Discovery of Melanin-concentrating Hormone Receptor 1 in Brown Adipose Tissue

Overview

Journal Ann N Y Acad Sci

Specialty Science

Date 2021 Jan 27

PMID 33502798

Authors

Cecile Philippe

Eva-Maria Klebermass

Theresa Balber

Oana C Kulterer

Markus Zeilinger

Gerda Egger

Monika Dumanic

Carsten T Herz

Florian W Kiefer

Christian Scheuba

Thomas Scherer

Clemens Furnsinn

Chrysoula Vraka

Katharina Pallitsch

Helmut Spreitzer

Wolfgang Wadsak

Helmut Viernstein

Marcus Hacker

Markus Mitterhauser

Affiliations

Soon will be listed here.

Abstract

Although extensive research on brown adipose tissue (BAT) has stimulated optimism in the battle against obesity and diabetes, BAT physiology and organ crosstalk are not fully understood. Besides BAT, melanin-concentrating hormone (MCH) and its receptor (MCHR1) play an important role in energy homeostasis. Because of the link between hypothalamic MCH neurons and sympathetic BAT activation via β-adrenoceptors, we investigated the expression and physiological role of the MCHR1 in BAT. MCHR1 was detected in rodent and human BAT with RT-qPCR and western blot analyses. In vivo imaging in rats used the glucose analog [ F]FDG and the MCHR1-tracer [ C]SNAP-7941. We found that the β3-adrenoceptor (ADRB3) agonist CL316,243 increased [ C]SNAP-7941 uptake in BAT. Additionally, a pharmacological concentration of SNAP-7941-a low-affinity ADRB3 ligand-stimulated [ F]FDG uptake, reflecting BAT activation. In cultured human adipocytes, CL316,243 induced MCHR1 expression, further supporting a direct interaction between MCHR1 and ADRB3. These findings characterized MCHR1 expression in rodent and human BAT for the first time, including in vitro and in vivo data demonstrating a link between MCHR1 and the β3-adrenergic system. The presence of MCHR1 in BAT emphasizes the role of BAT in energy homeostasis and may help uncover treatment approaches for obesity.

References

Kiefer F . The significance of beige and brown fat in humans. Endocr Connect. 2017; 6(5):R70-R79. PMC: 5510441. DOI: 10.1530/EC-17-0037. View

Borowsky B, Durkin M, Ogozalek K, Marzabadi M, DeLeon J, Lagu B . Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nat Med. 2002; 8(8):825-30. DOI: 10.1038/nm741. View

Shimomura Y, Mori M, Sugo T, Ishibashi Y, Abe M, Kurokawa T . Isolation and identification of melanin-concentrating hormone as the endogenous ligand of the SLC-1 receptor. Biochem Biophys Res Commun. 1999; 261(3):622-6. DOI: 10.1006/bbrc.1999.1104. View

Kokkotou E, Tritos N, Mastaitis J, Slieker L, Maratos-Flier E . Melanin-concentrating hormone receptor is a target of leptin action in the mouse brain. Endocrinology. 2001; 142(2):680-6. DOI: 10.1210/endo.142.2.7981. View

Philippe C, Haeusler D, Scherer T, Furnsinn C, Zeilinger M, Wadsak W . [(18)F]FE@SNAP-a specific PET tracer for melanin-concentrating hormone receptor 1 imaging?. EJNMMI Res. 2016; 6(1):31. PMC: 4816952. DOI: 10.1186/s13550-016-0186-7. View

Vraka C, Pichler V, Pfaff S, Balber T, Hacker M, Mitterhauser M . Technical Aspect of the Automated Synthesis and Real-Time Kinetic Evaluation of [11C]SNAP-7941. J Vis Exp. 2019; (146). DOI: 10.3791/59557. View

Lembo P, Grazzini E, Cao J, Hubatsch D, Pelletier M, Hoffert C . The receptor for the orexigenic peptide melanin-concentrating hormone is a G-protein-coupled receptor. Nat Cell Biol. 1999; 1(5):267-71. DOI: 10.1038/12978. View

