title: AHNAK deficiency promotes browning and lipolysis in mice via increased responsiveness to β-adrenergic signalling.
abstract: In adipose tissue, agonists of the β3-adrenergic receptor (ADRB3) regulate lipolysis, lipid oxidation, and thermogenesis. The deficiency in the thermogenesis induced by neuroblast differentiation-associated protein AHNAK in white adipose tissue (WAT) of mice fed a high-fat diet suggests that AHNAK may stimulate energy expenditure via development of beige fat. Here, we report that AHNAK deficiency promoted browning and thermogenic gene expression in WAT but not in brown adipose tissue of mice stimulated with the ADRB3 agonist CL-316243. Consistent with the increased thermogenesis, Ahnak(-/-) mice exhibited an increase in energy expenditure, accompanied by elevated mitochondrial biogenesis in WAT depots in response to CL-316243. Additionally, AHNAK-deficient WAT contained more eosinophils and higher levels of type 2 cytokines (IL-4/IL-13) to promote browning of WAT in response to CL-316243. This was associated with enhanced sympathetic tone in the WAT via upregulation of adrb3 and tyrosine hydroxylase (TH) in response to β-adrenergic activation. CL-316243 activated PKA signalling and enhanced lipolysis, as evidenced by increased phosphorylation of hormone-sensitive lipase and release of free glycerol in Ahnak(-/-) mice compared to wild-type mice. Overall, these findings suggest an important role of AHNAK in the regulation of thermogenesis and lipolysis in WAT via β-adrenergic signalling.
authors.affiliation: Laboratory of Developmental Biology and Genomics, Institute for Veterinary Science, and BK21 Program for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul, Republic of Korea.
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Laboratory of Developmental Biology and Genomics, Institute for Veterinary Science, and BK21 Program for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul, Republic of Korea.
authors.forename: Seo Hyun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Laboratory of Developmental Biology and Genomics, Institute for Veterinary Science, and BK21 Program for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul, Republic of Korea.
authors.forename: Yo Na
authors.initials: YN
authors.lastname: Kim
authors.affiliation: Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul, Republic of Korea.
authors.forename: Il Yong
authors.initials: IY
authors.lastname: Kim
authors.affiliation: Laboratory of Developmental Biology and Genomics, Institute for Veterinary Science, and BK21 Program for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul, Republic of Korea.
authors.forename: Youn Ju
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Laboratory of Developmental Biology and Genomics, Institute for Veterinary Science, and BK21 Program for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul, Republic of Korea.
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Kyeong
authors.affiliation: Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul, Republic of Korea.
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Lim
authors.affiliation: Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul, Republic of Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Department of Life Science, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea.
authors.forename: Junhee
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Life Science, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea.
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Wi
authors.affiliation: Department of Life Science, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Department of Anatomy and Cell Biology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea.
authors.forename: Yeo Sung
authors.initials: YS
authors.lastname: Yoon
authors.affiliation: Division of Life Sciences, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Yun Soo
authors.initials: YS
authors.lastname: Bae
authors.affiliation: Laboratory of Developmental Biology and Genomics, Institute for Veterinary Science, and BK21 Program for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul, Republic of Korea.|Interdisciplinary Program for Bioinformatics, Program for Cancer Biology, and Bio MAX Institute, Seoul National University, Seoul, Republic of Korea.
authors.forename: Je Kyung
authors.initials: JK
authors.lastname: Seong
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D004149:Dioxoles / Q000494:pharmacology; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D008066:Lipolysis; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D009363:Neoplasm Proteins / Q000172:deficiency*; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D022722:Thermogenesis
chemical_list: C489572:Ahnak protein, mouse; D004149:Dioxoles; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011943:Receptors, Adrenergic, beta; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate