Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin - PubMed (original) (raw)
. 2013 Oct 17;3(1):64-72.
doi: 10.1016/j.molmet.2013.10.001. eCollection 2014 Feb.
Chen Liu 1, Aki Uchida 1, Jen-Chieh Chuang 1, Angela Walker 2, Tiemin Liu 1, Sherri Osborne-Lawrence 1, Brittany L Mason 1, Christina Mosher 1, Eric D Berglund 1, Joel K Elmquist 1, Jeffrey M Zigman 2
Affiliations
- PMID: 24567905
- PMCID: PMC3929914
- DOI: 10.1016/j.molmet.2013.10.001
Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin
Qian Wang et al. Mol Metab. 2013.
Abstract
The hormone ghrelin stimulates eating and helps maintain blood glucose upon caloric restriction. While previous studies have demonstrated that hypothalamic arcuate AgRP neurons are targets of ghrelin, the overall relevance of ghrelin signaling within intact AgRP neurons is unclear. Here, we tested the functional significance of ghrelin action on AgRP neurons using a new, tamoxifen-inducible AgRP-CreER(T2) transgenic mouse model that allows spatiotemporally-controlled re-expression of physiological levels of ghrelin receptors (GHSRs) specifically in AgRP neurons of adult GHSR-null mice that otherwise lack GHSR expression. AgRP neuron-selective GHSR re-expression partially restored the orexigenic response to administered ghrelin and fully restored the lowered blood glucose levels observed upon caloric restriction. The normalizing glucoregulatory effect of AgRP neuron-selective GHSR expression was linked to glucagon rises and hepatic gluconeogenesis induction. Thus, our data indicate that GHSR-containing AgRP neurons are not solely responsible for ghrelin's orexigenic effects but are sufficient to mediate ghrelin's effects on glycemia.
Keywords: ARC, arcuate nucleus; AgRP; AgRP, Agouti-related peptide; BAC, bacterial artificial chromosome; Blood glucose homeostasis; CNS, central nervous system; DG, dentate gyrus; DVC, dorsal vagal complex; Food intake; Foxo1, Forkhead box protein O1; G6p, glucose-6 phosphatase; GABA, gamma-aminobutyric acid; GHRH, Growth-hormone-releasing hormone; GHSR, growth hormone secretagogue receptor, ghrelin receptor; GOAT, ghrelin O-acyltransferase; Ghrelin; Ghrelin receptor; Hnf4α, hepatocyte nuclear factor 4α; NAc, nucleus accumbens; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; Pcx, pyruvate carboxylase; Pepck, phosphoenolpyruvate carboxykinase; Phox2b, paired-like homeobox 2b; VGAT, vesicular GABA transporter; VTA, ventral tegmental area.
Figures
Figure 1
Generation of a mouse model with selective GHSR expression in AgRP neurons. (A) Schematic diagram of the derivation of AgRP-CreERT2 mice. The coding sequence of AgRP, found in exons III and IV, was replaced by the coding sequence of a CreERT2 fusion protein. (B) The desired spatiotemporal expression of cre recombinase in AgRP-CreERT2 mice was validated by a cross to Rosa26-lox-STOP-lox-tdTomato reporter mice; tdTomato expression (white neurons) was detected selectively in the ARC of tamoxifen (TM)-injected mice but not in vehicle-injected mice (_n_=3 per group; representative photomicrographs shown; scale bar 100 µm). (C) Ghsr mRNA is expressed in the ARC and VTA of wild-type and wild-type/AgRP-CreERT2 mice but not in GHSR-null animals as expected, as determined using qRT-PCR; tamoxifen-induced Cre-mediated re-expression of Ghsr mRNA is only observed in the ARC of GHSR-null/AgRP-CreERT2 mice, but not other regions (mean±SEM, _n_=4–6 per group).
