Role of cAMP and cGMP Signaling in Brown Fat

  • Laia Reverte-Salisa
  • Abhishek Sanyal
  • Alexander PfeiferEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 251)


Cold-induced activation of brown adipose tissue (BAT) is mediated by norepinephrine and adenosine that are released during sympathetic nerve activation. Both signaling molecules induce an increase in intracellular levels of 3′,5′-cyclic adenosine monophosphate (cAMP) in murine and human BAT. In brown adipocytes, cAMP plays a central role, because it activates lipolysis, glucose uptake, and thermogenesis. Another well-studied intracellular second messenger is 3′,5′-cyclic guanosine monophosphate (cGMP), which closely resembles cAMP. Several studies have shown that intact cGMP signaling is essential for normal adipogenic differentiation and BAT-mediated thermogenesis in mice. This chapter highlights recent observations, demonstrating the physiological significance of cyclic nucleotide signaling in BAT as well as their potential to induce browning of white adipose tissue (WAT) in mice and humans.


Brown adipose tissue Browning cAMP cGMP UCP1 


  1. Alverdi V, Mazon H, Versluis C, Hemrika W, Esposito G, van den Heuvel R, Scholten A, Heck AJ (2008) cGMP-binding prepares PKG for substrate binding by disclosing the C-terminal domain. J Mol Biol 375:1380–1393PubMedGoogle Scholar
  2. Amieux PS, Cummings DE, Motamed K, Brandon EP, Wailes LA, Le K, Idzerda RL, McKnight GS (1997) Compensatory regulation of RIalpha protein levels in protein kinase A mutant mice. J Biol Chem 272:3993–3998PubMedGoogle Scholar
  3. Anthonsen MW, Ronnstrand L, Wernstedt C, Degerman E, Holm C (1998) Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro. J Biol Chem 273:215–221PubMedGoogle Scholar
  4. Ashman DF, Lipton R, Melicow MM, Price TD (1963) Isolation of adenosine 3′, 5′-monophosphate and guanosine 3′, 5′-monophosphate from rat urine. Biochem Biophys Res Commun 11:330–334PubMedGoogle Scholar
  5. Ayala JE, Bracy DP, Julien BM, Rottman JN, Fueger PT, Wasserman DH (2007) Chronic treatment with sildenafil improves energy balance and insulin action in high fat–fed conscious mice. Diabetes 56:1025–1033PubMedGoogle Scholar
  6. Bartness TJ, Vaughan CH, Song CK (2010) Sympathetic and sensory innervation of brown adipose tissue. Int J Obes 34:S36Google Scholar
  7. Bechtel PJ, Beavo JA, Krebs EG (1977) Purification and characterization of catalytic subunit of skeletal muscle adenosine 3′:5′-monophosphate-dependent protein kinase. J Biol Chem 252:2691–2697PubMedGoogle Scholar
  8. Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58:488–520PubMedGoogle Scholar
  9. Bengtsson T, Cannon B, Nedergaard J (2000) Differential adrenergic regulation of the gene expression of the beta-adrenoceptor subtypes beta1, beta2 and beta3 in brown adipocytes. Biochem J 347(Pt 3):643–651PubMedPubMedCentralGoogle Scholar
  10. Berthet J, Rall TW, Sutherland EW (1957a) The relationship of epinephrine and glucagon to liver phosphorylase. IV. Effect of epinephrine and glucagon on the reactivation of phosphorylase in liver homogenates. J Biol Chem 224:463–475PubMedGoogle Scholar
  11. Berthet J, Sutherland EW, Rall TW (1957b) The assay of glucagon and epinephrine with use of liver homogenates. J Biol Chem 229:351–361PubMedGoogle Scholar
  12. Billington CJ, Briggs JE, Link JG, Levine AS (1991) Glucagon in physiological concentrations stimulates brown fat thermogenesis in vivo. Am J Phys 261:R501–R507Google Scholar
  13. Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessì-Fulgheri P, Zhang C, Takahashi N, Sarzani R, Collins S (2012) Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest 122:1022–1036PubMedPubMedCentralGoogle Scholar
  14. Bradley J, Reisert J, Frings S (2005) Regulation of cyclic nucleotide-gated channels. Curr Opin Neurobiol 15:343–349PubMedGoogle Scholar
  15. Brandon EP, Logue SF, Adams MR, Qi M, Sullivan SP, Matsumoto AM, Dorsa DM, Wehner JM, McKnight GS, Idzerda RL (1998) Defective motor behavior and neural gene expression in RIIbeta-protein kinase A mutant mice. J Neurosci 18:3639–3649PubMedGoogle Scholar
