Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain
- PMID: 24506870
- PMCID: PMC3936883
- DOI: 10.1016/j.cmet.2013.12.015
Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain
Abstract
Leptin secreted by adipocytes acts on the brain to reduce food intake by regulating neuronal activity in the mediobasal hypothalamus (MBH). Obesity is associated with resistance to high circulating leptin levels. Here, we demonstrate that peripherally administered leptin activates its receptor (LepR) in median eminence tanycytes followed by MBH neurons, a process requiring tanycytic ERK signaling and the passage of leptin through the cerebrospinal fluid. In mice lacking the signal-transducing LepRb isoform or with diet-induced obesity, leptin taken up by tanycytes accumulates in the median eminence and fails to reach the MBH. Triggering ERK signaling in tanycytes with EGF reestablishes leptin transport, elicits MBH neuron activation and energy expenditure in obese animals, and accelerates the restoration of leptin sensitivity upon the return to a normal-fat diet. ERK-dependent leptin transport by tanycytes could thus play a critical role in the pathophysiology of leptin resistance, and holds therapeutic potential for treating obesity.
Copyright © 2014 Elsevier Inc. All rights reserved.
Figures
![Figure 1](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3936883/bin/nihms-554624-f0001.gif)
![Figure 2](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3936883/bin/nihms-554624-f0002.gif)
![Figure 3](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3936883/bin/nihms-554624-f0003.gif)
![Figure 4](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3936883/bin/nihms-554624-f0004.gif)
Comment in
-
Hypothalamic tanycytes: gatekeepers to metabolic control.Cell Metab. 2014 Feb 4;19(2):173-5. doi: 10.1016/j.cmet.2014.01.008. Cell Metab. 2014. PMID: 24506860
Similar articles
-
Leptin brain entry via a tanycytic LepR-EGFR shuttle controls lipid metabolism and pancreas function.Nat Metab. 2021 Aug;3(8):1071-1090. doi: 10.1038/s42255-021-00432-5. Epub 2021 Aug 2. Nat Metab. 2021. PMID: 34341568 Free PMC article.
-
Glial Endozepines Reverse High-Fat Diet-Induced Obesity by Enhancing Hypothalamic Response to Peripheral Leptin.Mol Neurobiol. 2020 Aug;57(8):3307-3333. doi: 10.1007/s12035-020-01944-z. Epub 2020 Jun 9. Mol Neurobiol. 2020. PMID: 32519243
-
Tanycyte ablation in the arcuate nucleus and median eminence increases obesity susceptibility by increasing body fat content in male mice.Glia. 2020 Oct;68(10):1987-2000. doi: 10.1002/glia.23817. Epub 2020 Mar 16. Glia. 2020. PMID: 32173924 Free PMC article.
-
What is the physiological role of hypothalamic tanycytes in metabolism?Am J Physiol Regul Integr Comp Physiol. 2021 Jun 1;320(6):R994-R1003. doi: 10.1152/ajpregu.00296.2020. Epub 2021 Apr 7. Am J Physiol Regul Integr Comp Physiol. 2021. PMID: 33826442 Review.
-
The role of tanycytes in hypothalamic glucosensing.J Cell Mol Med. 2015 Jul;19(7):1471-82. doi: 10.1111/jcmm.12590. Epub 2015 Jun 17. J Cell Mol Med. 2015. PMID: 26081217 Free PMC article. Review.
Cited by
-
The Pattern of GH Action in the Mouse Brain.Endocrinology. 2024 May 27;165(7):bqae057. doi: 10.1210/endocr/bqae057. Endocrinology. 2024. PMID: 38728240
-
Effects of a Diabetic Microenvironment on Neurodegeneration: Special Focus on Neurological Cells.Brain Sci. 2024 Mar 15;14(3):284. doi: 10.3390/brainsci14030284. Brain Sci. 2024. PMID: 38539672 Free PMC article. Review.
-
A brainstem-hypothalamus neuronal circuit reduces feeding upon heat exposure.Nature. 2024 Apr;628(8009):826-834. doi: 10.1038/s41586-024-07232-3. Epub 2024 Mar 27. Nature. 2024. PMID: 38538787 Free PMC article.
-
An analogue of the Prolactin Releasing Peptide reduces obesity and promotes adult neurogenesis.EMBO Rep. 2024 Jan;25(1):351-377. doi: 10.1038/s44319-023-00016-2. Epub 2023 Dec 20. EMBO Rep. 2024. PMID: 38177913 Free PMC article.
-
Metabolic control of puberty: 60 years in the footsteps of Kennedy and Mitra's seminal work.Nat Rev Endocrinol. 2024 Feb;20(2):111-123. doi: 10.1038/s41574-023-00919-z. Epub 2023 Dec 4. Nat Rev Endocrinol. 2024. PMID: 38049643 Review.
References
-
- Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000;62:413–437. - PubMed
-
- Briggs DI, Enriori PJ, Lemus MB, Cowley MA, Andrews ZB. Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. Endocrinology. 2010;151:4745–4755. - PubMed
-
- Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995;269:546–549. - PubMed
-
- Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet. 1996;348:159–161. - PubMed
-
- Conductier G, Brau F, Viola A, Langlet F, Ramkumar N, Dehouck B, Lemaire T, Chapot R, Lucas L, Rovère C, et al. Melanin-concentrating hormone regulates beat frequency of ependymal cilia and ventricular volume. Nat Neurosci. 2013;16:845–847. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous