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Leptin receptor-expressing pericytes mediate access of hypothalamic feeding centers to circulating leptin

Authors: Butiaeva, Liliia I.; Slutzki, Tal; Swick, Hannah E.; Bourguignon, Clément; Robins, Sarah C.; Liu, Xiaohong; Storch, Kai-Florian; Kokoeva, Maia V.

Online: https://www.sciencedirect.com/science/article/pii/S1550413121002680

Issue: Cell Metab. 2021 Jul 6;33(7):1433-1448.e5.

Abstract

Knowledge of how leptin receptor (LepR) neurons of the mediobasal hypothalamus (MBH) access circulating leptin is still rudimentary. Employing intravital microscopy, we found that almost half of the blood-vessel-enwrapping pericytes in the MBH express LepR. Selective disruption of pericytic LepR led to increased food intake, increased fat mass, and loss of leptin-dependent signaling in nearby LepR neurons. When delivered intravenously, fluorescently tagged leptin accumulated at hypothalamic LepR pericytes, which was attenuated upon pericyte-specific LepR loss. Because a paracellular tracer was also preferentially retained at LepR pericytes, we pharmacologically targeted regulators of inter-endothelial junction tightness and found that they affect LepR neuronal signaling and food intake. Optical imaging in MBH slices revealed a long-lasting, tonic calcium increase in LepR pericytes in response to leptin, suggesting pericytic contraction and vessel constriction. Together, our data indicate that LepR pericytes facilitate localized, paracellular blood-brain barrier leaks, enabling MBH LepR neurons to access circulating leptin.