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Porniece Kumar, M.* ; Cremer, A.L.* ; Klemm, P.* ; Steuernagel, L.* ; Sundaram, S.* ; Jais, A. ; Hausen, A.C.* ; Tao, J.* ; Secher, A.* ; Pedersen, T.* ; Schwaninger, M.* ; Wunderlich, F.T.* ; Lowell, B.B.* ; Backes, H.* ; Brüning, J.C.*

Insulin signalling in tanycytes gates hypothalamic insulin uptake and regulation of AgRP neuron activity.

Nat. Metab. 3, 1662-1679 (2021)

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Insulin acts on neurons and glial cells to regulate systemic glucose metabolism and feeding. However, the mechanisms of insulin access in discrete brain regions are incompletely defined. Here we show that insulin receptors in tanycytes, but not in brain endothelial cells, are required to regulate insulin access to the hypothalamic arcuate nucleus. Mice lacking insulin receptors in tanycytes (IR^∆Tan mice) exhibit systemic insulin resistance, while displaying normal food intake and energy expenditure. Tanycytic insulin receptors are also necessary for the orexigenic effects of ghrelin, but not for the anorexic effects of leptin. IR^∆Tan mice exhibit increased agouti-related peptide (AgRP) neuronal activity, while displaying blunted AgRP neuronal adaptations to feeding-related stimuli. Lastly, a highly palatable food decreases tanycytic and arcuate nucleus insulin signalling to levels comparable to those seen in IR^∆Tan mice. These changes are rooted in modifications of cellular stress responses and of mitochondrial protein quality control in tanycytes. Conclusively, we reveal a critical role of tanycyte insulin receptors in gating feeding-state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Blood-brain-barrier; Agouti-related Peptide; Causes Ghrelin Resistance; Expressing Neurons; Leptin Resistance; Body-weight; Glucose; Receptor; Obesity; Cells

ISSN (print) / ISBN 2522-5812

e-ISSN 2522-5812

Journal Nature metabolism

Quellenangaben Volume: 3, Issue: 12, Pages: 1662-1679

Publisher Springer

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)

Grants NIDDK NIH HHS