Multiple inducible thermogenic mechanisms in the development of cold acclimatization

Abstract

Extreme cold environment can threaten human health and life through increasing the risk of myocardial infarction, stroke, frostbite, and hypothermia. Insufficient heat production to maintain core body temperature is a major cause of cold injury. To cope with cold stress, human and other mammals have developed the capacity of cold acclimatization to adapt to such a harsh environment. Adaptive non-shivering thermogenesis is a ubiquitous form of cold acclimatization. This review article systematically summarizes the role of three inducible thermogenic forms, including food intake, circadian rhythms, and cold exposure in mediating non-shivering thermogenesis under cold exposure and presents the potential interventions for minimizing the adverse health consequences of cold temperature.

Keywords

cold exposure / proteomic profile / hypothalamus / pituitary

References

[[1]] Lei J, Chen R, Yin P, et al. Association between cold spells and mortality risk and burden: a nationwide study in China. Environ Health Perspect, 2022; 130(2): 27006.

[[2]] Mugele H, Marume K, Amin S B, et al. Control of blood pressure in the cold: differentiation of skin and skeletal muscle vascular resistance. Exp Physiol, 2022; 108(1): 38-49.

[[3]] Huang S G. Binding of fatty acids to the uncoupling protein from brown adipose tissue mitochondria. Arch Biochem Biophys, 2002; 412(1): 142-146.

[[4]] Schonfeld P, Wojtczak L. Brown adipose tissue mitochondria oxidizing fatty acids generate high levels of reactive oxygen species irrespective of the uncoupling protein-1 activity state. Biochim Biophys Acta, 2012; 1817(3): 410-418.

[[5]] De Meis L, Ketzer L A, Camacho-Pereira J, et al. Brown adipose tissue mitochondria: modulation by GDP and fatty acids depends on the respiratory substrates. Biosci Rep, 2012; 32(1): 53-59.

[[6]] Argentato P P, de Cassia Cesar H, Estadella D, et al. Programming mediated by fatty acids affects uncoupling protein 1 (UCP-1) in brown adipose tissue. Br J Nutr, 2018; 120(6): 619-627.

[[7]] Paulus A, Drude N, van Marken Lichtenbelt W, et al. Brown adipose tissue uptake of triglyceride-rich lipoprotein-derived fatty acids in diabetic or obese mice under different temperature conditions. EJNMMI Res, 2020; 10(1): 127.

[[8]] 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.

[[9]] Li B, Li L, Li M, et al. Microbiota depletion impairs thermogenesis of brown adipose tissue and browning of white adipose tissue. Cell Rep, 2019; 26(10): 2720-2737.

[[10]] Li Z, Yi C X, Katiraei S, et al. Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit. Gut, 2018; 67(7): 1269-1279.

[[11]] Huang W, Man Y, Gao C, et al. Short-Chain fatty acids ameliorate diabetic nephropathy via GPR43-Mediated inhibition of oxidative stress and NF-kappaB signaling. Oxid Med Cell Longev, 2020; 2020: 4074832.

[[12]] 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; (4): 768-783.

[[13]] Nagatake T, Shibata Y, Morimoto S, et al. 12-Hydroxyeicosapentaenoic acid inhibits foam cell formation and ameliorates high-fat diet-induced pathology of atherosclerosis in mice. Sci Rep, 2021; 11(1): 10426.

[[14]] Kharazmi-Khorassani J, Ghafarian Zirak R, Ghazizadeh H, et al. The role of serum monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) in cardiovascular disease risk. Acta Biomed, 2021; 92(2): e2021049.

[[15]] Fleckenstein-Elsen M, Dinnies D, Jelenik T, et al. Eicosapentaenoic acid and arachidonic acid differentially regulate adipogenesis, acquisition of a brite phenotype and mitochondrial function in primary human adipocytes. Mol Nutr Food Res, 2016; 60(9): 2065-2075.

