Submission systemSubmit
Advanced Search
Volume 6 Issue 1
Jan.  2026
Turn off MathJax
Article Contents
Article Navigation >  Frigid Zone Medicine  > 2026  >  6(1): 56-64
Yusha Yang, Guanyu Zhang, Xi Li, Danfeng Yang. Multiscale regulatory network underlying cold exposure-induced adipose tissue remodeling: Microscopic and macroscopic perspectives[J]. Frigid Zone Medicine, 2026, 6(1): 56-64. doi: 10.1515/fzm-2026-0006
Citation: Yusha Yang, Guanyu Zhang, Xi Li, Danfeng Yang. Multiscale regulatory network underlying cold exposure-induced adipose tissue remodeling: Microscopic and macroscopic perspectives[J]. Frigid Zone Medicine, 2026, 6(1): 56-64. doi: 10.1515/fzm-2026-0006
shu

Multiscale regulatory network underlying cold exposure-induced adipose tissue remodeling: Microscopic and macroscopic perspectives

doi: 10.1515/fzm-2026-0006
  • 1.

    Academy of Military Medical Sciences, Academy of Military Sciences, Tianjin 300050, China

  • 2.

    School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 561113, China

Funds:  Not applicable
More Information
    Abstract
  • Cold exposure, a prototypical environmental stressor, activates the metabolic plasticity of adipose tissue (AT) by inducing extensive AT remodeling. This adaptive process not only enhances cold tolerance but also critically improves glucose and lipid (glucolipid) metabolic homeostasis through systemic metabolic reprogramming. This review synthesizes recent high-resolution sequencing studies to comprehensively examine three core dimensions of cold exposure-induced AT remodeling: tissue phenotype, cellular architecture, and metabolic function. In addition, it elucidates intercellular communication and inter-organ interactions within the multiscale regulatory networks that govern AT remodeling, thereby providing a theoretical framework for the development of intervention strategies for metabolic diseases based on mechanisms of cold-induced AT remodeling.

     

