivational factors that characterize hyperphagia elicited by central PYY. Emphasis also is given to evidence that central PYY has properties functionally distinct from neuropeptide Y. Finally, future research directions are outlined that aim at accelerating our understanding of the roles that brain PYY and PYY-preferring receptors occupy in normal and abnormal feeding behavior.

An Animal Model of Bulimia Nervosa: Opioid Sensitivity to Fasting Episodes

A group of female rats was deprived and maintained at 75-80% of body weight at three different times during development. Following recovery to normal weight, food intake was measured with and without butorphanol tartrate, a kappa-sigma agonist, 8 mg/kg SC. Animals with a history of deprivation (DEP) showed an increase in postrecovery feeding when they were tested at normal body weight and not food deprived. More importantly, butorphanol prolonged food intake in the 3-h eating test only in the rats with a developmental history of food restriction. A developmental history of fasting in eating disorders may trigger changes in opiate systems that result in atypical feeding behavior in the adult.

Incidence of chaotic eating Behaviors in binge-eating disorder: Contributing factors

Abstract Because dieting is not as common in patients with binge-eating disorder (BED) as among patients with bulimia or anorexia nervosa, the authors assessed the incidence, frequency, and contributing factors of semistarvation-like eating patterns in BED patients in this study, the first to explore such behaviors in a clinical population. They administered the Semistarvation-Associated Behaviors Scale (SSABS) to 54 women seeking BED treatment and to 29 controls. The aberrant eating behaviors among BED clients were associated with current dieting and certain BED criteria, (p < .05). The strongest contributor to chaotic eating patterns was negative affect preceding BED (r - .45, p < .001). This finding highlights the behavioral psychopathology of BED and strengthens the role of negative affect in precipitating binge episodes associated with the disorder. These behaviors may help maintain BED by creating a binge-negative affect cycle. The SSABS is a tool that may help break this cycle.

Methanesulfonyl fluoride (MSF): a double-blind, placebo-controlled study of safety and efficacy in the treatment of senile dementia of the Alzheimer type.

The purpose of the present study was to evaluate methanesulfonyl fluoride (MSF), a very long-acting CNS-selective acetylcholinesterase (AChE) inhibitor, as a palliative treatment for senile dementia of the Alzheimer type (SDAT). In experiment I, MSF (0.03-0.18 mg/kg) was administered orally to 10 normal volunteers to measure toxicity and establish dose/response function in erythrocyte AChE. MSF produced a dose-response function of %inhibition = (40)(Log10[MSF mg/kg] + 51.7) with no toxicity at these doses. Experiment II was a 16-week double-blind, placebo-controlled study of the safety and efficacy of MSF in doses of up to 0.18 mg/kg given three times per week in 5 men and 10 women (60-82 years), with Mini-Mental State Examination (MMSE) scores of 9-24, who had SDAT. MSF produced a mean of 89.5% inhibition of erythrocyte AChE in patients and improved cognitive performance as measured by the MMSE, Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-COG), Global Deterioration Scale, and the Clinical Interview Based Impression of Change (CIBIC). Most of the improvement on the ADAS-COG was maintained 8 weeks after ending MSF. No patients left the study because of drug-related adverse events and there were no toxic effects. MSF may be a safe and effective palliative treatment for SDAT and further clinical trials in larger groups of patients are warranted.

Effect of naloxone and antidepressants on hyperphagia produced by peptide YY.

Central injection of peptide YY (PYY) elicits a powerful feeding response with a short latency in satiated rats. Because of this effect, PYY has been implicated as a neurochemical signal in bulimia nervosa. Serotonin agonists and opioid antagonists induce anorectic effects upon feeding behavior in humans and animals. Therefore, to investigate a possible interaction between PYY-induced eating and these anorexigenic agents rats were given injections of either naloxone (100 micrograms/3 microliters, ICV, and 10 mg/kg, SC), fluoxetine (3-30 micrograms/3 microliters and 5-10 mg/kg, IP), or clomipramine (3-30 micrograms/3 microliters and 5-10 mg/kg, IP) prior to fourth ventricular injections of PYY (15 micrograms/18 microliters). Central and peripheral naloxone and IP but not central injections of fluoxetine blocked PYY-induced intake. Clomipramine had no effect. This suggests that PYY-stimulated feeding may require the action of endogenous opioids and may be inhibited by serotonergic function.

Effect of peptide YY (PYY) on food-associated conflict ☆

Peptide YY (PYY) administered centrally in rats induces powerful overeating. PYY also occurs endogenously in humans and is elevated in abstaining bulimic patients. To examine the effect of PYY in an environment that parallels some aspects of bulimia, rats were tested in a paradigm associated with approach-avoidance behavior, choosing a preferred (sweet) food paired with shock, over regular food safe from shock. PYY-treated rats chose to sustain shock to retrieve and consume the preferred food, at a significantly greater speed and quantity. The number of approaches that were met without retrieval of food due to anxiety after PYY treatment indicates that PYY increased motivation towards feeding, rather than anxiolysis. This effect of PYY in a model of conflict associated with food choice resembles aspects of bulimic binge-eating, which is characterized by the repetitive, rapid intake of food, despite anxiety associated with this behavior.