[[16]] Kim J, Okla M, Erickson A, et al. Eicosapentaenoic acid potentiates brown thermogenesis through FFAR4-dependent up-regulation of miR-30b and miR-378. J Biol Chem, 2016; 291(39): 20551-20562.

[[17]] 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.

[[18]] Pinckard K M, Shettigar V K, Wright K R, et al. A novel endocrine role for the BAT-released lipokine 12,13-diHOME to mediate cardiac function. Circulation, 2021; 143(2): 145-159.

[[19]] Song Z, Xiaoli A M, Yang F. Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues. Nutrients, 2018; 10(10): 1383.

[[20]] Martinez Calejman C, Trefely S, Entwisle S W, et al. mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis. Nat Commun, 2020; 11(1): 575.

[[21]] Mills E L, Pierce K A, Jedrychowski M P, et al. Accumulation of succinate controls activation of adipose tissue thermogenesis. Nature, 2018; 560(7716): 102-106.

[[22]] Wang T, Xu Y Q, Yuan Y X, et al. Succinate induces skeletal muscle fiber remodeling via SUNCR1 signaling. EMBO Rep, 2019; 20(9): e47892.

[[23]] Yuan Y, Xu P, Jiang Q, et al. Exercise-induced alpha-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1- dependent adrenal activation. EMBO J, 2020; 39(7): e103304.

[[24]] Asadi Shahmirzadi A, Edgar D, Liao C Y, et al. Alpha-Ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metab, 2020; 32(3): 447-456.

[[25]] Lopez-Soriano F J, Fernandez-Lopez J A, Mampel T, et al. Amino acid and glucose uptake by rat brown adipose tissue. Effect of cold-exposure and acclimation. Biochem J, 1988; 252(3): 843-849.

[[26]] Tome D. Efficiency of free amino acids in supporting muscle protein synthesis. J Nutr, 2022; 152(1): 3-4.

[[27]] Wu Z, Satterfield M C, Bazer F W, et al. Regulation of brown adipose tissue development and white fat reduction by L-arginine. Curr Opin Clin Nutr Metab Care, 2012; 15(6): 529-38.

[[28]] Kazak L, Chouchani E T, Jedrychowski M P, et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell, 2015; 163(3): 643-655.

[[29]] Yoneshiro T, Wang Q, Tajima K, et al. BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. Nature, 2019; 572(7771): 614-619.

[[30]] Wallace M, Green C R, Roberts L S, et al. Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues. Nat Chem Biol, 2018; 14(11): 1021-1031.

[[31]] Balas L, Feillet-Coudray C, Durand T. Branched Fatty Acyl Esters of Hydroxyl Fatty Acids (FAHFAs), appealing beneficial endogenous fat against obesity and Type-2 diabetes. Chemistry, 2018; 24(38): 9463-9476.

[[32]] Benlebna M, Balas L, Pessemesse L, et al. FAHFAs regulate the proliferation of C2C 12 myoblasts and induce a shift toward a more oxidative phenotype in mouse skeletal muscle. Int J Mol Sci, 2020; 21(23): 9046.

[[33]] Kellerer T, Kleigrewe K, Brandl B, et al. Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) are associated with diet, bmi, and age. Front Nutr, 2021; 8: 691401.

[[34]] Chappuis S, Ripperger J A, Schnell A, et al. Role of the circadian clock gene Per 2 in adaptation to cold temperature. Mol Metab, 2013; 2(3): 184-193.

[[35]] Moraes M N, de Assis L V M, Henriques F D S, et al. Cold-sensing TRPM8 channel participates in circadian control of the brown adipose tissue. Biochim Biophys Acta Mol Mol Metab, 2013; 2(3): 184-193.

[[36]] Fischl H, McManus D, Oldenkamp R, et al. Cold-induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm. EMBO J, 2020; 39(22): e105604.

