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Wired on sugar: the role of the CNS in the regulation of glucose homeostasis

Nature Reviews Neuroscience volume 14, pages 24–37 (2013)Cite this article

Subjects

Key Points

  • Recent findings indicate that neuronal populations in the hypothalamus that had already been identified as being crucial to the regulation of energy balance are also essential for the regulation of glucose homeostasis.

  • The melanocortin system within the arcuate nucleus (ARC) of the hypothalamus has an important role in the integration of signals from circulating hormones to maintain both energy and glucose homeostasis.

  • ATP-sensitive potassium channels, ATP-activated protein kinase and mammalian target of rapamycin act as 'general' fuel sensors — they sense changes in overall energy status through changes in ATP. The sensing of fuel and ATP specifically within the hypothalamus has the capacity to modulate both glucose and energy homeostasis.

  • Neuronal populations outside the ARC (including steroidogenic factor 1 neurons within the ventromedial hypothalamus) and multiple populations of neurons within the hindbrain (melanocortin receptor 4-expressing neurons in the sympathetic nervous system and NMDA receptor-expressing neurons) contribute to the regulation of glucose and energy homeostasis.

  • Within the gut, cholecystokinin and glucagon-like peptide 1 provide a conduit for CNS-induced regulation of energy and glucose homeostasis.

  • A key outstanding question in the field is whether the neuronal circuits that are crucial for body weight regulation and that may be dysregulated in obesity also contribute to the poor glucose homeostasis that eventually results in type 2 diabetes mellitus.

  • New strategies such as optogenetics and DREADD (designer receptors exclusively activated by designer drugs) provide an avenue for further understanding the crossroads of glucose and energy homeostasis.

Abstract

Obesity and type 2 diabetes mellitus (T2DM) — disorders of energy homeostasis and glucose homeostasis, respectively — are tightly linked and the incidences of both conditions are increasing in parallel. The CNS integrates information regarding peripheral nutrient and hormonal changes and processes this information to regulate energy homeostasis. Recent findings indicate that some of the neural circuits and mechanisms underlying energy balance are also essential for the regulation of glucose homeostasis. We propose that disruption of these overlapping pathways links the metabolic disturbances associated with obesity and T2DM. A better understanding of these converging mechanisms may lead to therapeutic strategies that target both T2DM and obesity.

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Figure 1: Leptin and insulin actions in the ARC.
Figure 2: Fuel sensing in CNS neurons.
Figure 3: Overlapping CNS circuitries regulate energy balance and glucose homeostasis.

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Acknowledgements

We are grateful for the helpful comments of S.C. Woods and S.C. Benoit. The work of the laboratory is supported in part by the US National Institutes of Health (NIH) Awards DK56863, DK57900, U01CA141464, DK082480, MH069860, DK082480 and also work with Ethicon Endo-Surgery, F. Hoffman-La Roche, Pfizer and Novo Nordisk A/S. B.E.G. is also supported by NIH Award 1F32HD68103.

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  1. Metabolic Diseases Institute, University of Cincinnati, Cincinnati, 45237, Ohio, USA

    Bernadette E. Grayson, Randy J. Seeley & Darleen A. Sandoval

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  1. Bernadette E. Grayson
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  3. Darleen A. Sandoval
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Correspondence to Darleen A. Sandoval.

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Competing interests

D.A.S. has received research support from Ethicon Endo-Surgery, Mannkind and Novo Nordisk. R.J.S. has received research support from Ethicon Endo-Surgery, Mannkind, Novo Nordisk, Pfizer and Roche. R.J.S. has served on scientific advisory boards for Ethicon Endo-Surgery, Angiochem and Novo Nordisk. R.J.S. is also a paid speaker for Merck, Ethicon Endo-Surgery, Pfizer and Novo Nordisk.

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Glossary

Glucose fluxes

Changes in glucose uptake, glucose production by the liver and glucose metabolism within a tissue or cell.

Melanocortin system

Neurons in the arcuate nucleus of the hypothalamus and the nucleus of the solitary tract that express pro-opiomelanocortin, agouti-related protein and neuropeptide Y with downstream actions on melanocortin receptor 3 and melanocortin receptor 4.

Antagonist/inverse agonist

A ligand that can both block a receptor's activity and produce the opposite action of the agonist.

Gluconeogenesis

The process of making glucose from non-glucose precursors such as lactate, glycerol and alanine.

Glycogenolysis

The breakdown of glycogen to glucose.

Hepatic insulin sensitivity

The degree to which insulin suppresses glucose production by the liver.

Glucose tolerance test

(GTT). A test that measures the glucose excursion after a bolus administration of glucose; it is an index of the body's ability to tolerate and/or handle a glucose load.

Insulin tolerance tests

Tests that measure the fall in glucose levels after an injection of a bolus of insulin.

Whole-body insulin sensitivity

The degree to which the body responds to insulin; it is usually assessed by comparing the glucose infusion rate during a hyperinsulinaemic–euglcyaemic clamp in control versus experimental animals.

Mass action of glucose

Refers to glucose uptake into tissues, which is driven by how much glucose there is in the blood.

Insulin resistance

A metabolic state in which the tissues of the body exhibit reduced responsiveness to chronically high levels of insulin in the circulation.

Negative-feedback proteins

Proteins that suppress signalling by other molecules.

Leptin resistance

A state in which the body is no longer responsive to the anorexic effect of exogenous leptin.

Nodose ganglia

Inferior ganglia of the vagus nerve.

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Grayson, B., Seeley, R. & Sandoval, D. Wired on sugar: the role of the CNS in the regulation of glucose homeostasis. Nat Rev Neurosci 14, 24–37 (2013). https://doi.org/10.1038/nrn3409

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