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

Autor: Porniece Kumar M; Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany., Cremer AL; Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany., Klemm P; Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany., Steuernagel L; Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany., Sundaram S; Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany., Jais A; Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany.; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany., Hausen AC; Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany., Tao J; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.; Program in Neuroscience, Harvard Medical School, Boston, MA, USA., Secher A; Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark., Pedersen TÅ; Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark., Schwaninger M; Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany., Wunderlich FT; Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany., Lowell BB; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.; Program in Neuroscience, Harvard Medical School, Boston, MA, USA., Backes H; Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany., Brüning JC; Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany. bruening@sf.mpg.de.; Policlinic for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Cologne, Germany. bruening@sf.mpg.de.; National Center for Diabetes Research (DZD), Neuherberg, Germany. bruening@sf.mpg.de.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2021 Dec; Vol. 3 (12), pp. 1662-1679. Date of Electronic Publication: 2021 Dec 20.
DOI: 10.1038/s42255-021-00499-0
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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