Figure 2
GHSR-expressing AgRP neurons partially mediate ghrelin's orexigenic action. (A) Ghrelin-induced 2 h-food intake is partially restored in male GHSR-null/AgRP-CreERT2 mice with tamoxifen administration (mean±SEM, _n_=7–12 per group). (B) Ghrelin-induced 2 h-food intake is also partially restored in female GHSR-null/AgRP-CreERT2 mice with tamoxifen administration (mean±SEM, _n_=7 per group). (C) Ghrelin-induced acute food intake is not restored in male GHSR-null/AgRP-CreERT2 mice with vehicle injection (mean±SEM, _n_=3–7 per group). (D) Induction of c-fos (dark orange cell bodies) in response to ghrelin in ARC of wild-type/AgRP-CreERT2 and GHSR-null/AgRP-CreERT2 mice but not in GHSR-null mice or in response to saline (_n_=3 per group, representative photomicrographs shown; scale bar 100 µm). *P<0.05; **P<0.01; ***P<0.001.
Figure 3
GHSR-expressing AgRP neurons mediate the glucoregulatory action of ghrelin. (A) Fasting blood glucose levels are restored to wild-type levels in male GHSR-null/AgRP-CreERT2 mice with tamoxifen administration (mean±SEM, _n_=7–12 per group). (B) Fasting blood glucose levels are also restored to wild-type levels in female GHSR-null/AgRP-CreERT2 mice with tamoxifen administration (mean±SEM, _n_=7 per group). (C) Fasting blood glucose levels are not restored in male GHSR-null/AgRP-CreERT2 mice with vehicle (Veh) injection (mean±SEM, _n_=3–7 per group). (D) Blood glucose levels during severe calorie restriction are restored to wild-type levels in male tamoxifen-treated GHSR-null/AgRP-CreERT2 mice (mean±SEM, _n_=5–12 per group). *P<0.05; **P<0.01; ***P<0.001.
Figure 4
AgRP neuronal expression of GHSR restores fasting glucagon levels and increases fasting-induced liver gluconeogenesis. (A) Fasting glucagon levels are restored in male GHSR-null/AgRP-CreERT2 mice with tamoxifen administration (mean±SEM, _n_=8–14 per group). (B) Fasting insulin levels are similar for all genotypes (mean±SEM, _n_=8–14 per group). (C) Expression of hepatic gluconeogenesis genes after overnight fasting, as determined using qRT-PCR, is increased in male GHSR-null/AgRP-CreERT2 mice with tamoxifen injection (mean±SEM, _n_=4–8 per group). ∧_P_=0.07; *P<0.05.
Similar articles
- Ghrelin receptors mediate ghrelin-induced excitation of agouti-related protein/neuropeptide Y but not pro-opiomelanocortin neurons.
Chen SR, Chen H, Zhou JJ, Pradhan G, Sun Y, Pan HL, Li DP. Chen SR, et al. J Neurochem. 2017 Aug;142(4):512-520. doi: 10.1111/jnc.14080. Epub 2017 Jun 21. J Neurochem. 2017. PMID: 28547758 - Ghrelin's orexigenic action in the lateral hypothalamic area involves indirect recruitment of orexin neurons and arcuate nucleus activation.
Barrile F, Cassano D, Fernandez G, De Francesco PN, Reynaldo M, Cantel S, Fehrentz JA, Donato J Jr, Schiöth HB, Zigman JM, Perello M. Barrile F, et al. Psychoneuroendocrinology. 2023 Oct;156:106333. doi: 10.1016/j.psyneuen.2023.106333. Epub 2023 Jul 13. Psychoneuroendocrinology. 2023. PMID: 37454647 Free PMC article. - Fasting induces remodeling of the orexigenic projections from the arcuate nucleus to the hypothalamic paraventricular nucleus, in a growth hormone secretagogue receptor-dependent manner.
Cabral A, Fernandez G, Tolosa MJ, Rey Moggia Á, Calfa G, De Francesco PN, Perello M. Cabral A, et al. Mol Metab. 2020 Feb;32:69-84. doi: 10.1016/j.molmet.2019.11.014. Epub 2019 Dec 16. Mol Metab. 2020. PMID: 32029231 Free PMC article. - The controversial role of the vagus nerve in mediating ghrelin's actions: gut feelings and beyond.