    • FullText(HTML)
  • loading
    • References(77)
  • [1]
    Saito M, Okamatsu-Ogura Y, Matsushita M, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans. Diabetes, 2009; 58(7): 1526-1531. doi: 10.2337/db09-0530
    [2]
    Hanssen M J, Hoeks J, Brans B, et al. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat Med, 2015; 21(8): 863-865. doi: 10.1038/nm.3891
    [3]
    Seki T, Yang Y, Sun X, et al. Brown-fat-mediated tumour suppression by cold-altered global metabolism. Nature, 2022; 608(7922): 421-428. doi: 10.1038/s41586-022-05030-3
    [4]
    Jurado-Fasoli L, Sanchez-Delgado G, Di X, et al. Cold-induced changes in plasma signaling lipids are associated with a healthier cardiometabolic profile independently of brown adipose tissue. Cell Rep Med, 2024; 5(2): 101387. doi: 10.1016/j.xcrm.2023.101387
    [5]
    Cohen P, Kajimura S. The cellular and functional complexity of thermogenic fat. Nat Rev Mol Cell Biol, 2021; 22(6): 393-409. doi: 10.1038/s41580-021-00350-0
    [6]
    Bartelt A, Heeren J. Adipose tissue browning and metabolic health. Nat Rev Endocrinol, 2014; 10(1): 24-36. doi: 10.1038/nrendo.2013.204
    [7]
    Cohen P, Spiegelman B M. Brown and beige fat: Molecular parts of a thermogenic machine. Diabetes, 2015; 64(7): 2346-2351. doi: 10.2337/db15-0318
    [8]
    Wang T, Sharma A K, Wolfrum C. Novel insights into adipose tissue heterogeneity. Rev Endocr Metab Disord, 2022; 23(1): 5-12. doi: 10.1007/s11154-021-09703-8
    [9]
    Cook K S, Min H Y, Johnson D, et al. Adipsin: A circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science, 1987; 237(4813): 402-405. doi: 10.1126/science.3299705
    [10]
    Liu W, Liu T, Zhao Q, et al. Adipose tissue-derived extracellular vesicles: A promising biomarker and therapeutic strategy for metabolic disorders. Stem Cells Int, 2023; 2023: 1-16. doi: 10.1155/2023/9517826
    [11]
    Cannon B, Nedergaard J. Brown adipose tissue: Function and physiological significance. Physiol Rev, 2004; 84(1): 277-359. doi: 10.1152/physrev.00015.2003
    [12]
    Hull D. The structure and function of brown adipose tissue. Br Med Bull, 1966; 22(1): 92-96. doi: 10.1093/oxfordjournals.bmb.a070447
    [13]
    Colleluori G, Perugini J, Di Vincenzo A, et al. Brown fat anatomy in humans and rodents. Methods Mol Biol, 2022; 2448: 19-42. doi: 10.1007/978-1-0716-2087-8_2
    [14]
    Cypess A M, Lehman S, Williams G, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med, 2009; 360(15): 1509-1517. doi: 10.1056/NEJMoa0810780
    [15]
    Lidell M E. Brown adipose tissue in human infants. Handb Exp Pharmacol, 2019; 251: 107-123 doi: 10.1007/164_2018_118
    [16]
    Truong M T, Erasmus J J, Munden R F, et al. Focal FDG uptake in mediastinal brown fat mimicking malignancy: a potential pitfall resolved on PET/CT. Am J Roentgenol, 2004; 183(4): 1127-1132. doi: 10.2214/ajr.183.4.1831127
    [17]
    Wang W, Seale P. Control of brown and beige fat development. Nat Rev Mol Cell Biol, 2016; 17(11): 691-702. doi: 10.1038/nrm.2016.96
    [18]
    Cristancho A G, Lazar M A. Forming functional fat: A growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol, 2011; 12(11): 722-734. doi: 10.1038/nrm3198
    [19]
    Seale P, Bjork B, Yang W, et al. PRDM16 controls a brown fat/ skeletal muscle switch. Nature, 2008; 454(7207): 961-967. doi: 10.1038/nature07182
    [20]
    Srivastava S, Veech R L. Brown and brite: The fat soldiers in the anti-obesity fight. Front Physiol, 2019; 10: 38. doi: 10.3389/fphys.2019.00038
    [21]
    Pahlavani M, Razafimanjato F, Ramalingam L, et al. Eicosapentaenoic acid regulates brown adipose tissue metabolism in high-fat-fed mice and in clonal brown adipocytes. J Nutr Biochem, 2017; 39: 101-109. doi: 10.1016/j.jnutbio.2016.08.012
    [22]
