Yunlei Yang, PhD, MD
Principal Investigator, Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Tel. 315-464-7733; Fax: 315-464-7712; E-mail: yangyun@upstate.edu
Without homeostatic control of feeding behavior, energy balance will be disturbed towards either energy surfeit or deficit, respectively, leading to obesity or wasting. Anorexia Nervosa (AN) is a disorder characterized with food restriction and weight loss1,2 due to intense fear of gaining weight and a distorted perception of body weight. The individuals with anorexia believe they are fat and seek to prevent weight gain by restricting the amount of energy intake even when they are starvation. Anorexia and its associated disorders impose a huge burden to our society, so treating and reversing anorexia are of paramount importance. However, the underlying mechanisms of anorexia are poorly understood, and there is a lack of effective treatments.
The nervous system consists of two classes of cells, neurons and glia. Thus, it is important to define the integrative processes of neurons and glial cells in the brain regions that control food intake. It is well recognized that neurons play critical roles in controlling feeding behavior and appetite, while little is known about glial influences on feeding. Astrocytes, the most abundant glial cells in the brain, are closely associated with neuronal synapses to scale synaptic strength and modulate neural circuits,3,4,5,6,7,8,9 as well as with cerebral blood vessels to adjust blood supply.10,11 Emerging evidence demonstrates the functional role of astrocytes in complex behaviors.12,13 Interestingly, in response to high-fat diet (HFD) feeding, astrocytes in the ARC proliferate and express functional receptors for leptin,14 adipocyte-derived anorexigenic peptide.15,16 These studies strongly suggest the involvement of astrocytes in the regulation of appetite.
In the hypothalamic arcuate nucleus, AgRP (Agouti-related peptide) neurons are necessary and sufficient to rapidly evoke food intake while POMC (Pro-opiomelanocortin) neurons inhibit feeding.17,18 The electrical activities of the neurons are critical for them to regulate food intake.17,18 Prior studies demonstrate that both of the two types of neurons in the ARC receive synaptic inputs,19,20 and glutamatergic excitatory synaptic inputs are crucial for neuronal firing.19 We thus propose that astrocytes in the ARC could serve as surveyors of hunger states and in turn modulate feeding by rewiring the appetite control circuits in the ARC. In anorexic mice, astrocytes may negatively regulate feeding by reducing synaptic strength at and the firing rate of orexigenic AgRP neuron through release of the inhibitory gliotransmitter(s), such as adenosine. Adenosine in turn inhibits synapse transmission and neuron firing rate by acting on A1 receptors in both pre- and post-synaptic neurons.21,22,23,24 Collectively, we propose that glial cells may actively participate in regulating energy balance by modulating appetite control circuits. It is well recognized that hypothalamic arcuate nucleus is a key brain region that control energy intake and energy expenditure.25,26,27 In our recent studies, we find that food intake is also under the control of astrocytes. For instance, we find that the food intake is reduced by selective chemogenetic activation of astrocytes localized in the mediobasal hypothalamus in mice.28
Collectively, these results indicate that glial cells may also, at least in part, contribute to the development of anorexia nervosa. Furthermore, emerging evidence indicates that appetite is also under the control of “higher level” brain structures, such as cortex and hippocampus, well- recognized brain regions implicated in emotion and cognition.29 For instance, lesion of ventral hippocampus reduces appetite, indicating that ventral hippocampus exerts tonic inhibition on food intake. To fully understand the control of food intake and seek effective clinical therapeutics to treat appetite disorders, such as anorexia nervosa, it is of importance to consider both neuronal and glial processes localized in multiple brain regions.
