Elevated Glucagon-like Peptide-1 Receptor Level in the Paraventricular Hypothalamic Nucleus of Type 2 Diabetes Mellitus Patients

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Dec 23

PMID 36555587

Authors

Eva Renner

Fanni Dora

Erzsebet Oszwald

Arpad Dobolyi

Miklos Palkovits

Affiliations

Soon will be listed here.

Abstract

Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have been approved for the treatment of type 2 diabetes mellitus (T2DM); however, the brain actions of these drugs are not properly established. We used post mortem microdissected human hypothalamic samples for RT-qPCR and Western blotting. For in situ hybridization histochemistry and immunolabelling, parallel cryosections were prepared from the hypothalamus. We developed in situ hybridization probes for human GLP-1R and oxytocin. In addition, GLP-1 and oxytocin were visualized by immunohistochemistry. Radioactive in situ hybridization histochemistry revealed abundant GLP-1R labelling in the human paraventricular hypothalamic nucleus (PVN), particularly in its magnocellular subdivision (PVNmc). Quantitative analysis of the mRNA signal demonstrated increased GLP-1R expression in the PVNmc in post mortem hypothalamic samples from T2DM subjects as compared to controls, while there was no difference in the expression level of GLP-1R in the other subdivisions of the PVN, the hypothalamic dorsomedial and infundibular nuclei. Our results in the PVN were confirmed by RT-qPCR. Furthermore, we demonstrated by Western blot technique that the GLP-1R protein level was also elevated in the PVN of T2DM patients. GLP-1 fibre terminals were also observed in the PVNmc closely apposing oxytocin neurons using immunohistochemistry. The data suggest that GLP-1 activates GLP-1Rs in the PVNmc and that GLP-1R is elevated in T2DM patients, which may be related to the dysregulation of feeding behaviour and glucose homeostasis in T2DM.

References

Liu J, Conde K, Zhang P, Lilascharoen V, Xu Z, Lim B . Enhanced AMPA Receptor Trafficking Mediates the Anorexigenic Effect of Endogenous Glucagon-like Peptide-1 in the Paraventricular Hypothalamus. Neuron. 2017; 96(4):897-909.e5. PMC: 5729931. DOI: 10.1016/j.neuron.2017.09.042. View

Holt M, Richards J, Cook D, Brierley D, Williams D, Reimann F . Preproglucagon Neurons in the Nucleus of the Solitary Tract Are the Main Source of Brain GLP-1, Mediate Stress-Induced Hypophagia, and Limit Unusually Large Intakes of Food. Diabetes. 2018; 68(1):21-33. PMC: 6314470. DOI: 10.2337/db18-0729. View

Renner E, Puskas N, Dobolyi A, Palkovits M . Glucagon-like peptide-1 of brainstem origin activates dorsomedial hypothalamic neurons in satiated rats. Peptides. 2012; 35(1):14-22. DOI: 10.1016/j.peptides.2012.02.018. View

Rinaman L, Rothe E . GLP-1 receptor signaling contributes to anorexigenic effect of centrally administered oxytocin in rats. Am J Physiol Regul Integr Comp Physiol. 2002; 283(1):R99-106. DOI: 10.1152/ajpregu.00008.2002. View

Andermann M, Lowell B . Toward a Wiring Diagram Understanding of Appetite Control. Neuron. 2017; 95(4):757-778. PMC: 5657399. DOI: 10.1016/j.neuron.2017.06.014. View

Vrang N, Grove K . The brainstem preproglucagon system in a non-human primate (Macaca mulatta). Brain Res. 2011; 1397:28-37. DOI: 10.1016/j.brainres.2011.05.002. View

Theodorakis M, Carlson O, Michopoulos S, Doyle M, Juhaszova M, Petraki K . Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am J Physiol Endocrinol Metab. 2005; 290(3):E550-9. DOI: 10.1152/ajpendo.00326.2004. View

Sandoval D, Bagnol D, Woods S, DAlessio D, Seeley R . Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes. 2008; 57(8):2046-54. PMC: 2494674. DOI: 10.2337/db07-1824. View

Koutcherov Y, Mai J, Ashwell K, Paxinos G . Organization of the human paraventricular hypothalamic nucleus. J Comp Neurol. 2000; 423(2):299-318. View

10.

De Leon D, Crutchlow M, Ham J, Stoffers D . Role of glucagon-like peptide-1 in the pathogenesis and treatment of diabetes mellitus. Int J Biochem Cell Biol. 2005; 38(5-6):845-59. DOI: 10.1016/j.biocel.2005.07.011. View

11.

Katsurada K, Yada T . Neural effects of gut- and brain-derived glucagon-like peptide-1 and its receptor agonist. J Diabetes Investig. 2016; 7 Suppl 1:64-9. PMC: 4854507. DOI: 10.1111/jdi.12464. View

12.

Renner E, Szabo-Meltzer K, Puskas N, Toth Z, Dobolyi A, Palkovits M . Activation of neurons in the hypothalamic dorsomedial nucleus via hypothalamic projections of the nucleus of the solitary tract following refeeding of fasted rats. Eur J Neurosci. 2010; 31(2):302-14. DOI: 10.1111/j.1460-9568.2009.07053.x. View

13.

Palkovits M . Isolated removal of hypothalamic or other brain nuclei of the rat. Brain Res. 1973; 59:449-50. DOI: 10.1016/0006-8993(73)90290-4. View

14.

Boland B, Laker R, OBrien S, Sitaula S, Sermadiras I, Nielsen J . Peptide-YY/glucagon-like peptide-1 combination treatment of obese diabetic mice improves insulin sensitivity associated with recovered pancreatic β-cell function and synergistic activation of discrete hypothalamic and brainstem neuronal circuitries. Mol Metab. 2021; 55:101392. PMC: 8717237. DOI: 10.1016/j.molmet.2021.101392. View

15.

Van Gaal L, Gutkin S, Nauck M . Exploiting the antidiabetic properties of incretins to treat type 2 diabetes mellitus: glucagon-like peptide 1 receptor agonists or insulin for patients with inadequate glycemic control?. Eur J Endocrinol. 2008; 158(6):773-84. DOI: 10.1530/EJE-07-0804. View

16.

Sisley S, Gutierrez-Aguilar R, Scott M, DAlessio D, Sandoval D, Seeley R . Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect. J Clin Invest. 2014; 124(6):2456-63. PMC: 4038572. DOI: 10.1172/JCI72434. View

17.

Li C, Navarrete J, Liang-Guallpa J, Lu C, Funderburk S, Chang R . Defined Paraventricular Hypothalamic Populations Exhibit Differential Responses to Food Contingent on Caloric State. Cell Metab. 2018; 29(3):681-694.e5. PMC: 6402975. DOI: 10.1016/j.cmet.2018.10.016. View

18.

Maejima Y, Yokota S, Nishimori K, Shimomura K . The Anorexigenic Neural Pathways of Oxytocin and Their Clinical Implication. Neuroendocrinology. 2018; 107(1):91-104. DOI: 10.1159/000489263. View

19.

Maida A, Lamont B, Cao X, Drucker D . Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice. Diabetologia. 2010; 54(2):339-49. DOI: 10.1007/s00125-010-1937-z. View

20.

Trapp S, Stanford S . New developments in the prospects for GLP-1 therapy. Br J Pharmacol. 2022; 179(4):489-491. PMC: 8820181. DOI: 10.1111/bph.15788. View