Philippe C, Schirmer E, Mitterhauser M, Shanab K, Lanzenberger R, Karanikas G . Radiosynthesis of [11C]SNAP-7941--the first PET-tracer for the melanin concentrating hormone receptor 1 (MCHR1). Appl Radiat Isot. 2012; 70(10):2287-94. PMC: 3439630. DOI: 10.1016/j.apradiso.2012.07.010. View

Ludwig D, Tritos N, Mastaitis J, Kulkarni R, Kokkotou E, Elmquist J . Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. J Clin Invest. 2001; 107(3):379-86. PMC: 199192. DOI: 10.1172/JCI10660. View

10.

Ito M, Ishihara A, Gomori A, Matsushita H, Ito M, Metzger J . Mechanism of the anti-obesity effects induced by a novel melanin-concentrating hormone 1-receptor antagonist in mice. Br J Pharmacol. 2009; 159(2):374-83. PMC: 2825359. DOI: 10.1111/j.1476-5381.2009.00536.x. View

11.

Luthin D . Anti-obesity effects of small molecule melanin-concentrating hormone receptor 1 (MCHR1) antagonists. Life Sci. 2007; 81(6):423-40. DOI: 10.1016/j.lfs.2007.05.029. View

12.

Shimada M, Tritos N, Lowell B, Flier J, Maratos-Flier E . Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature. 1999; 396(6712):670-4. DOI: 10.1038/25341. View

13.

Tews D, Wabitsch M . Renaissance of brown adipose tissue. Horm Res Paediatr. 2011; 75(4):231-9. DOI: 10.1159/000324806. View

14.

Hamamoto A, Horikawa M, Saho T, Saito Y . Mutation of Phe318 within the NPxxY(x)(5,6)F motif in melanin-concentrating hormone receptor 1 results in an efficient signaling activity. Front Endocrinol (Lausanne). 2012; 3:147. PMC: 3515998. DOI: 10.3389/fendo.2012.00147. View

15.

Zeilinger M, Dumanic M, Pichler F, Budinsky L, Wadsak W, Pallitsch K . In vivo evaluation of radiotracers targeting the melanin-concentrating hormone receptor 1: [C]SNAP-7941 and [F]FE@SNAP reveal specific uptake in the ventricular system. Sci Rep. 2017; 7(1):8054. PMC: 5556108. DOI: 10.1038/s41598-017-08684-6. View

16.

Oldfield B, Giles M, Watson A, Anderson C, Colvill L, McKinley M . The neurochemical characterisation of hypothalamic pathways projecting polysynaptically to brown adipose tissue in the rat. Neuroscience. 2002; 110(3):515-26. DOI: 10.1016/s0306-4522(01)00555-3. View

17.

Chondronikola M, Volpi E, Borsheim E, Porter C, Annamalai P, Enerback S . Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes. 2014; 63(12):4089-99. PMC: 4238005. DOI: 10.2337/db14-0746. View

18.

Saito Y, Tetsuka M, Yue L, Kawamura Y, Maruyama K . Functional role of N-linked glycosylation on the rat melanin-concentrating hormone receptor 1. FEBS Lett. 2002; 533(1-3):29-34. DOI: 10.1016/s0014-5793(02)03744-4. View

19.

Philippe C, Ungersboeck J, Schirmer E, Zdravkovic M, Nics L, Zeilinger M . [¹⁸F]FE@SNAP-A new PET tracer for the melanin concentrating hormone receptor 1 (MCHR1): microfluidic and vessel-based approaches. Bioorg Med Chem. 2012; 20(19):5936-40. PMC: 3460236. DOI: 10.1016/j.bmc.2012.07.051. View

20.

Goncalves L, Machado T, Castro-Pinheiro C, de Souza N, Oliveira K, Fernandes-Santos C . Ageing is associated with brown adipose tissue remodelling and loss of white fat browning in female C57BL/6 mice. Int J Exp Pathol. 2017; 98(2):100-108. PMC: 5485357. DOI: 10.1111/iep.12228. View