Kumar, Marta Porniece, Cremer, Anna Lena, Klemm, Paul, Steuernagel, Lukas ORCID: 0000-0003-0043-1436, Sundaram, Sivaraj, Jais, Alexander, Hausen, A. Christine, Tao, Jenkang, Secher, Anna, Pedersen, Thomas Askov, Schwaninger, Markus, Wunderlich, F. Thomas, Lowell, Bradford B., Backes, Heiko and Bruening, Jens C. (2021). Insulin signalling in tanycytes gates hypothalamic insulin uptake and regulation of AgRP neuron activity. Nat. Metab., 3 (12). S. 1662 - 1695. BERLIN: NATURE PORTFOLIO. ISSN 2522-5812

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Abstract

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 increment 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 increment 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 increment 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kumar, Marta PornieceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cremer, Anna LenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klemm, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steuernagel, LukasUNSPECIFIEDorcid.org/0000-0003-0043-1436UNSPECIFIED
Sundaram, SivarajUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jais, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hausen, A. ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tao, JenkangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Secher, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pedersen, Thomas AskovUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwaninger, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wunderlich, F. ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lowell, Bradford B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Backes, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruening, Jens C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-598477
DOI: 10.1038/s42255-021-00499-0
Journal or Publication Title: Nat. Metab.
Volume: 3
Number: 12
Page Range: S. 1662 - 1695
Date: 2021
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 2522-5812
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
BLOOD-BRAIN-BARRIER; AGOUTI-RELATED PEPTIDE; CAUSES GHRELIN RESISTANCE; EXPRESSING NEURONS; LEPTIN RESISTANCE; BODY-WEIGHT; GLUCOSE; RECEPTOR; OBESITY; CELLSMultiple languages
Endocrinology & MetabolismMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59847

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