  16. Bronnikov G, Houstek J, Nedergaard J (1992) Beta-adrenergic, cAMP-mediated stimulation of proliferation of brown fat cells in primary culture. Mediation via beta 1 but not via beta 3 adrenoceptors. J Biol Chem 267:2006–2013PubMedGoogle Scholar
  17. Bronnikov G, Bengtsson T, Kramarova L, Golozoubova V, Cannon B, Nedergaard J (1999) Beta1 to beta3 switch in control of cyclic adenosine monophosphate during brown adipocyte development explains distinct beta-adrenoceptor subtype mediation of proliferation and differentiation. Endocrinology 140:4185–4197PubMedGoogle Scholar
  18. Bryant NJ, Govers R, James DE (2002) Regulated transport of the glucose transporter GLUT4. Nat Rev Mol Cell Biol 3:267–277PubMedGoogle Scholar
  19. Cao Z, Umek RM, McKnight SL (1991) Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev 5:1538–1552PubMedGoogle Scholar
  20. Cao W, Medvedev AV, Daniel KW, Collins S (2001) beta-Adrenergic activation of p38 MAP kinase in adipocytes: cAMP induction of the uncoupling protein 1 (UCP1) gene requires p38 MAP kinase. J Biol Chem 276:27077–27082PubMedGoogle Scholar
  21. Cao W, Collins QF, Becker TC, Robidoux J, Lupo EG Jr, Xiong Y, Daniel KW, Floering L, Collins S (2005) p38 Mitogen-activated protein kinase plays a stimulatory role in hepatic gluconeogenesis. J Biol Chem 280:42731–42737PubMedGoogle Scholar
  22. Carmona MC, Hondares E, Rodriguez de la Concepcion ML, Rodriguez-Sureda V, Peinado-Onsurbe J, Poli V, Iglesias R, Villarroya F, Giralt M (2005) Defective thermoregulation, impaired lipid metabolism, but preserved adrenergic induction of gene expression in brown fat of mice lacking C/EBPbeta. Biochem J 389:47–56PubMedPubMedCentralGoogle Scholar
  23. Chernick SS, Spooner PM, Garrison MM, Scow RO (1986) Effect of epinephrine and other lipolytic agents on intracellular lipolysis and lipoprotein lipase activity in 3T3-L1 adipocytes. J Lipid Res 27:286–294PubMedGoogle Scholar
  24. Chernogubova E, Cannon B, Bengtsson T (2004) Norepinephrine increases glucose transport in brown adipocytes via beta3-adrenoceptors through a cAMP, PKA, and PI3-kinase-dependent pathway stimulating conventional and novel PKCs. Endocrinology 145:269–280PubMedGoogle Scholar
  25. Choi SM, Tucker DF, Gross DN, Easton RM, Dipilato LM, Dean AS, Monks BR, Birnbaum MJ (2010) Insulin regulates adipocyte lipolysis via an Akt-independent signaling pathway. Mol Cell Biol 30:5009–5020PubMedPubMedCentralGoogle Scholar
  26. Corbin JD, Sugden PH, Lincoln TM, Keely SL (1977) Compartmentalization of adenosine 3′:5′-monophosphate and adenosine 3′:5′-monophosphate-dependent protein kinase in heart tissue. J Biol Chem 252:3854–3861PubMedGoogle Scholar
  27. Cummings DE, Brandon EP, Planas JV, Motamed K, Idzerda RL, McKnight GS (1996) Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A. Nature 382:622–626PubMedGoogle Scholar
  28. Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elia E, Kessler SH, Kahn PA, English J, Chatman K, Trauger SA, Doria A, Kolodny GM (2015) Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist. Cell Metab 21:33–38PubMedPubMedCentralGoogle Scholar
  29. Dao KK, Teigen K, Kopperud R, Hodneland E, Schwede F, Christensen AE, Martinez A, Doskeland SO (2006) Epac1 and cAMP-dependent protein kinase holoenzyme have similar cAMP affinity, but their cAMP domains have distinct structural features and cyclic nucleotide recognition. J Biol Chem 281:21500–21511PubMedGoogle Scholar
  30. Darlington GJ, Ross SE, MacDougald OA (1998) The role of C/EBP genes in adipocyte differentiation. J Biol Chem 273:30057–30060PubMedGoogle Scholar
  31. Daval M, Diot-Dupuy F, Bazin R, Hainault I, Viollet B, Vaulont S, Hajduch E, Ferre P, Foufelle F (2005) Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes. J Biol Chem 280:25250–25257PubMedGoogle Scholar
  32. Deng C, Paoloni-Giacobino A, Kuehne F, Boss O, Revelli JP, Moinat M, Cawthorne MA, Muzzin P, Giacobino JP (1996) Respective degree of expression of beta 1-, beta 2- and beta 3-adrenoceptors in human brown and white adipose tissues. Br J Pharmacol 118:929–934PubMedPubMedCentralGoogle Scholar