[[37]] Zhang Z, Cheng L, Ma J, et al. Chronic cold exposure leads to daytime preference in the circadian expression of hepatic metabolic genes. Front Physiol, 2022; 13: 865627.

[[38]] Barber A F, Sehgal A. Cold temperatures fire up circadian neurons. Cell Metab, 2018; 27(5): 951-953.

[[39]] Ishii M. Circadian variations in response to cold. Kurume Med J, 1981; 28(3): 211-221.

[[40]] De Jonghe B C, Hayes M R, Banno R, et al. Deficiency of PTP1B in POMC neurons leads to alterations in energy balance and homeostatic response to cold exposure. Am J Physiol Endocrinol Metab, 201; 300(6): E1002-1011.

[[41]] Xi D, Gandhi N, Lai M, et al. Ablation of Sim 1 neurons causes obesity through hyperphagia and reduced energy expenditure. PLoS One, 2012; 7(4): e36453.

[[42]] Takahashi Y, Zhang W, Sameshima K, et al. Orexin neurons are indispensable for prostaglandin E2-induced fever and defence against environmental cooling in mice. J Physiol, 2013; 591(22): 5623-5643.

[[43]] Jeong J H, Lee D K, Blouet C, et al. Cholinergic neurons in the dorsomedial hypothalamus regulate mouse brown adipose tissue metabolism. Mol Metab, 2015; 4(6): 483-492.

[[44]] Wu C S, Bongmba O Y N, Yue J, et al. Suppression of GHS-R in AgRP neurons mitigates diet-induced obesity by activating thermogenesis. Int J Mol Sci, 2017; 18(4): 832.

[[45]] Francois M, Qualls-Creekmore E, Berthoud H R. Genetics-based manipulation of adipose tissue sympathetic innervation. Physiol Behav, 2018; 190: 21-27.

[[46]] Yang W Z, Du X, Zhang W, et al. Parabrachial neuron types categorically encode thermoregulation variables during heat defense. Sci Adv, 2020; 6(36): eabb9414.

[[47]] Gizowski C, Bourque C W. Sodium regulates clock time and output via an excitatory GABAergic pathway. Nature, 2020; 583(7816): 421-424.

[[48]] Touitou Y, Haus E. Alterations with aging of the endocrine and neuroendocrine circadian system in humans. Chronobiol Int, 2000; 17(3): 369-390.

[[49]] Sato M, Murakami M, Node K, et al. The role of the endocrine system in feeding-induced tissue-specific circadian entrainment. Cell Rep, 2014; 8(2): 393-401.

[[50]] Hernandez-Morante J J, Gomez-Santos C, Milagro F, et al. Expression of cortisol metabolism-related genes shows circadian rhythmic patterns in human adipose tissue. I nt J Obes (Lond), 2009; 33(4): 473-480.

[[51]] Stimson R H, Andersson J, Andrew R, et al. Cortisol release from adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 in humans. Diabetes, 2009; 58(1): 46-53.

[[52]] Richards E M, McElhaney E, Zeringue K, et al. Transcriptomic evidence that cortisol alters perinatal epicardial adipose tissue maturation. Am J Physiol Endocrinol Metab, 2019; 317(4): E573-E585.

[[53]] Vella C A, Nelson O L, Jansen H T, et al. Regulation of metabolism during hibernation in brown bears (Ursus arctos): Involvement of cortisol, PGC-1alpha and AMPK in adipose tissue and skeletal muscle. Comp Biochem Physiol A Mol Integr Physiol, 2020; 240: 110591.

[[54]] Lechan R M, Fekete C. The TRH neuron: a hypothalamic integrator of energy metabolism. Prog Brain Res, 2006; 153: 209-235.

[[55]] Martinez de Mena R, Scanlan T S, Obregon M J. The T3 receptor beta1 isoform regulates UCP1 and D2 deiodinase in rat brown adipocytes. Endocrinology, 2010; 151(10): 5074-5083.

