Genetic evidence for involvement of β2-adrenergic receptor in brown adipose tissue thermogenesis in humans

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

doi:10.1038/s41366-024-01522-6

Genetic evidence for involvement of β2-adrenergic receptor in brown adipose tissue thermogenesis in humans

Int J Obes (Lond). 2024 Apr 17. doi: 10.1038/s41366-024-01522-6. Online ahead of print.

Authors

Yuka Ishida¹, Mami Matsushita², Takeshi Yoneshiro^{3

4}, Masayuki Saito^{2

5}, Sayuri Fuse⁶, Takafumi Hamaoka⁶, Miyuki Kuroiwa⁶, Riki Tanaka⁷, Yuko Kurosawa⁶, Takayuki Nishimura^{8

9}, Midori Motoi⁸, Takafumi Maeda^{8

9}, Kazuhiro Nakayama¹⁰

Affiliations

¹ Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, 277-8562, Japan.
² Department of Nutrition, School of Nursing and Nutrition, Tenshi College, Sapporo, Hokkaido, 065-0013, Japan.
³ Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, 153-8904, Japan.
⁴ Department of Molecular Metabolism and Physiology, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, 980-8575, Japan.
⁵ Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan.
⁶ Department of Sports Medicine for Health Promotion, Tokyo Medical University, Shinjuku-ku, Tokyo, 160-8402, Japan.
⁷ Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Fukuoka, 814-0180, Japan.
⁸ Department of Human Life Design and Science, Faculty of Design, Kyushu University, Fukuoka, Fukuoka, 815-8540, Japan.
⁹ Physiological Anthropology Research Center, Faculty of Design, Kyushu University, Fukuoka, Fukuoka, 815-8540, Japan.
¹⁰ Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, 277-8562, Japan. knakayama@edu.k.u-tokyo.ac.jp.

PMID: 38632325
DOI: 10.1038/s41366-024-01522-6

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_TRS) 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_TRS 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.