  33. Denninger JW, Marletta MA (1999) Guanylate cyclase and the·NO/cGMP signaling pathway. Biochim Biophys Acta 1411:334–350PubMedGoogle Scholar
  34. Derbyshire ER, Marletta MA (2012) Structure and regulation of soluble guanylate cyclase. Annu Rev Biochem 81:533–559PubMedGoogle Scholar
  35. Dickson LM, Gandhi S, Layden BT, Cohen RN, Wicksteed B (2016) Protein kinase A induces UCP1 expression in specific adipose depots to increase energy expenditure and improve metabolic health. Am J Physiol Regul Integr Comp Physiol 311:R79–R88PubMedPubMedCentralGoogle Scholar
  36. Dipilato LM, Ahmad F, Harms M, Seale P, Manganiello V, Birnbaum MJ (2015) The role of PDE3B phosphorylation in the inhibition of lipolysis by insulin. Mol Cell Biol 35:2752–2760PubMedPubMedCentralGoogle Scholar
  37. Djouder N, Tuerk RD, Suter M, Salvioni P, Thali RF, Scholz R, Vaahtomeri K, Auchli Y, Rechsteiner H, Brunisholz RA, Viollet B, Makela TP, Wallimann T, Neumann D, Krek W (2010) PKA phosphorylates and inactivates AMPKalpha to promote efficient lipolysis. EMBO J 29:469–481PubMedGoogle Scholar
  38. Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS (2007) Regulation of lipolysis in adipocytes. Annu Rev Nutr 27:79–101PubMedPubMedCentralGoogle Scholar
  39. Eide T, Tasken KA, Carlson C, Williams G, Jahnsen T, Tasken K, Collas P (2003) Protein kinase A-anchoring protein AKAP95 interacts with MCM2, a regulator of DNA replication. J Biol Chem 278:26750–26756PubMedGoogle Scholar
  40. Enns LC, Morton JF, Treuting PR, Emond MJ, Wolf NS, Dai DF, McKnight GS, Rabinovitch PS, Ladiges WC (2009) Disruption of protein kinase A in mice enhances healthy aging. PLoS One 4:e5963PubMedPubMedCentralGoogle Scholar
  41. Fedorenko A, Lishko PV, Kirichok Y (2012) Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151:400–413PubMedPubMedCentralGoogle Scholar
  42. Förstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33:829–837PubMedGoogle Scholar
  43. Francis SH, Busch JL, Corbin JD (2010) cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev 62:525–563PubMedPubMedCentralGoogle Scholar
  44. Fredriksson JM, Nedergaard J (2002) Norepinephrine specifically stimulates ribonucleotide reductase subunit R2 gene expression in proliferating brown adipocytes: mediation via a cAMP/PKA pathway involving Src and Erk1/2 kinases. Exp Cell Res 274:207–215PubMedGoogle Scholar
  45. Fukuda M, Williams KW, Gautron L, Elmquist JK (2011) Induction of leptin resistance by activation of cAMP-Epac signaling. Cell Metab 13:331–339PubMedPubMedCentralGoogle Scholar
  46. Gauthier MS, Miyoshi H, Souza SC, Cacicedo JM, Saha AK, Greenberg AS, Ruderman NB (2008) AMP-activated protein kinase is activated as a consequence of lipolysis in the adipocyte: potential mechanism and physiological relevance. J Biol Chem 283:16514–16524PubMedPubMedCentralGoogle Scholar
  47. Glöde A, Naumann J, Gnad T, Cannone V, Kilic A, Burnett JC Jr, Pfeifer A (2017) Divergent effects of a designer natriuretic peptide CD-NP in the regulation of adipose tissue and metabolism. Mol Metab 6:276–287PubMedPubMedCentralGoogle Scholar
  48. Gnad T, Scheibler S, von Kugelgen I, Scheele C, Kilic A, Glode A, Hoffmann LS, Reverte-Salisa L, Horn P, Mutlu S, El-Tayeb A, Kranz M, Deuther-Conrad W, Brust P, Lidell ME, Betz MJ, Enerback S, Schrader J, Yegutkin GG, Muller CE, Pfeifer A (2014) Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516:395–399PubMedGoogle Scholar
  49. Gold MG, Lygren B, Dokurno P, Hoshi N, McConnachie G, Tasken K, Carlson CR, Scott JD, Barford D (2006) Molecular basis of AKAP specificity for PKA regulatory subunits. Mol Cell 24:383–395PubMedGoogle Scholar
  50. Granneman JG, Lahners KN (1992) Differential adrenergic regulation of beta 1- and beta 3-adrenoreceptor messenger ribonucleic acids in adipose tissues. Endocrinology 130:109–114PubMedGoogle Scholar
  51. Greco-Perotto R, Zaninetti D, Assimacopoulos-Jeannet F, Bobbioni E, Jeanrenaud B (1987) Stimulatory effect of cold adaptation on glucose utilization by brown adipose tissue. Relationship with changes in the glucose transporter system. J Biol Chem 262:7732–7736PubMedGoogle Scholar