[[56]] Guilherme A, Yenilmez B, Bedard A H, et al. Control of adipocyte thermogenesis and lipogenesis through beta3-Adrenergic and thyroid hormone signal integration. Cell Rep, 2020; 31(5): 107598.

[[57]] Yau W W, Yen P M. Thermogenesis in adipose tissue activated by thyroid hormone. Int J Mol Sci, 2020; 21(8): 3020.

[[58]] Zhou J, Tripathi M, Ho J P, et al. Thyroid hormone decreases hepatic steatosis, inflammation, and fibrosis in a dietary mouse model of NASH. Thyroid, 2022; 32(6): 725-738.

[[59]] Froy O, Garaulet M. The circadian clock in white and brown adipose tissue: mechanistic, endocrine, and clinical aspects. Endocr Rev, 2018; 39(3): 261-273.

[[60]] Straat M E, Hogenboom R, Boon M R, et al. Circadian control of brown adipose tissue. Biochim Biophys Acta Mol Cell Biol Lipids, 2021; 1866(8): 158961.

[[61]] Heyde I, Begemann K, Oster H. Contributions of white and brown adipose tissues to the circadian regulation of energy metabolism. Endocrinology, 2021; 162(3): bqab009.

[[62]] Gerhart-Hines Z, Feng D, Emmett M J, et al. The nuclear receptor Rev-erbalpha controls circadian thermogenic plasticity. Nature, 2013; 503(7476): 410-413.

[[63]] Adlanmerini M, Carpenter B J, Remsberg J R, et al. Circadian lipid synthesis in brown fat maintains murine body temperature during chronic cold. Proc Natl Acad Sci U S A, 2019; 116(37): 18691-18699.

[[64]] Dashti H S, Scheer F, Saxena R, et al. Timing of food intake: identifying contributing factors to design effective interventions. Adv Nutr, 2019; 10(4): 606-620.

[[65]] Romo-Nava F, Guerdjikova A I, Mori N N, et al. A matter of time: A systematic scoping review on a potential role of the circadian system in binge eating behavior. Front Nutr, 2022; 9: 978412.

[[66]] Chellappa S L, Qian J, Vujovic N, et al. Daytime eating prevents internal circadian misalignment and glucose intolerance in night work. Sci Adv, 2021; 7(49): eabg9910.

[[67]] Damiola F, Le Minh N, Preitner N, et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev, 2000; 14(23): 2950-2961.

[[68]] Stunkard A J, Allison K C. Two forms of disordered eating in obesity: binge eating and night eating. Int J Obes Relat Metab Disord, 2003; 27(1): 1-12.

[[69]] Youngstedt S D, Elliott J A, Kripke D F. Human circadian phase-response curves for exercise. J Physiol, 2019; 597(8): 2253-2268.

[[70]] Lewis P, Korf H W, Kuffer L, et al. Exercise time cues (zeitgebers) for human circadian systems can foster health and improve performance: a systematic review. BMJ Open Sport Exerc Med, 2018; 4(1): e000443.

[[71]] Kraemer W J, Ratamess N A, Hymer W C, et al. Growth hormone(s), testosterone, insulin-like growth factors, and cortisol: roles and integration for cellular development and growth with exercise. Front Endocrinol (Lausanne), 2020; 11: 33.

[[72]] Haupt S, Eckstein M L, Wolf A, et al. Eat, train, sleep-retreat? hormonal interactions of intermittent fasting, exercise and circadian rhythm. Biomolecules, 2021; 11(4): 516.

[[73]] Chaput J P, McHill A W, Cox R C, et al. The role of insufficient sleep and circadian misalignment in obesity. Nat Rev Endocrinol, 2022: 1-16.

[[74]] Buckley T M, Schatzberg A F. On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders. J Clin Endocrinol Metab, 2005; 90(5): 3106-3114.

