Amylin Selectively Signals Onto POMC Neurons in the Arcuate Nucleus of the Hypothalamus

Overview

Journal Diabetes

Specialty Endocrinology

Date 2018 Feb 23

PMID 29467172

Citations 17

Authors

Thomas A Lutz

Bernd Coester

Lynda Whiting

Ambrose A Dunn-Meynell

Christina N Boyle

Sebastien G Bouret

Barry E Levin

Christelle Le Foll

Affiliations

Soon will be listed here.

Abstract

Amylin phosphorylates ERK (p-ERK) in the area postrema to reduce eating and synergizes with leptin to phosphorylate STAT3 in the arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei to reduce food intake and body weight. The current studies assessed potential amylin and amylin-leptin ARC/VMN interactions on ERK signaling and their roles in postnatal hypothalamic pathway development. In amylin knockout mice, the density of agouti-related protein (AgRP)-immunoreactive (IR) fibers in the hypothalamic paraventricular nucleus (PVN) was increased, while the density of α-melanocyte-stimulating hormone (αMSH) fibers was decreased. In mice deficient of the amylin receptor components RAMP1/3, both AgRP and αMSH-IR fiber densities were decreased, while only αMSH-IR fiber density was decreased in rats injected neonatally in the ARC/VMN with an adeno-associated virus short hairpin RNA against the amylin core receptor. Amylin induced p-ERK in ARC neurons, 60% of which was present in POMC-expressing neurons, with none in NPY neurons. An amylin-leptin interaction was shown by an additive effect on ARC ERK signaling in neonatal rats and a 44% decrease in amylin-induced p-ERK in the ARC of leptin receptor-deficient and of ob/ob mice. Together, these results suggest that amylin directly acts, through a p-ERK-mediated process, on POMC neurons to enhance ARC-PVN αMSH pathway development.

Citing Articles

Intestinal gluconeogenesis controls the neonatal development of hypothalamic feeding circuits.

Estrada-Meza J, Videlo J, Bron C, Duchampt A, Saint-Beat C, Zergane M Mol Metab. 2024; 89:102036.

PMID: 39304064 PMC: 11470480. DOI: 10.1016/j.molmet.2024.102036.

Microglia mediate the early-life programming of adult glucose control.

Valdearcos M, McGrath E, Brown Mayfield S, Folick A, Cheang R, Li L bioRxiv. 2024; .

PMID: 39005380 PMC: 11244970. DOI: 10.1101/2024.07.02.601752.

Neurodevelopmental Programming of Adiposity: Contributions to Obesity Risk.

Skowronski A, Leibel R, LeDuc C Endocr Rev. 2023; 45(2):253-280.

PMID: 37971140 PMC: 10911958. DOI: 10.1210/endrev/bnad031.

Recent advancements in pharmacological strategies to modulate energy balance for combating obesity.

Pati B, Sendh S, Sahu B, Pani S, Jena N, Bal N RSC Med Chem. 2023; 14(8):1429-1445.

PMID: 37593583 PMC: 10429841. DOI: 10.1039/d3md00107e.

Neural Progenitor Cells and the Hypothalamus.

Makrygianni E, Chrousos G Cells. 2023; 12(14).

PMID: 37508487 PMC: 10378393. DOI: 10.3390/cells12141822.

References

Sahu A, Kalra S, Crowley W, Kalra P . Evidence that NPY-containing neurons in the brainstem project into selected hypothalamic nuclei: implication in feeding behavior. Brain Res. 1988; 457(2):376-8. DOI: 10.1016/0006-8993(88)90710-x. View

Bouret S, Draper S, Simerly R . Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci. 2004; 24(11):2797-805. PMC: 6729527. DOI: 10.1523/JNEUROSCI.5369-03.2004. View

Ahima R, Hileman S . Postnatal regulation of hypothalamic neuropeptide expression by leptin: implications for energy balance and body weight regulation. Regul Pept. 2000; 92(1-3):1-7. DOI: 10.1016/s0167-0115(00)00142-7. View

Ahima R, Prabakaran D, Flier J . Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest. 1998; 101(5):1020-7. PMC: 508653. DOI: 10.1172/JCI1176. View