  52. Gruden G, Landi A, Bruno G (2014) Natriuretic peptides, heart, and adipose tissue: new findings and future developments for diabetes research. Diabetes Care 37:2899–2908PubMedGoogle Scholar
  53. Haas B, Mayer P, Jennissen K, Scholz D, Diaz MB, Bloch W, Herzig S, Fässler R, Pfeifer A (2009) Protein kinase G controls brown fat cell differentiation and mitochondrial biogenesis. Sci Signal 2:ra78PubMedGoogle Scholar
  54. Handa P, Tateya S, Rizzo NO, Cheng AM, Morgan-Stevenson V, Han C-Y, Clowes AW, Daum G, O’Brien KD, Schwartz MW, Chait A, Kim F (2011) Reduced vascular nitric oxide–cGMP signaling contributes to adipose tissue inflammation during high-fat feeding. Arterioscler Thromb Vasc Biol 31:2827–2835PubMedPubMedCentralGoogle Scholar
  55. Hankir MK, Kranz M, Gnad T, Weiner J, Wagner S, Deuther-Conrad W, Bronisch F, Steinhoff K, Luthardt J, Kloting N, Hesse S, Seibyl JP, Sabri O, Heiker JT, Bluher M, Pfeifer A, Brust P, Fenske WK (2016) A novel thermoregulatory role for PDE10A in mouse and human adipocytes. EMBO Mol Med 8:796–812PubMedPubMedCentralGoogle Scholar
  56. Hanoune J, Defer N (2001) Regulation and role of adenylyl cyclase isoforms. Annu Rev Pharmacol Toxicol 41:145–174PubMedGoogle Scholar
  57. Heckemeyer CM, Barker J, Duckworth WC, Solomon SS (1983) Studies of the biological effect and degradation of glucagon in the rat perifused isolated adipose cell. Endocrinology 113:270–276PubMedGoogle Scholar
  58. Himms-Hagen J, Melnyk A, Zingaretti MC, Ceresi E, Barbatelli G, Cinti S (2000) Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am J Physiol Cell Physiol 279:C670–C681PubMedPubMedCentralGoogle Scholar
  59. Hoffmann LS, Etzrodt J, Willkomm L, Sanyal A, Scheja L, Fischer AWC, Stasch J-P, Bloch W, Friebe A, Heeren J, Pfeifer A (2015) Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue. Nat Commun 6:7235PubMedPubMedCentralGoogle Scholar
  60. Hofmann F, Feil R, Kleppisch T, Schlossmann J (2006) Function of cGMP-dependent protein kinases as revealed by gene deletion. Physiol Rev 86:1–23PubMedGoogle Scholar
  61. Hom GJ, Forrest MJ, Bach TJ, Brady E, Candelore MR, Cascieri MA, Fletcher DJ, Fisher MH, Iliff SA, Mathvink R, Metzger J, Pecore V, Saperstein R, Shih T, Weber AE, Wyvratt M, Zafian P, Macintyre DE (2001) Beta(3)-adrenoceptor agonist-induced increases in lipolysis, metabolic rate, facial flushing, and reflex tachycardia in anesthetized rhesus monkeys. J Pharmacol Exp Ther 297:299–307PubMedGoogle Scholar
  62. Hondares E, Rosell M, Gonzalez FJ, Giralt M, Iglesias R, Villarroya F (2010) Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab 11:206–212PubMedPubMedCentralGoogle Scholar
  63. Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, Villarroya F (2011) Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 286:12983–12990PubMedPubMedCentralGoogle Scholar
  64. Howland RJ, Benning AD (1986) Differential effects of noradrenaline and glucagon on lipolysis and fatty-acid utilization in brown adipose tissue. FEBS Lett 208:128–132PubMedGoogle Scholar
  65. Hu Y, Robichaux WG 3rd, Mei FC, Kim ER, Wang H, Tong Q, Jin J, Xu M, Chen J, Cheng X (2016) Role of exchange protein directly activated by cyclic AMP isoform 1 in energy homeostasis: regulation of leptin expression and secretion in white adipose tissue. Mol Cell Biol 36:2440–2450PubMedPubMedCentralGoogle Scholar
  66. Hutchinson DS, Chernogubova E, Dallner OS, Cannon B, Bengtsson T (2005) Beta-adrenoceptors, but not alpha-adrenoceptors, stimulate AMP-activated protein kinase in brown adipocytes independently of uncoupling protein-1. Diabetologia 48:2386–2395PubMedGoogle Scholar
  67. Hwang M, Go Y, Park JH, Shin SK, Song SE, Oh BC, Im SS, Hwang I, Jeon YH, Lee IK, Seino S, Song DK (2017) Epac2a-null mice exhibit obesity-prone nature more susceptible to leptin resistance. Int J Obes (Lond) 41:279–288Google Scholar
  68. Jahnsen T, Hedin L, Kidd VJ, Schulz T, Richards JS (1988) Molecular cloning of cDNA for a hormone-regulated isoform of the regulatory subunit of type II cAMP-dependent protein kinase from rat ovaries. Methods Enzymol 159:318–324PubMedGoogle Scholar
