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Adipokine Gene Expression in a Novel Hypothalamic Neuronal Cell Line: Resistin-Dependent Regulation of Fasting-Induced Adipose Factor and SOCS-3

Brown R.a, b · Imran S.A.a, c · Belsham D.D.d · Ur E.a, c · Wilkinson M.a-c
aDepartments of Obstetrics and Gynaecology, bPhysiology and Biophysics and cDivision of Endocrinology and Metabolism, Faculty of Medicine, Dalhousie University, Halifax, N.S., and dDepartments of Physiology, Obstetrics and Gynaecology, and Medicine, University of Toronto, Toronto, Ont., Canada Neuroendocrinology 2007;85:232–241 (DOI:10.1159/000104248)

Abstract

Adipokines such as leptin, resistin, and fasting-induced adipose factor (FIAF) are secreted by adipocytes, but their expression is also detectable in the brain and pituitary. The role of central adipokines remains elusive, but we speculate that they may modulate those hypothalamic signaling pathways that control energy homeostasis. Here we describe experiments to test this in which we exploited a novel hypothalamic neuronal cell line (N-1) that expresses a variety of neuropeptides and receptors that are known to be implicated in appetite regulation. Using real-time RT-PCR, we confirmed that N-1 neurons express resistin (rstn) and fiaf, as well as suppressor of cytokine signaling-3 (socs-3), a feedback inhibitor of leptin signaling. Treating N-1 cells with recombinant resistin (200 ng/ml, 30 min) reduced both fiaf (25%, p < 0.005) and socs-3 (29%, p < 0.005) mRNA levels, and similar reductions in fiaf (40%, p < 0.001) and socs-3 (25%, p < 0.001) resulted following the overexpression of resistin. Conversely, when RNA interference (RNAi) was used to reduce endogenous rstn levels (–60%, p < 0.005), fiaf and socs-3 expression was increased (46 and 65% respectively, p < 0.005). A similar reduction in rstn mRNA was achieved using RNAi in differentiated 3T3-L1 adipocytes, and this manipulation also reduced fiaf and socs-3 expression (–53, –21 and –20% respectively, p < 0.005). In contrast, although RNAi successfully reduced fiaf mRNA by 50% (p < 0.001) in N-1 cells and 40% (p < 0.001) in 3T3-L1 cells, there was no effect on rstn or socs-3 mRNA. These data suggest that resistin exerts a novel autocrine/paracrine control over fiaf and socs-3 expression in both 3T3-L1 adipocytes and N-1 neurons. Such a mechanism could be part of the central feedback system that modulates the effects of adipokines, and other adiposity signals, implicated in hypothalamic energy homeostasis. However, it remains to be determined whether these in vitro results can be translated to the control of adipokine expression in brain and adipose tissue.

 

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