Perelló M, Cornejo MP, De Francesco PN, Fernandez G, Gautron L, Valdivia LS. Perelló M, et al. IBRO Neurosci Rep. 2022 Mar 12;12:228-239. doi: 10.1016/j.ibneur.2022.03.003. eCollection 2022 Jun. IBRO Neurosci Rep. 2022. PMID: 35746965 Free PMC article. Review. - Regulation of Agouti-Related Protein and Pro-Opiomelanocortin Gene Expression in the Avian Arcuate Nucleus.
Boswell T, Dunn IC. Boswell T, et al. Front Endocrinol (Lausanne). 2017 Apr 13;8:75. doi: 10.3389/fendo.2017.00075. eCollection 2017. Front Endocrinol (Lausanne). 2017. PMID: 28450851 Free PMC article. Review.
Cited by
- microRNA-33 controls hunger signaling in hypothalamic AgRP neurons.
Price NL, Fernández-Tussy P, Varela L, Cardelo MP, Shanabrough M, Aryal B, de Cabo R, Suárez Y, Horvath TL, Fernández-Hernando C. Price NL, et al. Nat Commun. 2024 Mar 8;15(1):2131. doi: 10.1038/s41467-024-46427-0. Nat Commun. 2024. PMID: 38459068 Free PMC article. - Identification of AgRP cells in the murine hindbrain that drive feeding.
Bachor TP, Hwang E, Yulyaningsih E, Attal K, Mifsud F, Pham V, Vagena E, Huarcaya R, Valdearcos M, Vaisse C, Williams KW, Emmerson PJ, Xu AW. Bachor TP, et al. Mol Metab. 2024 Feb;80:101886. doi: 10.1016/j.molmet.2024.101886. Epub 2024 Jan 19. Mol Metab. 2024. PMID: 38246589 Free PMC article. - Crosstalk between Gut Sensory Ghrelin Signaling and Adipose Tissue Sympathetic Outflow Regulates Metabolic Homeostasis.
Alex Thomas M, Cui X, Artinian LR, Cao Q, Jing J, Silva FC, Wang S, Zigman JM, Sun Y, Shi H, Xue B. Alex Thomas M, et al. bioRxiv [Preprint]. 2023 Nov 27:2023.11.25.568689. doi: 10.1101/2023.11.25.568689. bioRxiv. 2023. PMID: 38076894 Free PMC article. Preprint. - The Coding Logic of Interoception.
Wang RL, Chang RB. Wang RL, et al. Annu Rev Physiol. 2024 Feb 12;86:301-327. doi: 10.1146/annurev-physiol-042222-023455. Epub 2023 Dec 7. Annu Rev Physiol. 2024. PMID: 38061018 Free PMC article. Review. - Ghrelin-responsive mediobasal hypothalamic neurons mediate exercise-associated food intake and exercise endurance.
Singh O, Ogden SB, Varshney S, Shankar K, Gupta D, Paul S, Osborne-Lawrence S, Richard CP, Metzger NP, Lawrence C, Leon Mercado L, Zigman JM. Singh O, et al. JCI Insight. 2023 Dec 22;8(24):e172549. doi: 10.1172/jci.insight.172549. JCI Insight. 2023. PMID: 37962950 Free PMC article.
References
- Kojima M., Hosoda H., Date Y., Nakazato M., Matsuo H., Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656–660. - PubMed
- Cummings D.E., Purnell J.Q., Frayo R.S., Schmidova K., Wisse B.E., Weigle D.S. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50:1714–1719. - PubMed
Grants and funding
- R01 DK088423/DK/NIDDK NIH HHS/United States
- R37 DK053301/DK/NIDDK NIH HHS/United States
- K01 DK098317/DK/NIDDK NIH HHS/United States
- R01 DK071320/DK/NIDDK NIH HHS/United States
- T32 DK007307/DK/NIDDK NIH HHS/United States
- P01 DK088761/DK/NIDDK NIH HHS/United States
- T32 DA007290/DA/NIDA NIH HHS/United States
- R01 DA024680/DA/NIDA NIH HHS/United States
- R01 MH085298/MH/NIMH NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous