Genetic Evidence for Involvement of β2-adrenergic Receptor in Brown Adipose Tissue Thermogenesis in Humans

Overview

Journal Int J Obes (Lond)

Specialty Endocrinology

Date 2024 Apr 17

PMID 38632325

Authors

Yuka Ishida

Mami Matsushita

Takeshi Yoneshiro

Masayuki Saito

Sayuri Fuse

Takafumi Hamaoka

Miyuki Kuroiwa

Riki Tanaka

Yuko Kurosawa

Takayuki Nishimura

Midori Motoi

Takafumi Maeda

Kazuhiro Nakayama

Affiliations

Soon will be listed here.

Abstract

Background: Sympathetic activation of brown adipose tissue (BAT) thermogenesis can ameliorate obesity and related metabolic abnormalities. However, crucial subtypes of the β-adrenergic receptor (AR), as well as effects of its genetic variants on functions of BAT, remains unclear in humans. We conducted association analyses of genes encoding β-ARs and BAT activity in human adults.

Methods: Single nucleotide polymorphisms (SNPs) in β1-, β2-, and β3-AR genes (ADRB1, ADRB2, and ADRB3) were tested for the association with BAT activity under mild cold exposure (19 °C, 2 h) in 399 healthy Japanese adults. BAT activity was measured using fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT). To validate the results, we assessed the effects of SNPs in the two independent populations comprising 277 healthy East Asian adults using near-infrared time-resolved spectroscopy (NIR) or infrared thermography (IRT). Effects of SNPs on physiological responses to intensive cold exposure were tested in 42 healthy Japanese adult males using an artificial climate chamber.

Results: We found a significant association between a functional SNP (rs1042718) in ADRB2 and BAT activity assessed with FDG-PET/CT (p < 0.001). This SNP also showed an association with cold-induced thermogenesis in the population subset. Furthermore, the association was replicated in the two other independent populations; BAT activity was evaluated by NIR or IRT (p < 0.05). This SNP did not show associations with oxygen consumption and cold-induced thermogenesis under intensive cold exposure, suggesting the irrelevance of shivering thermogenesis. The SNPs of ADRB1 and ADRB3 were not associated with these BAT-related traits.

Conclusions: The present study supports the importance of β2-AR in the sympathetic regulation of BAT thermogenesis in humans. The present collection of DNA samples is the largest to which information on the donor's BAT activity has been assigned and can serve as a reference for further in-depth understanding of human BAT function.

Citing Articles

Recent updates on cold adaptation in population and laboratory studies, including cross-adaptation with nonthermal factors.

Wakabayashi H, Sakaue H, Nishimura T J Physiol Anthropol. 2025; 44(1):7.

PMID: 39972479 PMC: 11837704. DOI: 10.1186/s40101-025-00387-6.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of Oxytocin (OT)-elicited reductions of body weight gain and adiposity in male diet-induced obese rats.

Edwards M, Nguyen H, Dodson A, Herbertson A, Honeycutt M, Slattery J Front Drug Deliv. 2025; 4.

PMID: 39866535 PMC: 11759500. DOI: 10.3389/fddev.2024.1497746.

Sympathetic Innervation of Interscapular Brown Adipose Tissue Is Not a Predominant Mediator of Oxytocin-Induced Brown Adipose Tissue Thermogenesis in Female High Fat Diet-Fed Rats.

Dodson A, Herbertson A, Honeycutt M, Vered R, Slattery J, Goldberg M Curr Issues Mol Biol. 2024; 46(10):11394-11424.

PMID: 39451559 PMC: 11506511. DOI: 10.3390/cimb46100679.

Association of brown adipose tissue activity with circulating sex hormones and fibroblast growth factor 21 in the follicular and luteal phases in young women.

Taniguchi H, Hashimoto Y, Dowaki N, Nirengi S J Physiol Anthropol. 2024; 43(1):23.

PMID: 39354624 PMC: 11446134. DOI: 10.1186/s40101-024-00371-6.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of OT-elicited reductions of body weight gain and adiposity in male diet-induced obese rats.

Edwards M, Nguyen H, Dodson A, Herbertson A, Honeycutt M, Slattery J bioRxiv. 2024; .

PMID: 39345420 PMC: 11430106. DOI: 10.1101/2024.09.12.612710.

References

Cypess A, White A, Vernochet C, Schulz T, Xue R, Sass C . Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med. 2013; 19(5):635-9. PMC: 3650129. DOI: 10.1038/nm.3112. View

Ward L, Kellis M . HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2011; 40(Database issue):D930-4. PMC: 3245002. DOI: 10.1093/nar/gkr917. View

Yoneshiro T, Aita S, Matsushita M, Kameya T, Nakada K, Kawai Y . Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men. Obesity (Silver Spring). 2010; 19(1):13-6. DOI: 10.1038/oby.2010.105. View

Haslam D, James W . Obesity. Lancet. 2005; 366(9492):1197-209. DOI: 10.1016/S0140-6736(05)67483-1. View

Astle W, Elding H, Jiang T, Allen D, Ruklisa D, Mann A . The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease. Cell. 2016; 167(5):1415-1429.e19. PMC: 5300907. DOI: 10.1016/j.cell.2016.10.042. View

Symonds M, Henderson K, Elvidge L, Bosman C, Sharkey D, Perkins A . Thermal imaging to assess age-related changes of skin temperature within the supraclavicular region co-locating with brown adipose tissue in healthy children. J Pediatr. 2012; 161(5):892-8. DOI: 10.1016/j.jpeds.2012.04.056. View

Cypess A, Weiner L, Roberts-Toler C, Franquet Elia E, Kessler S, Kahn P . Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 2015; 21(1):33-8. PMC: 4298351. DOI: 10.1016/j.cmet.2014.12.009. View

Zeng Z, Aptekmann A, Bromberg Y . Decoding the effects of synonymous variants. Nucleic Acids Res. 2021; 49(22):12673-12691. PMC: 8682775. DOI: 10.1093/nar/gkab1159. View

Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J . High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009; 58(7):1526-31. PMC: 2699872. DOI: 10.2337/db09-0530. View

10.

Vamos A, Arianti R, Vinnai B, Alrifai R, Shaw A, Poliska S . Human abdominal subcutaneous-derived active beige adipocytes carrying rs1421085 obesity-risk alleles exert lower thermogenic capacity. Front Cell Dev Biol. 2023; 11:1155673. PMC: 10321670. DOI: 10.3389/fcell.2023.1155673. View

11.

Sharp L, Shinoda K, Ohno H, Scheel D, Tomoda E, Ruiz L . Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS One. 2012; 7(11):e49452. PMC: 3500293. DOI: 10.1371/journal.pone.0049452. View

12.

Ernande L, Stanford K, Thoonen R, Zhang H, Clerte M, Hirshman M . Relationship of brown adipose tissue perfusion and function: a study through β2-adrenoreceptor stimulation. J Appl Physiol (1985). 2016; 120(8):825-32. PMC: 4835910. DOI: 10.1152/japplphysiol.00634.2015. View

13.

Gjesing A, Sparso T, Borch-Johnsen K, Jorgensen T, Pedersen O, Hansen T . No consistent effect of ADRB2 haplotypes on obesity, hypertension and quantitative traits of body fatness and blood pressure among 6,514 adult Danes. PLoS One. 2009; 4(9):e7206. PMC: 2745753. DOI: 10.1371/journal.pone.0007206. View

14.

Nirengi S, Yoneshiro T, Sugie H, Saito M, Hamaoka T . Human brown adipose tissue assessed by simple, noninvasive near-infrared time-resolved spectroscopy. Obesity (Silver Spring). 2015; 23(5):973-80. DOI: 10.1002/oby.21012. View

15.

Toth B, Arianti R, Shaw A, Vamos A, Vereb Z, Poliska S . FTO Intronic SNP Strongly Influences Human Neck Adipocyte Browning Determined by Tissue and PPARγ Specific Regulation: A Transcriptome Analysis. Cells. 2020; 9(4). PMC: 7227023. DOI: 10.3390/cells9040987. View

16.

Kumar A, Pandit A, Vivekanandhan S, Srivastava M, Tripathi M, Prasad K . Association between beta-1 adrenergic receptor gene polymorphism and ischemic stroke in North Indian population: a case control study. J Neurol Sci. 2014; 348(1-2):201-5. DOI: 10.1016/j.jns.2014.12.003. View

17.

Akiyama M, Okada Y, Kanai M, Takahashi A, Momozawa Y, Ikeda M . Genome-wide association study identifies 112 new loci for body mass index in the Japanese population. Nat Genet. 2017; 49(10):1458-1467. DOI: 10.1038/ng.3951. View

18.

Westra H, Peters M, Esko T, Yaghootkar H, Schurmann C, Kettunen J . Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013; 45(10):1238-1243. PMC: 3991562. DOI: 10.1038/ng.2756. View

19.

Pereira T, Mingroni-Netto R, Yamada Y . ADRB2 and LEPR gene polymorphisms: synergistic effects on the risk of obesity in Japanese. Obesity (Silver Spring). 2011; 19(7):1523-7. DOI: 10.1038/oby.2010.322. View

20.

Chernogubova E, Cannon B, Bengtsson T . Norepinephrine increases glucose transport in brown adipocytes via beta3-adrenoceptors through a cAMP, PKA, and PI3-kinase-dependent pathway stimulating conventional and novel PKCs. Endocrinology. 2003; 145(1):269-80. DOI: 10.1210/en.2003-0857. View