  69. Jaumann M, Dettling J, Gubelt M, Zimmermann U, Gerling A, Paquet-Durand F, Feil S, Wolpert S, Franz C, Varakina K, Xiong H, Brandt N, Kuhn S, Geisler H-S, Rohbock K, Ruth P, Schlossmann J, Hütter J, Sandner P, Feil R, Engel J, Knipper M, Rüttiger L (2012) cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function. Nat Med 18:252PubMedGoogle Scholar
  70. Jennissen K, Siegel F, Liebig-Gonglach M, Hermann MR, Kipschull S, van Dooren S, Kunz WS, Fassler R, Pfeifer A (2012) A VASP-Rac-soluble guanylyl cyclase pathway controls cGMP production in adipocytes. Sci Signal 5:ra62PubMedGoogle Scholar
  71. Jennissen K, Haas B, Mitschke MM, Siegel F, Pfeifer A (2013) Analysis of cGMP signaling in adipocytes. Methods Mol Biol 1020:175–192PubMedGoogle Scholar
  72. Jiang C, Zhai M, Yan D, Li D, Li C, Zhang Y, Xiao L, Xiong D, Deng Q, Sun W (2017) Dietary menthol-induced TRPM8 activation enhances WAT “browning” and ameliorates diet-induced obesity. Oncotarget 8:75114–75126PubMedPubMedCentralGoogle Scholar
  73. Kasai K, Kon S, Sato N, Muraishi K, Yoshida H, Nakai N, Hamakawa H, Itoh C, Yamaoka S (1999) Case report of lymphoepithelioma-like carcinoma of the lung – lymphoid population consisting of cytotoxic T cells in resting state. Pathol Res Pract 195:773–779PubMedGoogle Scholar
  74. Kaupp UB, Seifert R (2001) Molecular diversity of pacemaker ion channels. Annu Rev Physiol 63:235–257PubMedGoogle Scholar
  75. Kaupp UB, Seifert R (2002) Cyclic nucleotide-gated ion channels. Physiol Rev 82:769–824PubMedGoogle Scholar
  76. Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, Housman DE, Graybiel AM (1998) A family of cAMP-binding proteins that directly activate Rap1. Science 282:2275–2279PubMedGoogle Scholar
  77. Kelley GG, Chepurny OG, Schwede F, Genieser HG, Leech CA, Roe MW, Li X, Dzhura I, Dzhura E, Afshari P, Holz GG (2009) Glucose-dependent potentiation of mouse islet insulin secretion by Epac activator 8-pCPT-2′-O-Me-cAMP-AM. Islets 1:260–265PubMedPubMedCentralGoogle Scholar
  78. Kim SH, Plutzky J (2016) Brown fat and browning for the treatment of obesity and related metabolic disorders. Diabetes Metab J 40:12–21PubMedPubMedCentralGoogle Scholar
  79. Kim SP, Ha JM, Yun SJ, Kim EK, Chung SW, Hong KW, Kim CD, Bae SS (2010) Transcriptional activation of peroxisome proliferator-activated receptor-gamma requires activation of both protein kinase A and Akt during adipocyte differentiation. Biochem Biophys Res Commun 399:55–59PubMedGoogle Scholar
  80. Kinderman FS, Kim C, von Daake S, Ma Y, Pham BQ, Spraggon G, Xuong NH, Jennings PA, Taylor SS (2006) A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase. Mol Cell 24:397–408PubMedPubMedCentralGoogle Scholar
  81. Kinoshita K, Ozaki N, Takagi Y, Murata Y, Oshida Y, Hayashi Y (2014) Glucagon is essential for adaptive thermogenesis in brown adipose tissue. Endocrinology 155:3484–3492PubMedGoogle Scholar
  82. Kitamura T, Kitamura Y, Kuroda S, Hino Y, Ando M, Kotani K, Konishi H, Matsuzaki H, Kikkawa U, Ogawa W, Kasuga M (1999) Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt. Mol Cell Biol 19:6286–6296PubMedPubMedCentralGoogle Scholar
  83. Koesling D, Böhme E, Schultz G (1991) Guanylyl cyclases, a growing family of signal-transducing enzymes. FASEB J 5:2785–2791PubMedGoogle Scholar
  84. Koh HJ, Hirshman MF, He H, Li Y, Manabe Y, Balschi JA, Goodyear LJ (2007) Adrenaline is a critical mediator of acute exercise-induced AMP-activated protein kinase activation in adipocytes. Biochem J 403:473–481PubMedPubMedCentralGoogle Scholar
  85. Kong X, Banks A, Liu T, Kazak L, Rao RR, Cohen P, Wang X, Yu S, Lo JC, Tseng YH, Cypess AM, Xue R, Kleiner S, Kang S, Spiegelman BM, Rosen ED (2014) IRF4 is a key thermogenic transcriptional partner of PGC-1alpha. Cell 158:69–83PubMedPubMedCentralGoogle Scholar
  86. Kots AY, Martin E, Sharina IG, Murad F (2009) A short history of cGMP, guanylyl cyclases, and cGMP-dependent protein kinases. Handb Exp Pharmacol:1–14Google Scholar
