{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T17:04:51Z","timestamp":1773421491485,"version":"3.50.1"},"reference-count":41,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":29,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shandong Agricultural Elite Variety Project","award":["2025LZGC006"],"award-info":[{"award-number":["2025LZGC006"]}]},{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["ZR2022QC088"],"award-info":[{"award-number":["ZR2022QC088"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Local cattle breeds have been domesticated and adapted to various climatic environments through natural and artificial selection. However, the molecular mechanisms underlying cold adaptation remain unknown. Adipose tissue browning may play a crucial role in this adaptation. Our analysis of 777K SNP genotyping data from 25 local Chinese cattle breeds revealed that the HSPA12B (heat shock protein A12B) gene underwent positive selection in Chinese northern cold-adapted breeds and Tibetan Plateau breeds. The results of the Western blot experiment showed that HSPA12B was highly expressed in adipose tissues of cattle and mice, with a relatively high expression level in the interscapular brown adipose tissue (iBAT) of mice. Following cold induction, the expression of HSPA12B was upregulated in both the iBAT and subcutaneous white adipose tissue (sWAT) of mice. We generated a Hspa12b knockout mouse model, and qRT-PCR data analysis showed that the deletion of Hspa12b promoted adipose browning thermogenesis by increasing the expression of Elovl3 and Ucp1 (P\uff1c0.05) at low temperature. Protein-protein interaction prediction results showed that interactions exist between HSPA12B and ELOVL3 in both mice and cattle. Furthermore, glucose and insulin tolerance testing experiments showed that the deletion of Hspa12b promoted glucose metabolism and insulin sensitivity (P\uff1c0.05) in mice. Taken together, our results provide compelling evidence that HSPA12B acts as a negative regulator of adipose tissue browning and thermogenesis, and this regulatory effect is mediated through the modulation of ELOVL3 expression. Moreover, HSPA12B is activated by low temperatures, which acts as a homeostatic mechanism to prevent excessive browning of fat and to maintain body temperature. These findings offer new insights into the molecular mechanisms of cold adaptation in animals and may serve as a potential therapeutic target for human obesity and diabetes.<\/jats:p>","DOI":"10.1093\/jas\/skag016","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T10:18:28Z","timestamp":1769422708000},"source":"Crossref","is-referenced-by-count":0,"title":["From selection signatures in cattle to functional validation in mice: HSPA12B negatively regulates adipose browning and thermogenesis"],"prefix":"10.1093","volume":"104","author":[{"given":"Yaping","family":"Gao","sequence":"first","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences , Jinan 250100,","place":["China"]},{"name":"Shandong Technical Innovation Center for Dairy Cattle Breeding, Department of Molecular Breeding , Jinan 250100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinpeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences , Jinan 250100,","place":["China"]},{"name":"Shandong Technical Innovation Center for Dairy Cattle Breeding, Department of Molecular Breeding , Jinan 250100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences , Jinan 250100,","place":["China"]},{"name":"Shandong Technical Innovation Center for Dairy Cattle Breeding, Department of Molecular Breeding , Jinan 250100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiuge","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences , Jinan 250100,","place":["China"]},{"name":"Shandong Technical Innovation Center for Dairy Cattle Breeding, Department of Molecular Breeding , Jinan 250100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihua","family":"Ju","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences , Jinan 250100,","place":["China"]},{"name":"Shandong Technical Innovation Center for Dairy Cattle Breeding, Department of Molecular Breeding , Jinan 250100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunhong","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences , Jinan 250100,","place":["China"]},{"name":"Shandong Technical Innovation Center for Dairy Cattle Breeding, Department of Molecular Breeding , Jinan 250100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaochao","family":"Wei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences , Jinan 250100,","place":["China"]},{"name":"Shandong Technical Innovation Center for Dairy Cattle Breeding, Department of Molecular Breeding , Jinan 250100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaran","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences , Jinan 250100,","place":["China"]},{"name":"Shandong Technical Innovation Center for Dairy Cattle Breeding, Department of Molecular Breeding , Jinan 250100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5153-6839","authenticated-orcid":false,"given":"Yao","family":"Xiao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences , Jinan 250100,","place":["China"]},{"name":"Shandong Technical Innovation Center for Dairy Cattle Breeding, Department of Molecular Breeding , Jinan 250100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinming","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences , Jinan 250100,","place":["China"]},{"name":"Shandong Technical Innovation Center for Dairy Cattle Breeding, Department of Molecular Breeding , Jinan 250100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"2026031312015450400_skag016-B1","doi-asserted-by":"publisher","first-page":"2428938","DOI":"10.1080\/21623945.2024.2428938","article-title":"The early transition to cold-induced browning in mouse subcutaneous white adipose tissue (scWAT) involves proteins related to nerve remodeling, cytoskeleton, mitochondria, and immune cells","volume":"13","author":"Blaszkiewicz","year":"2024","journal-title":"Adipocyte"},{"key":"2026031312015450400_skag016-B2","doi-asserted-by":"publisher","first-page":"2077","DOI":"10.1016\/j.cmet.2023.09.002","article-title":"Comprehensive quantification of metabolic flux during acute cold stress in mice","volume":"35","author":"Bornstein","year":"2023","journal-title":"Cell Metab"},{"key":"2026031312015450400_skag016-B3","doi-asserted-by":"publisher","first-page":"3158","DOI":"10.1210\/en.2007-1402","article-title":"Steroid hormones control circadian Elovl3 expression in mouse liver","volume":"149","author":"Brolinson","year":"2008","journal-title":"Endocrinology"},{"key":"2026031312015450400_skag016-B4","doi-asserted-by":"publisher","first-page":"3093","DOI":"10.1093\/molbev\/msab078","article-title":"Demographic history, adaptation, and NRAP convergent evolution at amino acid residue 100 in the world northernmost cattle from Siberia","volume":"38","author":"Buggiotti","year":"2021","journal-title":"Mol Biol Evol"},{"key":"2026031312015450400_skag016-B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.rvsc.2017.02.021","article-title":"Cold exposure induces the acquisition of brown adipocyte gene expression profiles in cattle inguinal fat normalized with a new set of reference genes for QRT-PCR","volume":"114","author":"Cao","year":"2017","journal-title":"Res Vet Sci"},{"key":"2026031312015450400_skag016-B6","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1080\/21623945.2020.1870060","article-title":"Brown and beige adipose tissue: a novel therapeutic strategy for obesity and type 2 diabetes mellitus","volume":"10","author":"Cheng","year":"2021","journal-title":"Adipocyte"},{"key":"2026031312015450400_skag016-B7","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/s41580-021-00350-0","article-title":"The cellular and functional complexity of thermogenic fat","volume":"22","author":"Cohen","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026031312015450400_skag016-B8","doi-asserted-by":"publisher","first-page":"e139640","DOI":"10.1172\/jci.insight.139640","article-title":"Endothelial HSPA12B and yes-associated protein cooperatively regulate angiogenesis following myocardial infarction","volume":"5","author":"Fan","year":"2020","journal-title":"JCI Insight"},{"key":"2026031312015450400_skag016-B9","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1534\/genetics.112.147231","article-title":"Detecting signatures of selection through haplotype differentiation among hierarchically structured populations","volume":"193","author":"Fariello","year":"2013","journal-title":"Genetics"},{"key":"2026031312015450400_skag016-B10","doi-asserted-by":"publisher","first-page":"3320","DOI":"10.1038\/s41467-021-23601-2","article-title":"Perilipin 5 links mitochondrial uncoupled respiration in brown fat to healthy white fat remodeling and systemic glucose tolerance","volume":"12","author":"Gallardo-Montejano","year":"2021","journal-title":"Nat Commun"},{"key":"2026031312015450400_skag016-B11","doi-asserted-by":"publisher","first-page":"661773","DOI":"10.3389\/fvets.2021.661773","article-title":"Melatonin regulates differentiation of sheep brown adipocyte precursor cells via AMP-activated protein kinase","volume":"8","author":"Gao","year":"2021","journal-title":"Front Vet Sci"},{"key":"2026031312015450400_skag016-B12","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/s12711-020-00571-5","article-title":"Signatures of selection reveal candidate genes involved in economic traits and cold acclimation in five Swedish cattle breeds","volume":"52","author":"Ghoreishifar","year":"2020","journal-title":"Genet Sel