Peter G. Clifton

Serotonin reciprocally regulates melanocortin neurons to modulate food intake

The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT1BRs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors. These results identify a primary mechanism underlying the serotonergic regulation of energy balance and provide an example of a centrally derived signal that reciprocally regulates melanocortin receptor agonists and antagonists in a similar manner to peripheral adiposity signals.

Reduced satiating effect of d-fenfluramine in serotonin 5-HT(2C) receptor mutant mice.

Abstract  Rationale:d-Fenfluramine stimulates the release of serotonin (5-HT) and is a potent inhibitor of the re-uptake of 5-HT into nerve terminals. Administration of d-fenfluramine suppresses food intake in both animals and humans. Objective: We have investigated the role of the 5-HT2C receptor in mediating the effect of d-fenfluramine on mouse food intake and the behavioural satiety sequence. Methods: Mutant mice lacking serotonin 5-HT2C receptors and wild-type animals were habituated to a daily presentation of wet mash. Animals were non-deprived and received d-fenfluramine (3–30 mg/kg) 30 min prior to being assessed for the presence of stereotypy and presented with wet mash. The behaviour of animals was observed for the subsequent 40 min and food intake was recorded. Results:d-Fenfluramine dose-dependently inhibited the consumption of a palatable wet mash by the mice. d-Fenfluramine (3 mg/kg) significantly reduced the amount of wet mash consumed by wild-type mice and induced a temporal advance in the behavioural satiety sequence consistent with an enhancement of satiety. Mutant mice were less sensitive to the satiating effects of 3 mg/kg d-fenfluramine. Hence, this dose of d-fenfluramine had a reduced effect on both food consumption and the behavioural satiety sequence in the 5-HT2C mutant mice. In contrast, mutant mice showed an increased sensitivity to the stereotypy induced by high doses of d-fenfluramine (10, 30 mg/kg) compared to that of wild-type littermates. Conclusion: These data demonstrate a role for the 5-HT2C receptor in mediating d-fenfluramine-induced satiety.

Serotonin 2C Receptor Agonists Improve Type 2 Diabetes via Melanocortin-4 Receptor Signaling Pathways

Summary The burden of type 2 diabetes and its associated premature morbidity and mortality is rapidly growing, and the need for novel efficacious treatments is pressing. We report here that serotonin 2C receptor (5-HT2CR) agonists, typically investigated for their anorectic properties, significantly improve glucose tolerance and reduce plasma insulin in murine models of obesity and type 2 diabetes. Importantly, 5-HT2CR agonist-induced improvements in glucose homeostasis occurred at concentrations of agonist that had no effect on ingestive behavior, energy expenditure, locomotor activity, body weight, or fat mass. We determined that this primary effect on glucose homeostasis requires downstream activation of melanocortin-4 receptors (MC4Rs), but not MC3Rs. These findings suggest that pharmacological targeting of 5-HT2CRs may enhance glucose tolerance independently of alterations in body weight and that this may prove an effective and mechanistically novel strategy in the treatment of type 2 diabetes.

Meal patterning in rodents: psychopharmacological and neuroanatomical studies.

Studies of meal patterning have made an important contribution to our understanding of ingestive behaviour. This paper initially reviews studies of normal meal patterning in rodents, with an emphasis on the determination of suitable meal criteria. Studies of serotonergic mechanisms in the control of meal size and feeding rate suggest important roles for the 5HT1B and 5-HT2C receptor. Analysis of dopaminergic mechanisms show that dopamine D2 receptor blockade is associated with enhancement of meal size and decrease of meal frequency; this probably represents a failure to switch from feeding to other behaviour when a meal is expected to terminate. Finally studies are described demonstrating that lesions of several forebrain structures, including hippocampus and nucleus accumbens, lead to a similar syndrome of short, frequent meals with little evidence of a deficit in body weight regulation. These structures may play a role in the organisation of meal patterning.

Little and often: ingestive behavior patterns following hippocampal lesions in rats.

Lesions of both dorsal and ventral hippocampus were produced by multiple infusions of the excitotoxin AMPA. Meal patterns recorded before and after lesioning showed no change in total food intake, but a striking behavioral syndrome in which the lesioned rats took smaller meals 2-3 times as frequently and showed a similar change in drinking. In addition, lesioned rats alternated more frequently between feeding and drinking during a single bout of ingestive behavior. There were no group differences in the satiety sequence that followed a meal. In an open field test, lesioned rats showed enhanced locomotion in the periphery and reduced rearing. An olfactory habituation-dishabituation task showed that the lesioned rats investigated olfactory stimuli less but dishabituation to a changed stimulus was normal. The data are discussed in terms of changes in behavioral switching or a possible interoceptive agnosia following hippocampal damage.

The cannabinoid CB1 receptor inverse agonist, rimonabant, modifies body weight and adiponectin function in diet-induced obese rats as a consequence of reduced food intake.