  87. Kozak UC, Kozak LP (1994) Norepinephrine-dependent selection of brown adipocyte cell lines. Endocrinology 134:906–913PubMedGoogle Scholar
  88. Kraynik SM, Miyaoka RS, Beavo JA (2013) PDE3 and PDE4 isozyme-selective inhibitors are both required for synergistic activation of brown adipose tissue. Mol Pharmacol 83:1155–1165PubMedPubMedCentralGoogle Scholar
  89. Kumar A, Shiloach J, Betenbaugh MJ, Gallagher EJ (2015) The beta-3 adrenergic agonist (CL-316,243) restores the expression of down-regulated fatty acid oxidation genes in type 2 diabetic mice. Nutr Metab (Lond) 12:8Google Scholar
  90. Kusminski CM, Bickel PE, Scherer PE (2016) Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat Rev Drug Discov 15:639–660PubMedPubMedCentralGoogle Scholar
  91. Langeberg LK, Scott JD (2015) Signalling scaffolds and local organization of cellular behaviour. Nat Rev Mol Cell Biol 16:232–244PubMedPubMedCentralGoogle Scholar
  92. Lee DC, Carmichael DF, Krebs EG, McKnight GS (1983) Isolation of a cDNA clone for the type I regulatory subunit of bovine cAMP-dependent protein kinase. Proc Natl Acad Sci U S A 80:3608–3612PubMedPubMedCentralGoogle Scholar
  93. Lee MY, Kong HJ, Cheong J (2001) Regulation of activating transcription factor-2 in early stage of the adipocyte differentiation program. Biochem Biophys Res Commun 281:1241–1247PubMedGoogle Scholar
  94. Lee CYW, Chen HH, Lisy O, Swan S, Cannon C, Lieu HD, Burnett JC (2009) Pharmacodynamics pharmacodynamics of a novel designer natriuretic peptide, CD-NP, in a first-in-human clinical trial in healthy subjects. J Clin Pharmacol 49:668–673PubMedPubMedCentralGoogle Scholar
  95. Lee YH, Kim SN, Kwon HJ, Maddipati KR, Granneman JG (2016) Adipogenic role of alternatively activated macrophages in beta-adrenergic remodeling of white adipose tissue. Am J Physiol Regul Integr Comp Physiol 310:R55–R65PubMedGoogle Scholar
  96. Li S, Li Y, Xiang L, Dong J, Liu M, Xiang G (2018) Sildenafil induces browning of subcutaneous white adipose tissue in overweight adults. Metabolism 78:106–117PubMedGoogle Scholar
  97. Loncar D (1991) Convertible adipose tissue in mice. Cell Tissue Res 266:149–161PubMedGoogle Scholar
  98. Louis SN, Jackman GP, Nero TL, Iakovidis D, Louis WJ (2000) Role of beta-adrenergic receptor subtypes in lipolysis. Cardiovasc Drugs Ther 14:565–577PubMedGoogle Scholar
  99. MacDougald OA, Lane MD (1995) Transcriptional regulation of gene expression during adipocyte differentiation. Annu Rev Biochem 64:345–373PubMedGoogle Scholar
  100. McDonald LJ, Murad F (1996) Nitric oxide and cyclic GMP signaling. Exp Biol Med 211:1–6Google Scholar
  101. Mitschke MM, Hoffmann LS, Gnad T, Scholz D, Kruithoff K, Mayer P, Haas B, Sassmann A, Pfeifer A, Kilić A (2013) Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J 27:1621–1630PubMedGoogle Scholar
  102. Miyashita K, Itoh H, Tsujimoto H, Tamura N, Fukunaga Y, Sone M, Yamahara K, Taura D, Inuzuka M, Sonoyama T, Nakao K (2009) Natriuretic peptides/cGMP/cGMP-dependent protein kinase cascades promote muscle mitochondrial biogenesis and prevent obesity. Diabetes 58:2880–2892PubMedPubMedCentralGoogle Scholar
  103. Miyoshi H, Souza SC, Zhang HH, Strissel KJ, Christoffolete MA, Kovsan J, Rudich A, Kraemer FB, Bianco AC, Obin MS, Greenberg AS (2006) Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms. J Biol Chem 281:15837–15844PubMedGoogle Scholar
  104. Miyoshi H, Perfield JW 2nd, Souza SC, Shen WJ, Zhang HH, Stancheva ZS, Kraemer FB, Obin MS, Greenberg AS (2007) Control of adipose triglyceride lipase action by serine 517 of perilipin A globally regulates protein kinase A-stimulated lipolysis in adipocytes. J Biol Chem 282:996–1002PubMedGoogle Scholar
  105. Moreland RB, Goldstein I, Traish A (1998) Sildenafil, a novel inhibitor of phosphodiesterase type 5 in human corpus cavernosum smooth muscle cells. Life Sci 62:PL309–PL318Google Scholar
  106. Moro C, Lafontan M (2012) Natriuretic peptides and cGMP signaling control of energy homeostasis. Am J Phys Heart Circ Phys 304:H358–H368Google Scholar
