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

• Published in: Nature metabolism Vol. 3; no. 12; pp. 1662 - 1679
• Main Authors: Porniece Kumar, Marta, Cremer, Anna Lena, Klemm, Paul, Steuernagel, Lukas, Sundaram, Sivaraj, Jais, Alexander, Hausen, A. Christine, Tao, Jenkang, Secher, Anna, Pedersen, Thomas Åskov, Schwaninger, Markus, Wunderlich, F. Thomas, Lowell, Bradford B., Backes, Heiko, Brüning, Jens C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2021
• Subjects: 14/19; 14/32; 14/63; 38/91; 59/78; 631/378/1341; 631/378/1488/1562; 631/443/319; 631/443/319/367/1562; 64/60; 82/51; 96/35; 96/63; Agouti-Related Protein - chemistry; Agouti-Related Protein - metabolism; Animals; Biomarkers; Biomedical and Life Sciences; Blood-Brain Barrier - metabolism; Calcium; Energy Metabolism; Ependymoglial Cells - metabolism; Fluorescent Antibody Technique; Ghrelin - metabolism; Glucose - metabolism; Hypothalamus - metabolism; Insulin - metabolism; Insulin Resistance; Life Sciences; Mice; Mice, Knockout; Mitochondria - metabolism; Models, Biological; Neurons - metabolism; Peptide Fragments - metabolism; Receptor, Insulin - metabolism; Signal Transduction
• ISSN: 2522-5812; 2522-5812
• DOI: 10.1038/s42255-021-00499-0

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.
Tanycytic insulin receptors allow insulin access to the hypothalamic arcuate nucleus and are relevant for driving AgRP neuronal activity in response to feeding.