The cannabinoid CB1 receptor inverse agonist rimonabant induces hypophagia and body weight loss. Reduced body weight may potentially be due to decreased food intake or to direct metabolic effects of drug administration on energy expenditure. This study uses a paired-feeding protocol to quantify the contributions of energy intake to rimonabant-induced body weight loss. Diet-induced obese (DIO) rats were dosed with rimonabant (3, 10 mg/kg PO once daily) and matched with pair-fed controls. Food intake and body weight were measured daily. Blood samples and adipose tissue were collected on day 15 for measurement of plasma adiponectin and adiponectin mRNA levels. DIO rats treated with rimonabant and pair-fed controls showed very similar changes in body weight. Although tolerance developed to the anorectic effect of rimonabant, total food intake was significantly decreased over the 14-day study period and fully accounted for the observed reductions in body weight. Adiponectin mRNA and plasma adiponectin were elevated in vehicle-treated chow-fed animals compared to obese controls, and did not differ between rimonabant-treated and pair-fed animals. The similarities between rimonabant-treated and pair-fed animals in body weight loss and the absence of differences in measures of adiponectin activity between drug-treated and pair-fed animals suggest that the outcomes of this experiment were solely mediated by the drug-induced reduction in food intake.

The cannabinoid CB1 receptor antagonist SR141716A reduces appetitive and consummatory responses for food

RationaleThe CB1 receptor antagonist SR141716A reduces food intake in rats. This effect is likely to depend on modulation of reward related processes.ObjectiveTo investigate the effects of SR141716A on responding for food under a second order instrumental task in which responding and consumption of food can be separated, and on Pavlovian responding for a stimulus predictive of food reward.MethodsInstrumental responding and pellet consumption following administration of SR141716A (0–3 mg/kg) were recorded under an FI5 min FR5(5:S) operant schedule that incorporates both a 5 min initial appetitive phase and a 25 min consummatory phase. We compared the drug-induced change in responding to that recorded following a reduction in motivational state induced by pre-feeding. In a second experiment we assessed the effects of SR141716A (0–3 mg/kg) on Pavlovian approach behaviour for a stimulus (lever) associated with food reward (CS+) and a neutral stimulus (lever) not associated with reward (CS−).ResultsSR141716A reduced pellet consumption and instrumental responding during both the appetitive and consummatory phases of the second order schedule. Pre-feeding had a similar effect on responding during the appetitive phase, suggesting an effect on incentive motivation. SR141716A also blocked an enhancement of responding that occurred during the consummatory phase in pre-fed animals. SR141716A and pre-feeding had no effect on responding in the Pavlovian autoshaping paradigm.ConclusionsSR141716A impacts on motivational processes in both the appetitive and consummatory phases of feeding behaviour.

A behavioural profile of fluoxetine-induced anorexia

Fluoxetine is a specific and long-lasting inhibitor of serotonin reuptake. In free-feeding rats a dose of 10 mg/kg reduced meal size but had no significant effect on meal frequency. Feeding rate during meals was also reduced. Direct observation of behaviour associated with eating suggested that fluoxetine did not act by enhancing sleep or other behaviour patterns that interfere with eating, although the transition from feeding to sleep occured more rapidly after drug treatment. Enhancement of satiety or interference with the sustaining of meals by fluoxetine would be consistent with these data. Rebound feeding after anorexia was not observed in either the meal pattern study or in a separate experiment using schedule fed animals. There was also no clear development of tolerance to the anorectic effect of fluoxetine, and we discuss possible reasons for an association of these two properties.

Effects of dopamine D1 and dopamine D2 antagonists on the free feeding and drinking patterns of rats

In male rats with food and water freely available, the specific dopamine D2 antagonist YM-09151-2 had little effect on total food or water intake across a 24-hr period. However, it produced a substantial dose-related decrease in feeding rate during meals and an enhancement of both meal size and duration. The equivalent parameters for water intake were affected to a much lesser extent. A second dopamine D2 antagonist, remoxipride, had similar effects on feeding patterns and, in addition, raised food intake during the 2 hr after drug administration. A third dopamine D2 antagonist, raclopride, produced a short-lived rise in food intake and a slowing of feeding rate with a nonsignificant increase in meal size at intermediate doses. Higher doses increased the latency to feed and drink. The specific D1 antagonist SCH 23390 had small effects on both total food intake and feeding patterns. Water intake was substantially reduced in the first 2-4 hr after drug administration by an increased latency to drink. The results are interpreted, first of all, in terms of two separate effects of dopamine D2 receptors on feeding behavior: the first mediating positive feedback processes important at meal initiation and the second mediating the preabsorptive effects of food on meal termination. D1 receptors, in contrast, are of greater importance in controlling water intake.

New approaches to the pharmacological treatment of obesity: can they break through the efficacy barrier?

In this review we assess the range of centrally active anorectics that are either in human clinical trials, or are likely to be so in the near future. We describe their weight loss efficacy, mode of action at both pharmacological and behavioural levels, where understood, together with the range of side effects that might be expected in clinical use. We have however evaluated these compounds against the considerably more rigorous criteria that are now being used by the Federal Drugs Agency and European Medicines Agency to decide approvals and market withdrawals. Several trends are evident. Recent advances in the understanding of energy balance control have resulted in the exploitation of a number of new targets, some of which have yielded promising data in clinical trials for weight loss. A second major trend is derived from the hypothesis that improved weight loss efficacy over current therapy is most likely to emerge from treatments targeting multiple mechanisms of energy balance control. This reasoning has led to the development of a number of new treatments for obesity where multiple mechanisms are targeted, either by a single molecule, such as tesofensine, or through drug combinations such as qnexa, contrave, empatic, and pramlintide+metreleptin. Many of these approaches also utilise advances in formulation technology to widen safety margins. Finally, the practicality of peptide therapies for obesity has become better validated in recent studies and this may allow more rapid exploitation of novel targets, rather than awaiting the development of orally available small molecules. We conclude that novel, more efficacious and better tolerated treatments for obesity may become available in the near future.