  107. Nádvorník R, Vomastek T, Janeček J, Techniková Z, Branny P (1999) Pkg2, a novel transmembrane protein Ser/Thr kinase of Streptomyces granaticolor. J Bacteriol 181:15–23PubMedPubMedCentralGoogle Scholar
  108. Newhall KJ, Cummings DE, Nolan MA, McKnight GS (2005) Deletion of the RIIbeta-subunit of protein kinase A decreases body weight and increases energy expenditure in the obese, leptin-deficient ob/ob mouse. Mol Endocrinol 19:982–991PubMedGoogle Scholar
  109. Newlon MG, Roy M, Morikis D, Carr DW, Westphal R, Scott JD, Jennings PA (2001) A novel mechanism of PKA anchoring revealed by solution structures of anchoring complexes. EMBO J 20:1651–1662PubMedPubMedCentralGoogle Scholar
  110. Nishikimi T, Maeda N, Matsuoka H (2006) The role of natriuretic peptides in cardioprotection. Cardiovasc Res 69:318–328PubMedGoogle Scholar
  111. Nisoli E, Clementi E, Tonello C, Sciorati C, Briscini L, Carruba MO (1998) Effects of nitric oxide on proliferation and differentiation of rat brown adipocytes in primary cultures. Br J Pharmacol 125:888–894PubMedPubMedCentralGoogle Scholar
  112. Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, Bracale R, Valerio A, Francolini M, Moncada S, Carruba MO (2003) Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science 299:896–899PubMedGoogle Scholar
  113. Nolan MA, Sikorski MA, McKnight GS (2004) The role of uncoupling protein 1 in the metabolism and adiposity of RII beta-protein kinase A-deficient mice. Mol Endocrinol 18:2302–2311PubMedGoogle Scholar
  114. Olsen JM, Sato M, Dallner OS, Sandstrom AL, Pisani DF, Chambard JC, Amri EZ, Hutchinson DS, Bengtsson T (2014) Glucose uptake in brown fat cells is dependent on mTOR complex 2-promoted GLUT1 translocation. J Cell Biol 207:365–374PubMedPubMedCentralGoogle Scholar
  115. Olsen JM, Csikasz RI, Dehvari N, Lu L, Sandstrom A, Oberg AI, Nedergaard J, Stone-Elander S, Bengtsson T (2017) beta3-Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: mediation through the mTOR pathway. Mol Metab 6:611–619PubMedPubMedCentralGoogle Scholar
  116. Omar B, Zmuda-Trzebiatowska E, Manganiello V, Goransson O, Degerman E (2009) Regulation of AMP-activated protein kinase by cAMP in adipocytes: roles for phosphodiesterases, protein kinase B, protein kinase A, Epac and lipolysis. Cell Signal 21:760–766PubMedPubMedCentralGoogle Scholar
  117. Pandit K, Mukhopadhyay P, Ghosh S, Chowdhury S (2011) Natriuretic peptides: diagnostic and therapeutic use. Indian J Endocrinol Metab 15:S345–S353PubMedPubMedCentralGoogle Scholar
  118. Perea A, Clemente F, Martinell J, Villanueva-Penacarrillo ML, Valverde I (1995) Physiological effect of glucagon in human isolated adipocytes. Horm Metab Res 27:372–375PubMedGoogle Scholar
  119. Perino A, Ghigo A, Ferrero E, Morello F, Santulli G, Baillie GS, Damilano F, Dunlop AJ, Pawson C, Walser R, Levi R, Altruda F, Silengo L, Langeberg LK, Neubauer G, Heymans S, Lembo G, Wymann MP, Wetzker R, Houslay MD, Iaccarino G, Scott JD, Hirsch E (2011) Integrating cardiac PIP3 and cAMP signaling through a PKA anchoring function of p110gamma. Mol Cell 42:84–95PubMedPubMedCentralGoogle Scholar
  120. Pfeifer A, Aszodi A, Seidler U, Ruth P, Hofmann F, Fassler R (1996) Intestinal secretory defects and dwarfism in mice lacking cGMP-dependent protein kinase II. Science 274:2082–2086PubMedGoogle Scholar
  121. Pidoux G, Tasken K (2010) Specificity and spatial dynamics of protein kinase A signaling organized by A-kinase-anchoring proteins. J Mol Endocrinol 44:271–284PubMedGoogle Scholar
  122. Pifferi S, Boccaccio A, Menini A (2006) Cyclic nucleotide-gated ion channels in sensory transduction. FEBS Lett 580:2853–2859PubMedGoogle Scholar
  123. Poulos TL (2006) Soluble guanylate cyclase. Curr Opin Struct Biol 16:736–743PubMedGoogle Scholar
  124. Puigserver P, Spiegelman BM (2003) Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 24:78–90Google Scholar
  125. Rehmann H, Das J, Knipscheer P, Wittinghofer A, Bos JL (2006) Structure of the cyclic-AMP-responsive exchange factor Epac2 in its auto-inhibited state. Nature 439:625–628PubMedGoogle Scholar