Hay D, Chen S, Lutz T, Parkes D, Roth J . Amylin: Pharmacology, Physiology, and Clinical Potential. Pharmacol Rev. 2015; 67(3):564-600. DOI: 10.1124/pr.115.010629. View

Hilton J, Chai S, Sexton P . In vitro autoradiographic localization of the calcitonin receptor isoforms, C1a and C1b, in rat brain. Neuroscience. 1995; 69(4):1223-37. DOI: 10.1016/0306-4522(95)00322-a. View

Bouret S, Bates S, Chen S, Myers Jr M, Simerly R . Distinct roles for specific leptin receptor signals in the development of hypothalamic feeding circuits. J Neurosci. 2012; 32(4):1244-52. PMC: 3567460. DOI: 10.1523/JNEUROSCI.2277-11.2012. View

Braegger F, Asarian L, Dahl K, Lutz T, Boyle C . The role of the area postrema in the anorectic effects of amylin and salmon calcitonin: behavioral and neuronal phenotyping. Eur J Neurosci. 2014; 40(7):3055-66. DOI: 10.1111/ejn.12672. View

Potes C, Turek V, Cole R, Vu C, Roland B, Roth J . Noradrenergic neurons of the area postrema mediate amylin's hypophagic action. Am J Physiol Regul Integr Comp Physiol. 2010; 299(2):R623-31. DOI: 10.1152/ajpregu.00791.2009. View

10.

Lutz T . Effects of amylin on eating and adiposity. Handb Exp Pharmacol. 2012; (209):231-50. DOI: 10.1007/978-3-642-24716-3_10. View

11.

Clark W, Rutter W . Synthesis and accumulation of insulin in the fetal rat pancreas. Dev Biol. 1972; 29(4):468-81. DOI: 10.1016/0012-1606(72)90084-x. View

12.

Lutz T, Mollet A, Rushing P, Riediger T, Scharrer E . The anorectic effect of a chronic peripheral infusion of amylin is abolished in area postrema/nucleus of the solitary tract (AP/NTS) lesioned rats. Int J Obes Relat Metab Disord. 2001; 25(7):1005-11. DOI: 10.1038/sj.ijo.0801664. View

13.

Dunn-Meynell A, Le Foll C, Johnson M, Lutz T, Hayes M, Levin B . Endogenous VMH amylin signaling is required for full leptin signaling and protection from diet-induced obesity. Am J Physiol Regul Integr Comp Physiol. 2015; 310(4):R355-65. PMC: 4868368. DOI: 10.1152/ajpregu.00462.2015. View

14.

Chang L, Karin M . Mammalian MAP kinase signalling cascades. Nature. 2001; 410(6824):37-40. DOI: 10.1038/35065000. View

15.

Torii S, Nakayama K, Yamamoto T, Nishida E . Regulatory mechanisms and function of ERK MAP kinases. J Biochem. 2005; 136(5):557-61. DOI: 10.1093/jb/mvh159. View

16.

Padilla S, Carmody J, Zeltser L . Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits. Nat Med. 2010; 16(4):403-5. PMC: 2854504. DOI: 10.1038/nm.2126. View

17.

Rahmouni K, Sigmund C, Haynes W, Mark A . Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin. Diabetes. 2008; 58(3):536-42. PMC: 2646051. DOI: 10.2337/db08-0822. View

18.

Larsen L, Le Foll C, Dunn-Meynell A, Levin B . IL-6 ameliorates defective leptin sensitivity in DIO ventromedial hypothalamic nucleus neurons. Am J Physiol Regul Integr Comp Physiol. 2016; 311(4):R764-R770. PMC: 5142158. DOI: 10.1152/ajpregu.00258.2016. View

19.

Potes C, Lutz T, Riediger T . Identification of central projections from amylin-activated neurons to the lateral hypothalamus. Brain Res. 2010; 1334:31-44. DOI: 10.1016/j.brainres.2010.03.114. View

20.

Grove K, Allen S, Grayson B, Smith M . Postnatal development of the hypothalamic neuropeptide Y system. Neuroscience. 2003; 116(2):393-406. DOI: 10.1016/s0306-4522(02)00668-1. View