    Kwok K H, Lam K S, Xu A. Heterogeneity of white adipose tissue: Molecular basis and clinical implications. Exp Mol Med, 2016; 48(3): e215. doi: 10.1038/emm.2016.5
    [23]
    Hwang I, Kim J B. Two faces of white adipose tissue with heterogeneous adipogenic progenitors. Diabetes Metab J, 2019; 43(6): 752-762. doi: 10.4093/dmj.2019.0174
    [24]
    Wu J, Bostrom P, Sparks L M, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell, 2012; 150(2): 366-376. doi: 10.1016/j.cell.2012.05.016
    [25]
    Montanari T, Pošćić N, Colitti M. Factors involved in white-to-brown adipose tissue conversion and in thermogenesis: A review. Obes Rev, 2017; 18(5): 495-513. doi: 10.1111/obr.12520
    [26]
    Yamashita H, Sato Y, Kizaki T, et al. Basic fibroblast growth factor (bFGF) contributes to the enlargement of brown adipose tissue during cold acclimation. Pflügers Archiv, 1994; 428: 352-356. doi: 10.1007/BF00724518
    [27]
    Xu H, Fukano K, Okamatsu-Ogura Y, et al. Cold exposure induces proliferation of mature brown adipocyte in a β3-adrenergic receptor-mediated pathway. Plos One, 2016; 11(11): e0166579. doi: 10.1371/journal.pone.0166579
    [28]
    Jia R, Luo X Q, Wang G, et al. Characterization of cold-induced remodelling reveals depot-specific differences across and within brown and white adipose tissues in mice. Acta Physiologica, 2016; 217(4): 311-324. doi: 10.1111/apha.12688
    [29]
    Néchad M, Ruka E, Thibault J. Production of nerve growth factor by brown fat in culture: Relation with the in vivo developmental stage of the tissue. Comp Biochem Physiol Comp Physiol, 1994; 107(2): 381-388. doi: 10.1016/0300-9629(94)90396-4
    [30]
    Mahdaviani K, Chess D, Wu Y, et al. Autocrine effect of vascular endothelial growth factor-A is essential for mitochondrial function in brown adipocytes. Metabolism, 2016; 65(1): 26-35. doi: 10.1016/j.metabol.2015.09.012
    [31]
    Nisoli E, Tonello C, Benarese M, et al. Expression of nerve growth factor in brown adipose tissue: Implications for thermogenesis and obesity. Endocrinology, 1996; 137(2): 495-503. doi: 10.1210/endo.137.2.8593794
    [32]
    Song A, Dai W, Jang M J, et al. Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue. J Clin Invest, 2019; 130(1): 247-257. doi: 10.1172/JCI129167
    [33]
    Merrick D, Sakers A, Irgebay Z, et al. Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science, 2019; 364(6438): eaav2501. doi: 10.1126/science.aav2501
    [34]
    Liu Q, Long Q, Zhao J, et al. Cold-induced reprogramming of subcutaneous white adipose tissue assessed by single-cell and single-nucleus RNA sequencing. Research (Wash D C), 2023; 6: 0182. doi: 10.34133/research.0182
    [35]
    Hui X, Gu P, Zhang J, et al. Adiponectin enhances cold-induced browning of subcutaneous adipose tissue via promoting M2 macrophage proliferation. Cell Metab, 2015; 22(2): 279-290. doi: 10.1016/j.cmet.2015.06.004
    [36]
    Ye Y, Wang H, Chen W, et al. Dynamic changes of immunocyte subpopulations in thermogenic activation of adipose tissues. Front Immunol, 2024; 15: 1375138. doi: 10.3389/fimmu.2024.1375138
    [37]
    Chouchani E T, Kajimura S. Metabolic adaptation and maladaptation in adipose tissue. Nature Metab, 2019; 1(2): 189-200. doi: 10.1038/s42255-018-0021-8
    [38]
    Cinti S. Adipose Organ Development and Remodeling. Compr Physiol, 2018; 8(4): 1357-1431. doi: 10.1002/j.2040-4603.2018.tb00046.x
    [39]
    Sun K, Kusminski C M, Luby-Phelps K, et al. Brown adipose tissue derived VEGF-A modulates cold tolerance and energy expenditure. Mol Metab, 2014; 3(4): 474-483. doi: 10.1016/j.molmet.2014.03.010
    [40]
    Villarroya F, Cereijo R, Villarroya J, et al. Brown adipose tissue as a secretory organ. Nat Rev Endocrinol, 2016; 13(1): 26-35. doi: 10.1038/nrendo.2016.136
    [41]
