Cell Rep. 2015 May 5;11(5):798-807

Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors.

 

Liang Yang1, Yong Qi1,2 and Yunlei Yang1*

  1. Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA
  2. Zhengzhou University People’s Hospital (He’nan Provincial People’s Hospital), Zhengzhou 450003, China

 

Abstract

It is well recognized that feeding behavior in mammals is orchestrated by neurons within medial basal hypothalamus. However, it remains unclear whether food intake is also under the control of glial cells. Here, we combine chemical-genetics, cell-type specific electrophysiology, pharmacology, and feeding assays, to show that stimulation of astrocytes within the medial basal hypothalamus reduces both basal and ghrelin-evoked food intake. This occurs by a mechanism of adenosine-mediated inactivation of the orexigenic agouti-related peptide (AGRP) neurons in the hypothalamic arcuate nucleus (ARC) via adenosine A1 receptors. Our data suggest that glial cells participate in regulating food intake by modulating extracellular levels of adenosine. These findings reveal the existence of a glial relay circuit that controls feeding behavior, one that might serve as a target for therapeutic intervention in the treatment of appetite disorders.

PMID: 25921535

 

Supplement:

Neurons that express Agouti-related protein (AGRP) are a molecularly defined population localized in the hypothalamic arcuate nucleus (ARC), and activation of AgRP neurons induces food intake (1, 2). In addition to behaving as interoceptive sensory neurons, AGRP neurons receive synaptic inputs which are adaptable to the hunger states (3, 4).

An extensive literature shows that glial cells exert crucial functions in the formation, operation and adaptation of neuronal circuits. For instance, astrocytes, the most abundant glial cells in the brain, are closely associated with neuronal synapses to scale synaptic strength and modulate neuronal circuits (5-7). However, an important but little explored was how astrocytes contributed to the regulation of energy states. We proposed that astrocytes may rapidly regulate food intake by rewiring the appetite control circuits within medial basal hypothalamus in the conditions of energy surfeit or deficit respectively. To test this, we specifically manipulated astrocytes within medial basal hypothalamus to determine the functional roles of astrocytes in regulating food intake and the action potential firing rate of AGRP neurons.

By combining the chemical-genetic DREADD approach with cell-type specific electrophysiology, pharmacology and feeding assays, we found that astrocyte activation depressed ghrelin-evoked hyperphagia, whereas it facilitated leptin-induced anorexia. In contrast, astrocyte inactivation potentiated ghrelin-evoked feeding but blunted leptin-regulated feeding behavior. We further examined astrocytic regulation of food intake and determined the underlying gliotransmitter(s). We found that endogenous adenosine mediated the astrocytic inhibition of food intake and of the firing rate of AGRP neurons by activating adenosine A1 receptors. Based on these experiments, we proposed that glial cells serve as a checkpoint of feeding by modulating the extracellular levels of adenosine to prevent from energy deficit or surfeit respectively.

 

References

  1. Aponte, Y., Atasoy, D. and Sternson, S. M. (2011). AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nature Neurosci. 14, 351-355.
  2. Atasoy, D., Betley, J. N., Su, H. H. and Sternson, S. M. (2012). Deconstruction of a neural circuit for hunger. Nature 488, 172-177.
  3. Liu, T., et al., (2012). Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron 73, 511-522.
  4. Yang, Y., Atasoy, D., Helen, H. H. and Sternson, S. M. (2011). Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146, 992-1003.
  5. Clarke, L. E. and Barres, B. A. (2013). Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci. 14, 311-321.
  6. Sasaki, T., Beppu, K., Tanaka, K. F., Fukazawa, Y., Shigemoto, R. and Matsui, K. (2012). Application of an optogenetic byway for perturbing neuronal activity via glial photostimulation. Proc. Natal. Acad. Sci. USA 109, 20720-20725.
  7. Stellwagen, D. and Malenka, R. C. (2006). Synaptic scaling mediated by glial TNF-α. Nature 440, 1054-1059.

 

yly fig1* Contact:

Yunlei Yang, MD; PhD

Assistant Professor

Department of Neuroscience and Physiology

505 Irving Ave, Syracuse, 13210

yangyun@upstate.edu

Phone: 315-464-7733

Fax: 315-464-7712

 

 

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