1. Bergh C, Södersten P. Anorexia nervosa, self-starvation and the reward of stress. Nat. Med.1996; 2(1): 21-22. doi: 10.1038/nm0196-21
2. Støving RK, Hangaard J, Hansen-Nord M, Hagen C. A review of endocrine changes in anorexia nervosa. J Psychiatr Res.1999; 33(2): 139-152. doi: 10.1016/S0022-3956(98)00049-1
3. Song H, Stevens CF, Gage FH. Astroglia induce neurogenesis from adult neural stem cells. Nature. 2002; 417: 39-44. doi: 10.1038/417039a
4. Mauch DH, Nagler K, Schumacher S, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science. 2001; 294: 1354-1357. doi: 10.1126/science.294.5545.1354
5. Ullian EM, Sapperstein SK, Christopherson KS, Barres BA. Control of synapse number by glia. Science. 2001; 291: 657-661. doi: 10.1126/science.291.5504.657
6. Araque A, Carmignoto G, Haydon PG. Dynamic signaling between astrocytes and neurons. Annu. Rev. Physiol. 2001; 63: 795-813. doi: 10.1146/annurev.physiol.63.1.795
7. Jourdain P, Bergersen LH, Bhaukaurally K, et al. Glutamate exocytosis from astrocytes controls synaptic strength. Nat. Neurosci. 2007; 10: 331-339. doi: 10.1038/nn1849
8. Beattie EC, David Stellwagen, Wade Morishita, et al. Control of synaptic strength by glial TNFa. Science. 2002; 295, 2282-85. doi: 10.1126/science.1067859
9. Oliet SHR, Piet R, Poulain DA. Control of glutamate clearance and synaptic efficacy by glial coverage of neurons. Science. 2001; 292: 923-926. doi: 10.1126/science.1059162
10. Daneman R, Zhou L, Kebede AA, Barres BA. Pericytes are required for blood- brain barrier integrity during embryogenesis. Nature. 2010; 466: 562-566. doi: 10.1038/nature09513
11. Schummers J, Yu H, Sur M. Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex. Science. 2008; 320, 1638-1643. doi: 10.1126/science.1156120
12. Gourine AV, Kasymov V, Marina N, et al. Astrocytes control breathing through pH-dependent release of ATP. Science. 2010; 329: 571-575. doi: 10.1126/science.1190721
13. Oliet SH, Piet R, Poulain DA. Control of glutamate clearance and synaptic efficacy by glial coverage pf neurons. Science. 2001; 292: 923-926. doi: 10.1126/science.1059162
14. Thaler JP, Yi C-X, Schur EA, et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 2012; 122: 153-162. doi: 10.1172/JCI59660
15. Pan W, Hsuchou H, Xu C. Astrocytes modulate distribution and neuronal signalling of leptin in the hypothalamus of Obese Avy mice. J. Mol. Neurosci. 2011; 43: 478-484. doi: 10.1007/s12031-010-9470-6
16. Hsuchou H, He Y, Kastin AJ, et al. Obesity induces functional astrocytic leptin receptors in hypothalamus. Brain. 2009; 132: 889-902. doi: 10.1093/brain/awp029
17. Atasoy D, Betley JN, Su HH, Sternson SM. Deconstruction of a neural circuit for hunger. Nature. 2012; 488: 172-177. doi: 10.1038/nature11270
18. Aponte Y, Atasoy D, Sternson SM. AgRP neurons are sufficient to Orchestrate feeding behavior rapidly and without training. Nature Neurosci. 2011; 14: 351-355. doi: 10.1038/nn.2739
19. Yang Y, Atasoy D, Helen HH, Sternson SM. Hunger states switch a flip- flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell. 2011; 146: 992-1003. doi: 10.1016/j.cell.2011.07.039
20. Pinto S, Roseberry AG, Liu H, et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science. 2004; 304: 110-115. doi: 10.1126/science.1089459
21. Stojikovic SS. Purinergic Regulation of Hypothalamo-Pituitary Functions. Trends Endocrinol. Metab. 2009; 20(9): 460-468. doi: 10.1016/j.tem.2009.05.005
22. Chen G, van Den Pol AN. Adenosine Modulation of Calcium Currents and Presynaptic Inhibition of GABA Release in Suprachiasmatic and Arcuate Nucleus Neurons. J. Neurophysiol. 1997; 77(6): 3035-3047. doi: 10.1152/jn.1997.77.6.3035
23. Robertson SJ, Ennion SJ, Evans RJ, Edwards FA. Synaptic P2X receptors. Current Opinion in Neurobiology. 2011; 11: 378-386. doi: 10.1016/S0959-4388(00)00222-1
24. Zhang J-M, Wang H-K, Ye C-Q, et al. ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression. Neuron. 2003; 40: 971-982. doi: 10.1016/S0896-6273(03)00717-7
25. Williams KW, Elmquist JK. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat Neurosci. 2012; 15: 1350-1355. doi: 10.1038/nn.3217
26. Berthoud HR. Metabolic and hedonic drives in the neural control of appetite: who is the boss? Curr Opin Neurobiol. 2011; 21: 888-896. doi: 10.1016/j.conb.2011.09.004
27. Shin AC, Zheng H, Berthoud HR. An expanded view of energy homeostasis: neural integration of metabolic, cognitive, and emotional drives to eat. Physiol Behav. 2009; 97: 572-580. doi: 10.1016/j.physbeh.2009.02.010
28. Yang L, Qi Y, Yang Y. Astrocytes control food intake by inhibiting AgRP neurons via A1 receptors. Cell Rep. 2015; 11: 798-807. doi: 10.1016/j.celrep.2015.04.002
29. Davidson TL, Chan K, Jarrard LE, Kanoski SE, Clegg DJ, Benoi SC. Contributions of the hippocampus and medial prefrontal cortex to energy and body weight regulation. Hippocampus. 2009; 19: 235-252 doi: 10.1002/hipo.20499
© 2014-2024 I Openventio Publisher is licensed by Creative Commons Attribution, unless otherwise indicated.