    Jespersen Naja Z, Larsen Therese J, Peijs L, et al. A classical brown adipose tissue mrna signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab, 2013; 17(5): 798-805. doi: 10.1016/j.cmet.2013.04.011
    [42]
    Xu Z, You W, Zhou Y, et al. Cold-induced lipid dynamics and transcriptional programs in white adipose tissue. BMC Biol, 2019; 17(1): 74. doi: 10.1186/s12915-019-0693-x
    [43]
    Li V L, Kim J T, Long J Z. Adipose tissue lipokines: Recent progress and future directions. Diabetes, 2020; 69(12): 2541-2548. doi: 10.2337/dbi20-0012
    [44]
    Leiria L O, Wang C-H, Lynes M D, et al. 12-lipoxygenase regulates cold adaptation and glucose metabolism by producing the omega-3 lipid 12-HEPE from brown fat. Cell Metab, 2019; 30(4): 768-783. doi: 10.1016/j.cmet.2019.07.001
    [45]
    Kim J T, Jedrychowski M P, Wei W, et al. A plasma protein network regulates PM20D1 and N-acyl amino acid bioactivity. Cell Chemi Biol, 2020; 27(9): 1130-1139. doi: 10.1016/j.chembiol.2020.04.009
    [46]
    Lynes M D, Leiria L O, Lundh M, et al. The cold-induced lipokine 12, 13-diHOME promotes fatty acid transport into brown adipose tissue. Nat Med, 2017; 23(5): 631-637. doi: 10.1038/nm.4297
    [47]
    Bartelt A, Bruns O T, Reimer R, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med, 2011; 17(2): 200-205. doi: 10.1038/nm.2297
    [48]
    Seale P, Conroe H M, Estall J, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest, 2011; 121(1): 96-105. doi: 10.1172/JCI44271
    [49]
    Chi J, Wu Z, Choi C H J, et al. Three-dimensional adipose tissue imaging reveals regional variation in beige fat biogenesis and PRDM16-dependent sympathetic neurite density. Cell metabolism, 2018; 27(1): 226-236. doi: 10.1016/j.cmet.2017.12.011
    [50]
    Zeng X, Ye M, Resch J M, et al. Innervation of thermogenic adipose tissue via a calsyntenin 3beta-S100b axis. Nature, 2019; 569(7755): 229-235. doi: 10.1038/s41586-019-1156-9
    [51]
    Schulz T J, Huang P, Huang T L, et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature, 2013; 495(7441): 379-383. doi: 10.1038/nature11943
    [52]
    Pellegrinelli V, Peirce V J, Howard L, et al. Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neuro-vascular network in adipose tissue. Nat Commun, 2018; 9(1): 4974. doi: 10.1038/s41467-018-07453-x
    [53]
    Lim S, Honek J, Xue Y, et al. Cold-induced activation of brown adipose tissue and adipose angiogenesis in mice. Nat Protoc, 2012; 7(3): 606-615. doi: 10.1038/nprot.2012.013
    [54]
    Xue Y, Petrovic N, Cao R, et al. Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab, 2009; 9(1): 99-109. doi: 10.1016/j.cmet.2008.11.009
    [55]
    Seki T, Hosaka K, Lim S, et al. Endothelial PDGF-CC regulates angiogenesis-dependent thermogenesis in beige fat. Nat Commun, 2016; 7: 12152. doi: 10.1038/ncomms12152
    [56]
    Huang Z, Zhong L, Lee J T H, et al. The FGF21-CCL11 axis mediates beiging of white adipose tissues by coupling sympathetic nervous system to type 2 immunity. Cell Metab, 2017; 26(3): 493-508. doi: 10.1016/j.cmet.2017.08.003
    [57]
    Rao Rajesh R, Long Jonathan Z, White James P, et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell, 2014; 157(6): 1279-1291. doi: 10.1016/j.cell.2014.03.065
    [58]
    Nguyen K D, Qiu Y, Cui X, et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature, 2011; 480(7375): 104-108. doi: 10.1038/nature10653
    [59]
    Wang Y N, Tang Y, He Z, et al. Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue. Nat Metab, 2021; 3(11): 1536-1551. doi: 10.1038/s42255-021-00482-9
    [60]
    Guilherme A, Henriques F, Bedard A H, et al. Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus. Nat Rev Endocrinol, 2019; 15(4): 207-225. doi: 10.1038/s41574-019-0165-y
    [61]
    Murano I, Barbatelli G, Giordano A, et al. Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ. J Anat, 2009; 214(1): 171-178. doi: 10.1111/j.1469-7580.2008.01001.x