Evol"},{"key":"2026031312015450400_skag016-B13","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1073\/pnas.252764399","article-title":"Two Hsp70 family members expressed in atherosclerotic lesions","volume":"100","author":"Han","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026031312015450400_skag016-B14","doi-asserted-by":"publisher","first-page":"C670","DOI":"10.1152\/ajpcell.2000.279.3.C670","article-title":"Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes","volume":"279","author":"Himms-Hagen","year":"2000","journal-title":"Am J Physiol Cell Physiol"},{"key":"2026031312015450400_skag016-B15","doi-asserted-by":"publisher","first-page":"4117","DOI":"10.1242\/jcs.03179","article-title":"A novel endothelial-specific heat shock protein HspA12B is required in both zebrafish development and endothelial functions in vitro","volume":"119","author":"Hu","year":"2006","journal-title":"J Cell Sci"},{"key":"2026031312015450400_skag016-B16","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1038\/s42255-021-00346-2","article-title":"Genome-wide discovery of genetic loci that uncouple excess adiposity from its comorbidities","volume":"3","author":"Huang","year":"2021","journal-title":"Nat Metab"},{"key":"2026031312015450400_skag016-B17","doi-asserted-by":"publisher","first-page":"skad006","DOI":"10.1093\/jas\/skad006","article-title":"Signatures of selection in indigenous Chinese cattle genomes reveal adaptive genes and genetic variations to cold climate","volume":"101","author":"Huang","year":"2023","journal-title":"J Anim Sci"},{"key":"2026031312015450400_skag016-B18","doi-asserted-by":"publisher","first-page":"940","DOI":"10.1038\/s41467-024-45270-7","article-title":"Ubiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates","volume":"15","author":"Jeon","year":"2024","journal-title":"Nat Commun"},{"key":"2026031312015450400_skag016-B19","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1038\/nm.2757","article-title":"Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue","volume":"18","author":"Kiefer","year":"2012","journal-title":"Nat Med"},{"key":"2026031312015450400_skag016-B20","doi-asserted-by":"publisher","first-page":"e1461","DOI":"10.1152\/ajpendo.00623.2011","article-title":"Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPAR\u03b3 in 3T3-L1 cells","volume":"302","author":"Kobayashi","year":"2012","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2026031312015450400_skag016-B21","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1096\/fj.14-263038","article-title":"Cellular origins of cold-induced brown adipocytes in adult mice","volume":"29","author":"Lee","year":"2015","journal-title":"Faseb J"},{"key":"2026031312015450400_skag016-B22","doi-asserted-by":"publisher","first-page":"100623","DOI":"10.1016\/j.jlr.2024.100623","article-title":"Natriuretic peptide receptor-C perturbs mitochondrial respiration in white adipose tissue","volume":"65","author":"Li","year":"2024","journal-title":"J Lipid Res"},{"key":"2026031312015450400_skag016-B23","doi-asserted-by":"publisher","first-page":"103446","DOI":"10.1016\/j.jtherbio.2022.103446","article-title":"Cold exposure induces browning of bovine subcutaneous white fat in vivo and in vitro","volume":"112","author":"Li","year":"2023","journal-title":"J Therm Biol"},{"key":"2026031312015450400_skag016-B24","doi-asserted-by":"publisher","first-page":"4803","DOI":"10.1080\/10495398.2023.2196316","article-title":"A missense mutation of the WNK1 gene affects cold tolerance in Chinese domestic cattle","volume":"34","author":"Liu","year":"2023","journal-title":"Anim Biotechnol"},{"key":"2026031312015450400_skag016-B25","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.cell.2022.12.024","article-title":"Light modulates glucose metabolism by a retina-hypothalamus-brown adipose tissue axis","volume":"186","author":"Meng","year":"2023","journal-title":"Cell"},{"key":"2026031312015450400_skag016-B26","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1016\/j.molcel.2019.12.002","article-title":"Aifm2, a NADH oxidase, supports robust glycolysis and is required for cold- and diet-induced thermogenesis","volume":"77","author":"Nguyen","year":"2020","journal-title":"Mol Cell"},{"key":"2026031312015450400_skag016-B27","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s42255-022-00718-2","article-title":"A critical assessment of the role of creatine in brown adipose tissue thermogenesis","volume":"5","author":"Nicholls","year":"2023","journal-title":"Nat Metab"},{"key":"2026031312015450400_skag016-B28","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s40104-021-00558-2","article-title":"Vitamin a regulates intramuscular adipose tissue and muscle development: promoting high-quality beef production","volume":"12","author":"Peng","year":"2021","journal-title":"J Anim Sci