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Monitoring of stored and available fuel by the CNS: implications for obesity

Key Points

  • Attempts to understand the neural underpinnings of eating have taken on an unfortunate urgency over the last decade owing to the exponential increase in obesity in both the developed and developing world. However, although our growing waistlines might indicate otherwise, the system that matches caloric intake to caloric expenditure is remarkably accurate.

  • Research on the neural control of energy balance began with the observation that lesions of specific nuclei in the hypothalamus produce profound increases or decreases in food intake and body weight. Recent work has shown that ingestive behaviour is influenced by a distributed neural network, which includes caudal brainstem, limbic and cortical structures.

  • Lipostatic theories propose that the hypothalamus monitors the storage and metabolism of fat, whereas glucostatic theories postulate that it monitors the storage and use of carbohydrate. Rather than choosing between these two theories, it might be more pertinent to ask how the signals from the two systems are integrated to control ingestive behaviour.

  • How does the central nervous system (CNS) monitor the collective status of adipocytes that are dispersed throughout the body? An 'adiposity' signal must circulate in proportion to the total amount of stored fat and should interact with the brain directly, and changes in its level or activity should alter food intake and energy expenditure. The hormones leptin and insulin both fulfil these criteria.

  • The primary tenet of the glucostatic hypothesis is that fluctuations of glucose-derived energy drive the initiation and cessation of most meals. However, most neurons are buffered from fluctuations in circulating glucose, and most meals occur when blood glucose is well within the normal range. So, fluctuations in glucose use by the CNS probably contribute minimally to normal adjustments in food uptake.

  • Recently, there has been a renewed interest in how metabolic-sensing neurons detect and respond to their ongoing metabolic status, and how this is related to energy homeostasis. This work challenges the idea that all neurons use glucose exclusively, and it raises the possibility that some neurons monitor and respond to a more global and integrated pool of intracellular fuel availability.

  • It is suggested that the ingestion of calories serves two functions — to maintain adequate stores of fuel and to provide readily available fuel to meet current cellular needs. This represents a departure from the debate between the lipostatic and glucostatic hypotheses, and it implies that energy balance is maintained by the simultaneous monitoring of stored and immediately available fuels.

Abstract

Adult mammals do a masterful job of matching caloric intake to caloric expenditure. To accomplish this, the central nervous system (CNS) must be able to monitor the status of peripheral energy stores and ongoing fuel availability. Recent observations support the hypothesis that ongoing fuel availability can be monitored directly in the CNS by mechanisms that extend beyond the sensing of glucose (the primary neuronal fuel). Questions remain as to how signals from stored and available fuel are integrated, and it will be vital to answer these key neuroscience questions to develop biological therapies to curb the growing human and monetary costs of obesity.

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Figure 1: The relationship between energy balance, adiposity signals and the activity of anabolic and catabolic effector pathways.
Figure 2: Actions of leptin and insulin on distinct neuronal populations in the arcuate nucleus of the hypothalamus.
Figure 3: A neuronal metabolic pathway that has been implicated in the control of energy balance.
Figure 4: Diagrams depicting how signals of stored and available fuel could be integrated.

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Acknowledgements

This work ws supported by NIH grants and funds from the Procter and Gamble company.

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Correspondence to Randy J. Seeley.

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AGRP

ASP

insulin

insulin receptor

leptin

MC1

MC3

MC4

NPY

ob

POMC

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Obesity

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LIMBIC

A term that refers to a system of cortical and subcortical structures that are important for processing memory and emotional information. Prominent structures include the hippocampus and amygdala.

BLOOD–BRAIN BARRIER

A barrier that is formed by endothelial tight junctions that limit the entry of leukocytes, immunoglobulins, cytokines and complement proteins into the central nervous system.

ANTISENSE OLIGONUCLEOTIDES

Single-stranded RNA molecules that are complementary to a portion of a messenger RNA (mRNA). They bind to the mRNA and arrest translation by physical blockade of ribosomal machinery and/or by activation of endogenous RNases.

HYPERPHAGIA

Increased feeding.

INVERSE AGONIST

A ligand that reduces the proportion of receptors that are in an active configuration, thereby producing the opposite effects to an agonist.

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Seeley, R., Woods, S. Monitoring of stored and available fuel by the CNS: implications for obesity. Nat Rev Neurosci 4, 901–909 (2003). https://doi.org/10.1038/nrn1245

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