Pharmacological management of appetite expression in obesity

Abstract

For obese individuals, successful weight loss and maintenance are notoriously difficult. Traditional drug development fails to exploit knowledge of the psychological factors that crucially influence appetite, concentrating instead on restrictive criteria of intake and weight reduction, allied to a mechanistic view of energy regulation. Drugs are under development that may produce beneficial changes in appetite expression in the obese. These currently include glucagon-like peptide-1 analogs such as liraglutide, an amylin analog davalintide, the 5-HT2C receptor agonist lorcaserin, the monoamine re-uptake inhibitor tesofensine, and a number of combination therapies such as pramlintide and metreleptin, bupropion and naltrexone, phentermine and topiramate, and bupropion and zonisamide. However, the effects of these treatments on eating behavior remain poorly characterized. Obesity is typically a consequence of overconsumption driven by an individual's natural sensitivity to food stimuli and the pleasure derived from eating. Intuitively, these processes should be effective targets for pharmacotherapy, and behavioral analysis can identify drugs that selectively affect desire to eat, enjoyment of eating, satiation or postmeal satiety. Rational interventions designed specifically to modulate these processes could limit the normally aversive consequences of caloric restriction and maximize an individual's capacity to successfully gain control over their appetite.

Key Points

  • Traditional antiobesity drug development focuses on weight and obesity-related disease end points, without adequate consideration of behavioral and psychological changes that initiate weight gain or that impede weight management

  • Classical energy homeostasis models emphasize energy regulation systems, but fail to acknowledge key motivational, emotional and behavioral factors that contribute to energy intake and the propensity to gain weight

  • Drug efficacy has been limited, as key behavioral features of appetite have been ignored—namely, hedonic aspects of consumption and the powerful influence of the environment in triggering overeating

  • Pharmaceutical companies are beginning to focus on treatments that combine existing compounds to exploit additive, or supra-additive, actions of separate agents

  • This approach could be advanced by exploiting the specific actions of drugs on distinct components of eating motivation rather than merely emphasizing simple effects on energy intake and body weight

  • Behavioral analysis can isolate drugs that reduce the desire to eat by acting on the processes that initiate, sustain and terminate meals or inhibit consumption

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Correspondence to Jason C. G. Halford.

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J. C. G. Halford declares associations with the following companies/organizations: GlaxoSmithKline (Speakers Bureau), Novo Nordisk (Speakers Bureau), Prosidion OSI Pharmaceuticals (Consultant). J. E. Blundell is an expert consultant to the NDA Panel of the European Food Safety Authority (EFSA), a Scientific Governor of the British Nutrition Foundation, and Treasurer and Trustee of the European Association for the Study of Obesity. He is also an advisor/consultant to industrial companies in the food and pharmaceutical sectors (Consultant: Merck, Amylin, Covance, Barilla, Danone; Speakers bureau: Kellogg's, Fonterra; Grant/research support: National Starch, Coca-Cola, Sanofi-aventis, Unilever). Lastly, he has grant/research support from the Biotechnology and Biological Sciences Research Council. The other authors declare no competing interests.

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Halford, J., Boyland, E., Blundell, J. et al. Pharmacological management of appetite expression in obesity. Nat Rev Endocrinol 6, 255–269 (2010). https://doi.org/10.1038/nrendo.2010.19

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