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Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons

Key Points

  • Hunger is the adaptive response to the need for higher energy levels, and promotes cellular and behavioural shifts that lead to changes in cognition and other higher brain functions.

  • Hunger is characteristic of a negative energy balance — for example, owing to calorie restriction — and promotion of these pathways leads to extended healthy lifespan. By contrast, promotion of satiety (a positive energy balance) leads to metabolic overload and chronic disorders.

  • Hunger and satiety are primarily controlled by the hypothalamus through two populations of neurons: the neuropeptide Y/agouti-related protein (NPY/AgRP) neurons and the pro-opiomelanocortin (POMC) neurons. NPY/AgRP neurons are active during negative energy balance, whereas POMC neurons are active during positive energy balance.

  • During a state of negative energy balance, the activity of NPY/AgRP neurons is sustained mainly by burning free fatty acids, and maintaining low levels of reactive oxygen species (ROS). POMC neurons, on the other hand, utilize mainly carbohydrates (glucose) as fuel, and their sustained activation during a state of long-term positive energy balance is correlated with high levels of ROS and tissue damage.

  • Most of the anti-obesity therapies are designed to promote satiety, with the exception of orlistat (a lipase inhibitor), which, together with lorcaserin and Qsymia (a combination of phentermine plus topiramate) are the only drugs approved by the US Food and Drug Administration for the long-term treatment of obesity. However, promotion of satiety leads to chronic disorders and consequently severe side effects.

  • New drug therapies for the chronic treatment of obesity should therefore focus on promoting the pathways involved in negative energy balance, such as those that are activated during calorie restriction and exercise.

  • Several new drugs being developed to treat obesity aim to target peripheral tissues, mainly the white adipose tissue, instead of the brain to avoid severe side effects. However, as peripheral tissues and the brain are interconnected, it is unlikely that one compound will be specific to one tissue during chronic treatment programmes.

  • We therefore propose that current obesity therapies should only be used for short periods of time, in conjunction with intense behavioural interventions. Moreover, targeting the molecular pathways that mediate the beneficial effects of such behavioural interventions (for example, calorie restriction and exercise) may represent a safer alternative therapeutic approach for the treatment of chronic metabolic disorders such as obesity.

Abstract

Current anti-obesity drugs aim to reduce food intake by either curbing appetite or suppressing the craving for food. However, many of these agents have been associated with severe psychiatric and/or cardiovascular side effects, highlighting the need for alternative therapeutic strategies. Emerging knowledge on the role of the hypothalamus in enabling the central nervous system to adapt to the changing environment — by managing peripheral tissue output and by regulating higher brain functions — may facilitate the discovery of new agents that are more effective and have an acceptable benefit–risk profile. Targeting the molecular pathways that mediate the beneficial effects of calorie restriction and exercise may represent an alternative therapeutic approach for the treatment of chronic metabolic disorders such as obesity.

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Figure 1: Humoral and nutritional crosstalk between peripheral tissues and the brain.
Figure 2: Summary of known mechanisms in the arcuate nucleus and MC4 receptor target areas involved in obesity in humans.
Figure 3: Mechanism of action of the main anti-obesity drugs currently in the market or recently withdrawn.
Figure 4: Relationship between the metabolic state and ROS production.
Figure 5: Alternative strategies for the development of improved anti-obesity pharmacotherapies.

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Acknowledgements

The preparation of this manuscript was supported by a US National Institutes of Health Director's Pioneer Award to T.L.M. M.O.D. was partially supported by CNPq-Brazil.

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Correspondence to Marcelo O. Dietrich or Tamas L. Horvath.

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IUPHAR Database of Receptors and Ion Channels

Glossary

Overnutrition

A positive energy balance in which the absorption of energy surpasses its metabolism by the body; that is, intake is higher than expenditure.

Appetite

A complex desire to fulfil the body's need with something, usually with food (perceived as hunger).

Food cravings

Intense desires to ingest specific types of food. These desires are not necessarily linked to hunger.

Satiety

A state in which the individual is fed and/or gratified with the amount of energy ingested.

Mnemonic functions

Cognitive functions of the brain that are involved in memory processes.

Endoplasmic reticulum (ER) stress

A state in an organelle that occurs owing to disturbances in metabolic homeostasis, which lead to an accumulation of unfolded proteins and consequent organelle dysfunction.

Peroxisome

An organelle found in virtually every mammalian cell that is mainly involved in the catabolism of very long-chain fatty acids.

Paresthaesia

The sensation of numbness or tingling on the skin, usually in the extremities (fingers and toes) without any apparent physical problem.

Nephrolithiasis

A common disease characterized by the presence of calculi in the kidneys that occurs mainly in men.

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Dietrich, M., Horvath, T. Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons. Nat Rev Drug Discov 11, 675–691 (2012). https://doi.org/10.1038/nrd3739

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