[[75]] Knutson K L, Spiegel K, Penev P, et al. The metabolic consequences of sleep deprivation. Sleep Med Rev, 2007; 11(3): 163-178.

[[76]] Mullington J M, Haack M, Toth M, et al. Cardiovascular, inflammatory, and metabolic consequences of sleep deprivation. Prog Cardiovasc Dis, 2009; 51(4): 294-302.

[[77]] Laposky A D, Bass J, Kohsaka A, et al. Sleep and circadian rhythms: key components in the regulation of energy metabolism. FEBS Lett, 2008; 582(1): 142-151.

[[78]] Kovanicova Z, Kurdiova T, Balaz M, et al. Cold exposure distinctively modulates parathyroid and thyroid hormones in cold-acclimatized and non-acclimatized humans. Endocrinology, 2020; 161(7): bqaa051.

[[79]] Li Q, Sun R, Huang C, et al. Cold adaptive thermogenesis in small mammals from different geographical zones of China. Comp Biochem Physiol A Mol Integr Physiol, 2001; 129(4): 949-961.

[[80]] Lu H, Ye Z, Zhai Y, et al. QKI regulates adipose tissue metabolism by acting as a brake on thermogenesis and promoting obesity. EMBO Rep, 2020; 21(1): e47929.

[[81]] Lu H, Tang S, Xue C, et al. Mitochondrial-Derived peptide MOTS-c increases adipose thermogenic activation to promote cold adaptation. Int J Mol Sci, 2019; 20(10): 2456.

[[82]] Wang T Y, Liu C, Wang A, et al. Intermittent cold exposure improves glucose homeostasis associated with brown and white adipose tissues in mice. Life Sci, 2015; 139: 153-159.

[[83]] Nishimura T, Katsumura T, Motoi M, et al. Experimental evidence reveals the UCP 1 genotype changes the oxygen consumption attributed to non-shivering thermogenesis in humans. Sci Rep, 2017; 7(1): 5570.

[[84]] Larson C J. Translational pharmacology and physiology of brown adipose tissue in human disease and treatment. Handb Exp Pharmacol, 2019; 251: 381-424.

[[85]] Gonzalez-Hurtado E, Lee J, Choi J, et al. Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing. Mol Metab, 2018; 7: 45-56.

[[86]] Shi M, Huang X Y, Ren X Y, et al. AIDA directly connects sympathetic innervation to adaptive thermogenesis by UCP1. Nat Cell Biol, 2021; 23(3): 268-277.

[[87]] Bianco A C, McAninch E A. The role of thyroid hormone and brown adipose tissue in energy homoeostasis. Lancet Diabetes Endocrinol, 2013; 1(3): 250-258.

[[88]] Razzoli M, Emmett M J, Lazar M A, et al. Beta-Adrenergic receptors control brown adipose UCP-1 tone and cold response without affecting its circadian rhythmicity. FASEB J, 2018; 32(10): 5640-5646.

[[89]] Lu W H, Chang Y M, Huang Y S. Alternative polyadenylation and differential regulation of Ucp1: implications for brown adipose tissue thermogenesis across species. FASEB J, 2018; 32(10): 5640-5646.

[[90]] 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.

[[91]] Honek J, Lim S, Fischer C, et al. Brown adipose tissue, thermogenesis, angiogenesis: pathophysiological aspects. Horm Mol Biol Clin Investig, 2014; 19(1): 5-11.

[[92]] Seki T, Hosaka K, Fischer C, et al. Ablation of endothelial VEGFR1 improves metabolic dysfunction by inducing adipose tissue browning. J Exp Med, 2018; 215(2): 611-626.

[[93]] Seki T, Hosaka K, Lim S, et al. Endothelial PDGF-CC regulates angiogenesis-dependent thermogenesis in beige fat. Nat Commun, 2016; 7: 12152.

[[94]] Xue Y, Petrovic N, Cao R, et al. Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab, 2009; 9(1): 99-109.

