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Leptin signaling in neurotensin neurons involves STAT, MAP kinases ERK1/2, and p38 through c-Fos and ATF1

Hong Cui^*, Fang Cai^* and Denise D. Belsham^*,,1

Departments of
^* Physiology,

Obstetrics and Gynaecology, and Medicine, University of Toronto and Division of Cellular and Molecular Biology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

¹Correspondence: Department of Physiology, University of Toronto, Medical Sciences Bldg. 3247A, 1 King’s College Cir., Toronto, ON, Canada M5S 1A8. E-mail: d.belsham{at}utoronto.ca

ABSTRACT

The adipokine leptin signals energy status to the hypothalamus, which triggers a network of neuropeptide responses. Each hypothalamic cell type expresses a unique complement of neuropeptides, receptors, and second messengers; thus each likely responds specifically to peripheral hormones. We describe here the analysis of leptin signaling in a clonal population of mouse neurotensin (NT) -expressing hypothalamic neurons, N-39. Leptin induced phosphorylation of STAT3 and MAPK ERK1/2, but not the downstream effector of PI3K, Akt, and also induced c-Fos protein. We found activation of p38 MAPK by leptin, accompanied by phosphorylation of its downstream effector ATF-1. Phosphorylation of ATF-1 is blocked by the p38 MAPK inhibitor SB 203580. We linked this signaling directly to NT transcription. Protein binding analysis indicates that both ATF-1 and c-Fos are capable of binding to the mouse NT/N gene predominantly at physiological or high concentrations of leptin. The evidence indicates activation of distinct leptin signal transduction pathways that directly result in changes in NT gene expression and links these specific neurons to the control of energy homeostasis.—Cui, H., Cai, F., Belsham, D. D. Leptin signaling in neurotensin neurons involves STAT, MAP kinases ERK1/2, and p38 through c-Fos and ATF1.

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