Objective. Continuous exposure to cold leads to an activation of adaptive thermogenesis in the brown adipose tissue and induction of brown/beige cell phenotype in the white adipose tissue. Thermogenic response is associated with alternatively activated macrophages producing catecholamines, which subsequently activate the uncoupling protein 1 (UCP-1). The aim of this work was to elucidate the effect of cold exposure on catecholamine and immune responses associated with adipocyte browning in the mesenteric adipose tissue (mWAT) of rat.
Methods. The rats were exposed to continuous cold (4 °C) for 1 or 7 days. Catecholamines production and gene expressions of inflammatory and other factors, related to adipocyte “browning”, were analyzed in the homogenized mWAT samples using 2-CAT ELISA kits.
Results. Cold exposure induced a sympathetic response in the mWAT, evidenced by the tyrosine hydroxylase (TH) protein level rise. Induction of non-sympathetical catecholamine production was observed 7 days after cold exposure by elevated TH and phenylethanolamine-N-methyltransferase (PNMT) expression, leading to an increased epinephrine levels. Cold exposure for 7 days stimulated the infiltration of macrophages, evaluated by F4/80 and CD68 expressions, and expression of anti-inflammatory mediators, while pro-inflammatory cytokines were inhibited. Anti- inflammatory response, accompanied by de novo catecholamine production and up-regulation of β3-adrenergic receptors, led to the stimulation of UCP-1 and PGC1α expression, suggesting a cold-induced “browning” of the mWAT, mediated by alternatively activated macrophages.
Conclusions. The present data indicate that prolonged cold exposure may induce anti-inflammatory response in mWAT associated with induction of UCP-1 expression. Although functional thermogenesis in the mWAT is most likely redundant, a highly efficient dissipation of energy by UCP1 may affect the energy homeostasis in this visceral fat.
Batra A, Heimesaat MM, Bereswill S, Fischer A, Glauben R, Kunkel D, Scheff old A, Erben U, Kuhl A, Loddenkemper C, Lehr HA, Schumann M, Schulzke JD, Zeitz M, Siegmund B. Mesenteric fat - control site for bacterial translocation in colitis? Mucosal Immunol 5, 580-591, 2012Bertin B, Desreumaux P, Dubuquoy L. Obesity, visceral fat and Crohn’s disease. Curr Opin Clin Nutr Metab Care 13, 574-580, 2010.
Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 84, 277-359, 2004.
Cohen P, Levy JD, Zhang Y, Frontini A, Kolodin DP, Svensson KJ. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156, 304-316, 2014.
Cousin B, Cinti S, Morroni M, Raimbault S, Ricquier D, Penicaud L, Casteilla L. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J Cell Sci 103 (Pt 4), 931-942, 1992.
Enerback S. Th e origins of brown adipose tissue. N Engl J Med 360, 2021-2023, 2009.
Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med 19, 1252-1263, 2013.
Kanhai DA, Kappelle LJ, van der Graaf Y, Uiterwaal CS, Visseren FL. SMART Study Group, The risk of general and abdominal adiposity in the occurrence of new vascular events and mortality in patients with various manifestations of vascular disease, Int J Obes 36, 695-702, 2012.
Khazen W, M’Bika JP, Tomkiewicz C, Benelli C, Chany C, Achour A, Forest C. Expression of macrophage-selective markers in human and rodent adipocytes. FEBS Lett 579, 5631-5634, 2005.
Kleiner S, Mepani RJ, Laznik D, Ye L, Jurczak MJ, Jornayvaz FR. Development of insulin resistance in mice lacking PGC-1alpha in adipose tissues. Proc Natl Acad Sci USA 109, 9635-9640, 2012.
Kranendonk ME, van Herwaarden JA, Stupkova T, de Jager W, Vink A, Moll FL, Kalkhoven E, Visseren FL.Inflammatory characteristics of distinct abdominal adipose tissue depots relate differently to metabolic risk factors for cardiovascular disease: distinct fat depots and vascular risk factors. Atherosclerosis 239, 419-427, 2015.
Kvetnansky R, Ukropec J, Laukova M, Manz B, Pacak K, Vargovic P. Stress stimulates production of catecholamines in rat adipocytes. Cell Mol Neurobiol 32, 801-813, 2012.
