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Common cellular and molecular mechanisms in obesity and drug addiction

Key Points

  • Common brain sites and neurotransmitter systems are activated in response to palatable food and drugs of abuse. Addictive drugs seem to be particularly effective in stimulating the very same brain systems whose function is to process information related to food palatability and regulate the incentive value of food.

  • The nucleus tractus solitarius (NTS) receives input related to food palatability from the mouth and gastrointestinal tract. Circulating hormonal regulators of hunger and satiety also influence NTS activity. The NTS contains at least three distinct populations of neurons, those containing catecholamines, proopiomelanocortin (POMC) or glucagon-like peptide 1 (GLP1; a cleavage product of glucagon). The NTS seems to play a key part in drug reward and also in some aspects of drug withdrawal.

  • The insular cortex encodes and stores information related to the valence and magnitude of food and drug reward. In particular, the insula seems to play an important part in contrasting the palatability of currently and previously available food or drug reinforcers and thereby determining if there has been a change in the relative value of food or drug reinforcers.

  • The orbitofrontal cortex (OFC) processes information about the relative motivational value of palatable food or addictive drugs at any given time based on information from metabolic or hedonic circuitries in the brain. As such, the OFC seems to have a key role in the development of satiety.

  • The striatum, and in particular dopamine, opioid and cannabinoid systems within the striatum, encode information related to the appetitive and incentive value of food and drugs of abuse.

  • Palatable food and drugs of abuse can trigger common molecular adaptations in brain reward systems, including increases in the transcription factor ΔFOSB. Such neuroadaptive responses are likely to contribute to the development of obesity and addiction.

  • Brain inflammatory responses have been implicated in the development of obesity and drug addiction. The transcription factor nuclear factor-κB (NF-κB) in particular may have a key role in driving excessive food or drug intake.

  • New areas of research in obesity and drug addiction include assessing the role for neurogenesis in the adult brain and the involvement of nuclear hormone receptors like peroxisome proliferator-activated receptor-γ (PPARγ). In addition, gene regulatory processes including DNA methylation and chromatin modifications, and post-transcriptional gene regulatory processes like RNA editing and microRNAs are also emerging as important regulators of vulnerability to obesity and drug addiction.

Abstract

The hedonic properties of food can stimulate feeding behaviour even when energy requirements have been met, contributing to weight gain and obesity. Similarly, the hedonic effects of drugs of abuse can motivate their excessive intake, culminating in addiction. Common brain substrates regulate the hedonic properties of palatable food and addictive drugs, and recent reports suggest that excessive consumption of food or drugs of abuse induces similar neuroadaptive responses in brain reward circuitries. Here, we review evidence suggesting that obesity and drug addiction may share common molecular, cellular and systems-level mechanisms.

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Figure 1: Overview of homeostatic feeding circuits.
Figure 2: The neurocircuitry controlling palatable food and drug consumption.
Figure 3: The nucleus tractus solitarius in food and drug consumption.
Figure 4: Intracellular signalling cascades in the striatum and mesoaccumbens dopamine pathway that regulate food intake and drug use.
Figure 5: Nuclear factor-κB signalling and its regulation by SIRT1.

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Acknowledgements

The author is supported by grants from the US National Institute on Drug Abuse (NIDA). This is manuscript number 21309 from The Scripps Research Institute.

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Glossary

Hyperphagia

Excessive consumption of food (above caloric requirements), which can reflect increased motivation to consume palatable food and/or deficits in brain circuitries that regulate satiety.

Protracted drug abstinence

This is an aversive state that can persist in drug-dependent subjects long after cessation of drug use. Protracted abstinence is thought to increase vulnerability to relapse to drug-taking behaviour.

Reinforcer

This is a stimulus (object or event) that is obtained or that occurs in response to a particular behaviour and that is associated with an increased probability that the behavioural response that resulted in delivery of the stimulus will occur again. In essence, a reinforcer is anything that increases the likelihood that a given behaviour will be repeated.

Direct pathway

The direct striatal pathway comprises medium spiny neurons (MSNs) that express dopamine D1 receptors and project directly to the globus pallidus interna (GPi). The indirect pathway comprises MSNs that express dopamine D2 receptors and project to the GPi indirectly through a pathway involving the globus pallidus externa (GPe) and the subthalamic nucleus.

Fixed and progressive ratio schedules

A fixed ratio schedule of reinforcement requires an animal to emit a fixed number of responses to earn a reinforcer. A progressive ratio schedule involves the animal emitting progressively greater numbers of responses to earn each subsequent reinforcer.

Anorexigenic

A stimulus (object or event) that decreases appetite and food consumption.

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Kenny, P. Common cellular and molecular mechanisms in obesity and drug addiction. Nat Rev Neurosci 12, 638–651 (2011). https://doi.org/10.1038/nrn3105

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