Body composition and endocrine status of long-term stress-induced binge-eating rats.

Clinical binge eating runs a protracted course. The etiology of binge eating remains perplexing in part because, in humans, it is difficult to isolate and assess the independent and aggregate impact of various contributing variables. Using rats, we found that footshock stress and a history of caloric restriction (S+R), combine synergistically to induce binge eating. Stress and dieting are also strong antecedents and relapse factors in human eating disorders. Here we report further behavioral and physiological parallels to human binge eating. Like the protracted course of human binge eating, young female Sprague-Dawley rats continued to binge eat after 23 restriction/stress cycles (7 months) and this despite experiencing no significant weight loss during the restriction phases. Stress alone reduced adiposity by 35% (p<0.001) but S+R rats had no significant fat loss. An endocrine profile of normal plasma leptin and insulin levels but marked elevation of plasma corticosterone levels was found only in the binge-eating (S+R) rats (p<0.01), also paralleling endocrine profiles reported in clinical binge-eating studies. These behavioral and physiological similarities between this animal model and clinical binge eating increase its utility in understanding binge eating. Importantly, our findings also highlight the stubborn nature of binge eating: once a critical experience with dieting and stress is experienced, little if any further weight loss or food restriction is necessary to sustain it.

PYY3-36 as an anti-obesity drug target.

The neuropeptide Y (NPY)/peptide YY (PYY) system has been implicated in the physiology of obesity for several decades. More recently ignited enormous interest in PYY3-36, an endogenous Y2-receptor agonist, as a promising anti-obesity compound. Despite this interest, there have been remarkably few subsequent reports reproducing or extending the initial findings, while at the same time studies finding no anti-obesity effects have surfaced. Out of 41 different rodent studies conducted (in 16 independent labs worldwide), 33 (83%) were unable to reproduce the reported effects and obtained no change or sometimes increased food intake, despite use of the same experimental conditions (i.e. adaptation protocols, routes of drug administration and doses, rodent strains, diets, drug vendors, light cycles, room temperatures). Among studies by authors in the original study, procedural caveats are reported under which positive effects may be obtained. Currently, data speak against a sustained decrease in food intake, body fat, or body weight gain following PYY3-36 administration and make the previously suggested role of the hypothalamic melanocortin system unlikely as is the existence of PYY deficiency in human obesity. We review the studies that are in the public domain which support or challenge PYY3-36 as a potential anti-obesity target.

Feeding response to melanocortin agonist predicts preference for and obesity from a high-fat diet.

Overconsumption and increased selection of high fat (HF) foods contribute to the development of common obesity. Because the hypothalamic melanocortin (MC) system plays an integral role in the regulation of food intake and dietary choice, we tested the hypothesis that proneness (-P) or resistance (-R) to dietary-induced obesity (DIO) may be due to differences in MC function. We found that prior to developing obesity and while still maintained on chow, acute, central administration of MTII, an MC agonist, produced a greater anorectic response in DIO-P rats than in DIO-R rats. However, after only 5 days of exclusive HF feeding, the DIO-R rats had significantly greater suppression of intake after MTII treatment than they did when maintained on chow. In addition, the DIO-P rats were much less responsive to MTII treatment than the DIO-R rats after only 5 days of the HF diet. In fact, MTII-induced anorexia during HF feeding correlated negatively with body weight gained on the HF diet. These results suggest that the voluntary decrease of HF feeding in DIO-R rats may be mediated by increased endogenous MC signaling, a signal likely compromised in DIO-P rats. Differences in MC regulation may also explain the observed preference for HF over a lower fat food choice in DIO-P rats. Finally, the results indicate that responses to exogenous MC challenge can be used to predict proneness or resistance to DIO.

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

Batterham 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.

Change in CCK-8 response after diet-induced obesity and MC3/4-receptor blockade.

Little is known regarding satiety effects of systemically administered cholecystokinin (CCK-8) in propensity or resistance to dietary-induced obesity (DIO), and of its effect under conditions of melanocortin-3/4R blockade. We found that CCK-8 exerted greater satiety effects in DIO-prone but not DIO-resistant rats, and this occurred only when the rats were placed on a high-fat (HF) diet, when DIO-prone rats failed to compensate for the greater energy density of the diet. CCK-8 also suppressed intake stimulated by melanocortin-3/4R antagonist, SHU9119, but only after 24h of increased feeding. This suggests that under both of these conditions, responsiveness to CCK's satiety effect is not so much affected by a HF diet or significant increases in body weight per se, but by a failure to rapidly limit food intake to that needed only for metabolic need. Identification of an early feeding mediator that is most strongly activated by a HF diet or by an acute challenge to energy homeostasis should provide an ideal anti-obesity target adjunct to CCK-8.