Laukova M, Vargovic P, Krizanova O, Kvetnansky R. Repeated stress down-regulates β(2)- and α (2C)-adrenergic receptors and up-regulates gene expression of IL-6 in the rat spleen. Cell Mol Neurobiol 30, 1077-1087, 2010.
Lee YH, Petkova Anelia P, Mottillo Emilio P, Granneman JG. In vivo identification of bipotential adipocyte progenitors recruited by beta 3-adrenoceptor activation and high-fat feeding. Cell Metab 15, 480-491, 2012.
Lee YH, Petkova Anelia P, Granneman JG. Identification of an adipogenic niche for adipose tissue remodeling and restoration. Cell Metab 18, 355-367, 2013.
Lee MW, Odegaard JI, Mukundan L, Qiu Y, Molofsky AB, Nussbaum JC, Yun K, Locksley RM, Chawla A. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160, 74-87, 2015.
Lin J, Wu PH, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY. Defects in adaptive energy metabolism with CNSlinked hyperactivity in PGC-1alpha null mice. Cell 119, 121-135, 2004.
Liu PS, Lin YW, Burton FH, Wei LN. M1-M2 balancing act in white adipose tissue browning - a new role for RIP140. Adipocyte 4, 146-148, 2015.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods 25, 402-408, 2001.
Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57, 3239-3246, 2008.
Miyazaki Y, Glass L, Triplitt C, Wajcberg E, Mandarino LJ, DeFronzo RA. Abdominal fat distribution and peripheral and hepatic insulin resistance in type 2 diabetes mellitus. Am J Physiol Endocrinol Metab 283, 1135-1143, 2002.
Nicklas BJ, Penninx BW, Cesari M, Kritchevsky SB, Newman AB, Kanaya AM, Pahor M, Jingzhong D, Harris TB. Association of v isceral adipose tissue with incident myocardial infarction in older men and women: the health, aging and body composition study, Am J Epidemiol 160, 741-749, 2004.
Nguyen KD, Qiu Y, Cui X, Goh YP, Mwangi J, David T, Mukundan L, Brombacher F, Locksley RM, Chawla A. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104-108, 2011.
Olefsky JM, Glass CK. Macrophages, inflammation and insulin resistance. Annu Rev Physiol 72, 219-246, 2010.
Qiu Y, Nguyen KD, Odegaard JI, Cui X, Tian X, Locksley RM, Palmiter RD, Chawla A. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292-1308, 2014.
Sam S, Haffner S, Davidson MH, D’Agostino RB Sr, Feinstein S, Kondos G, Perez A, Mazzone T. Relation of abdominal fat depots to systemic markers of inflammation in type 2 diabetes. Diabetes Care, 32, 932-937, 2009.
Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scime A, Devarakonda S, Conroe HM, Erdjument-Bromage H, Tempst P, Rudnicki MA, Beier DR, Spiegelman BM. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961-967, 2008.
Vargovic P, Ukropec J, Laukova M, Cleary S, Manz B, Pacak K, Kvetnansky R. Adipocytes as a new source of catecholamine production. FEBS Lett 585, 2279-2284, 2011.
Vargovic P, Ukropec J, Laukova M, Kurdiova T, Balaz M, Manz B, Ukropcova B, Kvetnansky R. Repeated immobilization stress induces catecholamine production in rat mesenteric adipocytes. Stress 16, 340-352, 2013.
Vargovic P, Laukova M, Ukropec J, Manz G, Kvetnansky R. Lipopolysaccharide induces catecholamine production in mesenteric adipose tissue of rats previously exposed to immobilization stress. Stress 2016. [Epub ahead of print].
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112, 1796-1808, 2003.
Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerback S, Schrauwen P, Spiegelman BM. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366-376, 2012.
Yang YK, Chen M, Clements RH, Abrams GA, Aprahamian CJ, Harmon CM. Human mesenteric adipose tissue plays unique role versus subcutaneous and omental fat in obesity related diabetes. Cell Physiol Biochem 22, 531-538, 2008.
Young P, Wilson S, Arch JR. Prolonged beta-adrenoceptor stimulation increases the amount of GDP-binding protein in brown adipose tissue mitochondria. Life Sci 34, 1111-1117, 1984.