[[95]] Nguyen K D, Qiu Y, Cui X, et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature, 2011; 480(7375): 104-108.

[[96]] Fischer K, Ruiz H H, Jhun K, et al. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat Med, 2017; 23(5): 623-630.

[[97]] Henriques F, Bedard A H, Guilherme A, et al. Single-Cell RNA profiling reveals adipocyte to macrophage signaling sufficient to enhance thermogenesis. Nat Med, 2017; 23(5): 623-630.

[[98]] 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): 279-90.

[[99]] Wei Q, Lee J H, Wang H, et al. Adiponectin is required for maintaining normal body temperature in a cold environment. BMC Physiol, 2017; 17(1): 8.

[[100]] Mathis D. IL-33, Imprimatur of adipocyte thermogenesis. Cell, 2016; 166(4): 794-795.

[[101]] Odegaard J I, Lee M W, Sogawa Y, et al. Perinatal licensing of thermogenesis by IL-33 and ST2. Cell, 2016; 166(4): 841-854.

[[102]] Lee M W, Odegaard J I, Mukundan L, et al. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell, 2015; 160(1- 2): 74-87.

[[103]] Lee P, Linderman J D, Smith S, et al. Irisin and FGF 21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab, 2014; 19(2): 302-309.

[[104]] Vliora M, Grillo E, Corsini M, et al. Irisin regulates thermogenesis and lipolysis in 3T3-L1 adipocytes. Biochim Biophys Acta Gen Subj, 2022; 1866(4): 130085

[[105]] Zheng S L, Li Z Y, Song J, et al. Metrnl: a secreted protein with new emerging functions. Acta Pharmacol Sin, 2016; 37(5): 571-579.

[[106]] Jung T W, Lee S H, Kim H C, et al. Metrnl attenuates lipid-induced inflammation and insulin resistance via AMPK or PPARdelta-dependent pathways in skeletal muscle of mice. Exp Mol Med, 2018; 50(9): 1-11.

[[107]] Lee J O, Byun W S, Kang M J, et al. The myokine meteorin-like (metrnl) improves glucose tolerance in both skeletal muscle cells and mice by targeting AMPKalpha2. FEBS J, 2020; 287(10): 2087-2104.

[[108]] Chartoumpekis D V, Habeos I G, Ziros P G, et al. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol Med, 2011; 17(7-8): 736-740.

[[109]] Lee P, Brychta R J, Linderman J, et al. Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm in humans: relationship between FGF21 levels, lipolysis, and cold-induced thermogenesis. J Clin Endocrinol Metab, 2013; 98(1): E98-102.

[[110]] Peres Valgas da Silva C, Hernandez-Saavedra D, White J D, et al. Cold and exercise: therapeutic tools to activate brown adipose tissue and combat obesity. Biology (Basel), 2019; 8(1): 9.

[[111]] Ameka M, Markan K R, Morgan D A, et al. Liver derived FGF 21 maintains core body temperature during acute cold exposure. Sci Rep, 2019; 9(1): 630.

[[112]] Ivanova Y M, Blondin D P. Examining the benefits of cold exposure as a therapeutic strategy for obesity and type 2 diabetes. J Appl Physiol, 2021; 130(5): 1448-1459.

[[113]] Sugimoto S, Mena H A, Sansbury B E, et al. Brown adipose tissue-derived MaR2 contributes to cold-induced resolution of inflammation. Nat Metab, 2022; 4(6): 775-790.

[[114]] Spiljar M, Steinbach K, Rigo D, et al. Cold exposure protects from neuroinflammation through immunologic reprogramming. Cell Metab, 2021; 33(11): 2231-2246.

[[115]] Seki T, Yang Y, Sun X, et al. Brown-fat-mediated tumour suppression by cold-altered global metabolism. Nature, 2022; 608(7922): 421-428.