Biotechnol"},{"key":"2026031312015450400_skag016-B29","doi-asserted-by":"crossref","first-page":"100937","DOI":"10.1016\/j.jlr.2025.100937","article-title":"ELOVL3 regulates phospholipid homeostasis and thermogenesis in brown adipose tissue","volume":"66","author":"Qin","year":"2025","journal-title":"J Lipid Res"},{"key":"2026031312015450400_skag016-B30","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.2741\/3786","article-title":"Brown fat biology and thermogenesis","volume":"16","author":"Richard","year":"2011","journal-title":"Front Biosci (Landmark Ed)"},{"key":"2026031312015450400_skag016-B31","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/s41556-023-01311-9","article-title":"EPAC1 enhances brown fat growth and beige adipogenesis","volume":"26","author":"Salisa","year":"2024","journal-title":"Nat Cell Biol"},{"key":"2026031312015450400_skag016-B32","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1016\/j.cmet.2017.09.004","article-title":"Cold-induced thermogenesis depends on ATGL-mediated lipolysis in cardiac muscle, but not brown adipose tissue","volume":"26","author":"Schreiber","year":"2017","journal-title":"Cell Metab"},{"key":"2026031312015450400_skag016-B33","doi-asserted-by":"publisher","first-page":"942","DOI":"10.2527\/2004.823942x","article-title":"Brown adipose tissue development and metabolism in ruminants","volume":"82","author":"Smith","year":"2004","journal-title":"J Anim Sci"},{"key":"2026031312015450400_skag016-B34","doi-asserted-by":"publisher","first-page":"2012","DOI":"10.1161\/01.ATV.0000235720.61091.c7","article-title":"HSPA12B is predominantly expressed in endothelial cells and required for angiogenesis","volume":"26","author":"Steagall","year":"2006","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2026031312015450400_skag016-B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-1-0716-2087-8_1","article-title":"Brown adipose tissue: a short historical perspective","volume":"2448","author":"Trayhurn","year":"2022","journal-title":"Methods Mol Biol"},{"key":"2026031312015450400_skag016-B36","doi-asserted-by":"publisher","first-page":"31738","DOI":"10.1074\/jbc.272.50.31738","article-title":"Cig30, a mouse member of a novel membrane protein gene family, is involved in the recruitment of brown adipose tissue","volume":"272","author":"Tvrdik","year":"1997","journal-title":"J Biol Chem"},{"key":"2026031312015450400_skag016-B37","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1038\/nrm.2016.96","article-title":"Control of brown and beige fat development","volume":"17","author":"Wang","year":"2016","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026031312015450400_skag016-B38","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1016\/j.ygeno.2021.03.023","article-title":"Introgression, admixture, and selection facilitate genetic adaptation to high-altitude environments in cattle","volume":"113","author":"Wang","year":"2021","journal-title":"Genomics"},{"key":"2026031312015450400_skag016-B39","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1007\/s12031-016-0768-x","article-title":"Impact of heat shock protein A12B overexpression on spinal astrocyte survival against oxygen-glucose-serum deprivation\/restoration in primary cultured astrocytes","volume":"59","author":"Xia","year":"2016","journal-title":"J Mol Neurosci"},{"key":"2026031312015450400_skag016-B40","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1186\/s12864-024-10387-y","article-title":"Genomic analysis uncovers novel candidate genes related to adaptation to tropical climates and milk production traits in native goats","volume":"25","author":"Zhang","year":"2024","journal-title":"BMC Genomics"},{"key":"2026031312015450400_skag016-B41","doi-asserted-by":"publisher","first-page":"29","DOI":"10.3389\/fphys.2016.00029","article-title":"Influencing factors of thermogenic adipose tissue activity","volume":"7","author":"Zhang","year":"2016","journal-title":"Front Physiol"}],"container-title":["Journal of Animal Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jas\/advance-article-pdf\/doi\/10.1093\/jas\/skag016\/66643310\/skag016.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jas\/article-pdf\/doi\/10.1093\/jas\/skag016\/66643310\/skag016.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jas\/article-pdf\/doi\/10.1093\/jas\/skag016\/66643310\/skag016.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T16:02:03Z","timestamp":1773417723000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jas\/article\/doi\/10.1093\/jas\/skag016\/8445899"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":41,"URL":"https:\/\/doi.org\/10.1093\/jas\/skag016","relation":{},"ISSN":["0021-8812","1525-3163"],"issn-type":[{"value":"0021-8812","type":"print"},{"value":"1525-3163","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2026]]},"article-number":"skag016"}}