Abstract
To test the hypothesis that astrocytic leptin signaling induces an overall potentiation of the neuronal response to leptin, we generated a new line of astrocyte-specific leptin receptor knockout (ALKO-Δ1) mice in which no leptin receptor is expressed in astrocytes. Corresponding to cell-specific Cre recombinase expression in hypothalamic astrocytes but not neurons, this new strain of ALKO mice had attenuated pSTAT3 signaling in the arcuate nucleus of the hypothalamus 30 min after intracerebroventricular delivery of leptin. In response to high-fat diet for 2 months, the ALKO mice showed a greater increase of percent fat and blood leptin concentration. This coincided with a mild reactive gliosis in the hypothalamus. Overall, the absence of leptin receptors in astrocytes attenuated hypothalamic pSTAT3 signaling, induced a mild reactive morphology, and promoted the development of diet-induced obesity. We conclude that leptin signaling in astrocytes is essential for the homeostasis of neuroendocrine regulation in obesity.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM (1996) Leptin enters the brain by a saturable system independent of insulin. Peptides 17:305–311
Casper KB, Jones K, McCarthy KD (2007) Characterization of astrocyte-specific conditional knockouts. Genesis 45:292–299
Chow LM, Zhang J, Baker SJ (2008) Inducible Cre recombinase activity in mouse mature astrocytes and adult neural precursor cells. Transgenic Res 17:919–928
Cohen P, Zhao C, Cai X, Montez JM, Rohani SC, Feinstein P, Mombaerts P, Friedman JM (2001) Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest 108:1113–1121
Garcia AD, Doan NB, Imura T, Bush TG, Sofroniew MV (2004) GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat Neurosci 7:1233–1241
He Y, Kastin AJ, Hsuchou H, Pan W (2009) The Cdk5/p35 kinases modulate leptin-induced STAT3 signaling. J Mol Neurosci 39:49–58
Hsuchou H, He Y, Kastin AJ, Tu H, Markadakis EN, Rogers RC, Fossier PB, Pan W (2009) Obesity induces functional astrocytic leptin receptors in hypothalamus. Brain 132:889–902
Hsuchou H, Kastin AJ, Tu H, Markadakis EN, Stone KP, Wang Y, Heymsfield SB, Chua SC Jr, Obici S, Magrisso IJ, Pan W (2011) Effects of cell type-specific leptin receptor mutation on leptin transport across the BBB. Peptides 32:1392–1399
Hsuchou H, Wang Y, Cornelissen-Guillaume GG, Kastin AJ, Jang E, Halberg F, Pan W (2013) Diminished leptin signaling can alter circadian rhythm of metabolic activity and feeding. J Appl Physiol 115:995–1003
Jayaram B, Pan W, Wang Y, Hsuchou H, Mace A, Cornélissen GG, Mishra PK, Koza RA, Kastin AJ (2013) Astrocytic leptin receptor knockout mice show partial rescue of leptin resistance in diet-induced obesity. J Appl Physiol 114:734–741
Kowalski TJ, Liu SM, Leibel RL, Chua SC Jr (2001) Transgenic complementation of leptin-receptor deficiency. I. Rescue of the obesity/diabetes phenotype of LEPR-null mice expressing a LEPR-B transgene. Diabetes 50:425–435
McMinn JE, Liu SM, Dragatsis I, Dietrich P, Ludwig T, Eiden S, Chua SC Jr (2004) An allelic series for the leptin receptor gene generated by CRE and FLP recombinase. Mamm Genome 15:677–685
McMinn JE, Liu SM, Liu H, Dragatsis I, Dietrich P, Ludwig T, Boozer CN, Chua SC Jr (2005) Neuronal deletion of Lepr elicits diabesity in mice without affecting cold tolerance or fertility. Am J Physiol Endocrinol Metab 289:E403–E411
Pan W, Kastin AJ (2007) Mahogany, blood-brain barrier, and fat mass surge in Avy mice. Int J Obes 31:1030–1032
Pan W, Hsuchou H, He Y, Sakharkar A, Cain C, Yu C, Kastin AJ (2008a) Astrocyte leptin receptor (ObR) and leptin transport in adult-onset obese mice. Endocrinology 149:2798–2806
Pan W, Hsuchou H, Tu H, Kastin AJ (2008b) Developmental changes of leptin receptors in cerebral microvessels: unexpected relation to leptin transport. Endocrinology 149:877–885
Pan W, Hsuchou H, He Y, Kastin AJ (2011a) The astroglial leptin receptors and obesity. In: Preedy VR (ed) Modern insights into disease—from molecules to man: adipokines. Science Publishers, Enfield, pp 185–196
Pan W, Hsuchou H, Xu CL, Wu X, Bouret SG, Kastin AJ (2011b) Astrocytes modulate distribution and neuronal signaling of leptin in the hypothalamus of obese Avy mice. J Mol Neurosci 43:478–484
Pan W, Hsuchou H, Cornelissen-Guillaume GG, Jayaram B, Wang Y, Tu H, Halberg F, Wu X, Chua SC Jr, Kastin AJ (2012a) Endothelial leptin receptor mutation provides partial resistance to diet-induced obesity. J Appl Physiol 112:1410–1418
Pan W, Hsuchou H, Jayaram B, Khan RS, Huang EYK, Wu X, Chen C, Kastin AJ (2012b) Leptin action on non-neuronal cells in the CNS: potential clinical implications. Ann N Y Acad Sci 1264:64–71
Philo J, Talvenheimo J, Wen J, Rosenfeld R, Welcher A, Arakawa T (1994) Interactions of neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), and the NT-3·BDNF heterodimer with the extracellular domains of the TrkB and TrkC receptors. J Biol Chem 269:27840–27846
Tu H, Kastin AJ, Hsuchou H, Pan W (2008) Soluble receptor inhibits leptin transport. J Cell Physiol 214:301–305
Tu H, Hsuchou H, Kastin AJ, Wu X, Pan W (2010) Unique leptin trafficking by a tailless receptor. FASEB J 24:2281–2291
Wang Y, He J, Kastin AJ, Hsuchou H, Pan W (2013) Hypersomnolence and reduced activity in pan-leptin receptor knockout mice. J Mol Neurosci 51:1038–1045
Yang G, Ge H, Boucher A, Yu X, Li C (2004) Modulation of direct leptin signalling by soluble leptin receptor. Mol Endocrinol 18:1354–1362
Acknowledgments
Grant support was provided by NIH (DK54880, DK92245, NS62291). Cryosectioning was performed in the Cell Biology and Cell Imaging Core Facility with service charge.
Conflict of Interest
All authors have nothing to declare.
Author information
Authors and Affiliations
Corresponding author
Additional information
Wang and Hsuchou made equal contributions and are co-first authors.
Rights and permissions
About this article
Cite this article
Wang, Y., Hsuchou, H., He, Y. et al. Role of Astrocytes in Leptin Signaling. J Mol Neurosci 56, 829–839 (2015). https://doi.org/10.1007/s12031-015-0518-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-015-0518-5