    [62]
    Collins S. β-adrenoceptor signaling networks in adipocytes for recruiting stored fat and energy expenditure. Front Endocrinol (Lausanne), 2012; 2: 102. doi: 10.3389/fendo.2011.00102
    [63]
    López M, Alvarez C V, Nogueiras R, et al. Energy balance regulation by thyroid hormones at central level. Trends Mol Med, 2013; 19(7): 418-427. doi: 10.1016/j.molmed.2013.04.004
    [64]
    Martínez-Sánchez N, Seoane-Collazo P, Contreras C, et al. Hypothalamic AMPK-ER stress-JNK1 axis mediates the central actions of thyroid hormones on energy balance. Cell Metab, 2017; 26(1): 212-229. doi: 10.1016/j.cmet.2017.06.014
    [65]
    Schreiber R, Diwoky C, Schoiswohl G, et al. Cold-induced thermogenesis depends on ATGL-mediated lipolysis in cardiac muscle, but not brown adipose tissue. Cell Metab, 2017; 26(5): 753-763. doi: 10.1016/j.cmet.2017.09.004
    [66]
    Shin H, Ma Y, Chanturiya T, et al. Lipolysis in brown adipocytes is not essential for cold-induced thermogenesis in mice. Cell metab, 2017; 26(5): 764-777. doi: 10.1016/j.cmet.2017.09.002
    [67]
    Locke R M, Rial E, Scott I D, et al. Fatty acids as acute regulators of the proton conductance of hamster brown-fat mitochondria. Eur J Biochem, 2005; 129(2): 373-380. doi: 10.1111/j.1432-1033.1982.tb07060.x
    [68]
    Abumrad N A. The liver as a hub in thermogenesis. Cell Metab, 2017; 26(3): 454-455. doi: 10.1016/j.cmet.2017.08.018
    [69]
    Simcox J, Geoghegan G, Maschek J A, et al. Global analysis of plasma lipids identifies liver-derived acylcarnitines as a fuel source for brown fat thermogenesis. Cell Metab, 2017; 26(3): 509-522. doi: 10.1016/j.cmet.2017.08.006
    [70]
    Wang Q, Sharma V P, Shen H, et al. The hepatokine Tsukushi gates energy expenditure via brown fat sympathetic innervation. Nat Metab, 2019; 1(2): 251-260. doi: 10.1038/s42255-018-0020-9
    [71]
    Ameka M, Markan K R, Morgan D A, et al. Liver derived FGF21 maintains core body temperature during acute cold exposure. Sci Rep, 2019; 9(1): 630. doi: 10.1038/s41598-018-37198-y
    [72]
    Wang G X, Zhao X Y, Meng Z X, et al. The brown fat–enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat Med, 2014; 20(12): 1436-1443. doi: 10.1038/nm.3713
    [73]
    Shen H, Jiang L, Lin J D, et al. Brown fat activation mitigates alcohol-induced liver steatosis and injury in mice. J Clin Invest, 2019; 129(6): 2305-2317. doi: 10.1172/JCI124376
    [74]
    Worthmann A, John C, Rühlemann M C, et al. Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis. Nat Med, 2017; 23(7): 839-849. doi: 10.1038/nm.4357
    [75]
    Chevalier C, Stojanović O, Colin Didier J, et al. Gut microbiota orchestrates energy homeostasis during cold. Cell, 2015; 163(6): 1360-1374. doi: 10.1016/j.cell.2015.11.004
    [76]
    Ziętak M, Kovatcheva-Datchary P, Markiewicz L H, et al. Altered microbiota contributes to reduced diet-induced obesity upon cold exposure. Cell Metab, 2016; 23(6): 1216-1223. doi: 10.1016/j.cmet.2016.05.001
    [77]
    Rosenwald M, Perdikari A, Rulicke T, et al. Bi-directional interconversion of brite and white adipocytes. Nat Cell Biol, 2013; 15(6): 659-667. doi: 10.1038/ncb2740
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(1)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (20) PDF downloads(0) Cited by()
    Proportional views
    Related

    Contact Us

    Editorial Office: Frigid Zone Medicine, Editorial Office of Frigid Zone Medicine, Heilongjiang Health Development Research Center, Zhongshan Road 112, Xiangfang District, Harbin, 150036, China

    Tel: 0451-87253028

    E-mail: editorialoffice@frigidzonemedicine.com

    Supported by: Beijing Renhe Information Technology Co., Ltd.    

    Links

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return