  126. Ringheim GE, Taylor SS (1990) Effects of cAMP-binding site mutations on intradomain cross-communication in the regulatory subunit of cAMP-dependent protein kinase I. J Biol Chem 265:19472–19478PubMedGoogle Scholar
  127. Robidoux J, Cao W, Quan H, Daniel KW, Moukdar F, Bai X, Floering LM, Collins S (2005) Selective activation of mitogen-activated protein (MAP) kinase kinase 3 and p38alpha MAP kinase is essential for cyclic AMP-dependent UCP1 expression in adipocytes. Mol Cell Biol 25:5466–5479PubMedPubMedCentralGoogle Scholar
  128. Rosen ED, Hsu CH, Wang X, Sakai S, Freeman MW, Gonzalez FJ, Spiegelman BM (2002) C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes Dev 16:22–26PubMedPubMedCentralGoogle Scholar
  129. Schimmel RJ, McCarthy L (1984) Role of adenosine as an endogenous regulator of respiration in hamster brown adipocytes. Am J Physiol 246:C301–C307PubMedGoogle Scholar
  130. Schlueter N, de Sterke A, Willmes DM, Spranger J, Jordan J, Birkenfeld AL (2014) Metabolic actions of natriuretic peptides and therapeutic potential in the metabolic syndrome. Pharmacol Ther 144:12–27PubMedGoogle Scholar
  131. Schreiber R, Diwoky C, Schoiswohl G, Feiler U, Wongsiriroj N, Abdellatif M, Kolb D, Hoeks J, Kershaw EE, Sedej S, Schrauwen P, Haemmerle G, Zechner R (2017) Cold-induced thermogenesis depends on ATGL-mediated lipolysis in cardiac muscle, but not brown adipose tissue. Cell Metab 26:753–763 e7PubMedPubMedCentralGoogle Scholar
  132. Scott JD, Glaccum MB, Fischer EH, Krebs EG (1986) Primary-structure requirements for inhibition by the heat-stable inhibitor of the cAMP-dependent protein kinase. Proc Natl Acad Sci U S A 83:1613–1616PubMedPubMedCentralGoogle Scholar
  133. Scott JD, Glaccum MB, Zoller MJ, Uhler MD, Helfman DM, McKnight GS, Krebs EG (1987) The molecular cloning of a type II regulatory subunit of the cAMP-dependent protein kinase from rat skeletal muscle and mouse brain. Proc Natl Acad Sci U S A 84:5192–5196PubMedPubMedCentralGoogle Scholar
  134. Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, Tavernier G, Langin D, Spiegelman BM (2007) Transcriptional control of brown fat determination by PRDM16. Cell Metab 6:38–54PubMedPubMedCentralGoogle Scholar
  135. Seitz HJ, Krone W, Wilke H, Tarnowski W (1981) Rapid rise in plasma glucagon induced by acute cold exposure in man and rat. Pflugers Arch 389:115–120PubMedGoogle Scholar
  136. Shabb JB (2001) Physiological substrates of cAMP-dependent protein kinase. Chem Rev 101:2381–2411PubMedGoogle Scholar
  137. Sheth S, Brito R, Mukherjea D, Rybak LP, Ramkumar V (2014) Adenosine receptors: expression, function and regulation. Int J Mol Sci 15:2024–2052PubMedPubMedCentralGoogle Scholar
  138. Sheyn D, Pelled G, Tawackoli W, Su S, Ben-David S, Gazit D, Gazit Z (2013) Transient overexpression of Ppargamma2 and C/ebpalpha in mesenchymal stem cells induces brown adipose tissue formation. Regen Med 8:295–308PubMedGoogle Scholar
  139. Shimizu Y, Satoh S, Yano H, Minokoshi Y, Cushman SW, Shimazu T (1998) Effects of noradrenaline on the cell-surface glucose transporters in cultured brown adipocytes: novel mechanism for selective activation of GLUT1 glucose transporters. Biochem J 330(Pt 1):397–403PubMedPubMedCentralGoogle Scholar
  140. Shin H, Ma Y, Chanturiya T, Cao Q, Wang Y, Kadegowda AKG, Jackson R, Rumore D, Xue B, Shi H, Gavrilova O, Yu L (2017) Lipolysis in brown adipocytes is not essential for cold-induced thermogenesis in mice. Cell Metab 26:764–777 e5PubMedPubMedCentralGoogle Scholar
  141. Sim AT, Scott JD (1999) Targeting of PKA, PKC and protein phosphatases to cellular microdomains. Cell Calcium 26:209–217PubMedGoogle Scholar
  142. Snyder PB, Esselstyn JM, Loughney K, Wolda SL, Florio VA (2005) The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis. J Lipid Res 46:494–503PubMedGoogle Scholar
  143. Su CL, Sztalryd C, Contreras JA, Holm C, Kimmel AR, Londos C (2003) Mutational analysis of the hormone-sensitive lipase translocation reaction in adipocytes. J Biol Chem 278:43615–43619PubMedGoogle Scholar
  144. Svensson KJ, Long JZ, Jedrychowski MP, Cohen P, Lo JC, Serag S, Kir S, Shinoda K, Tartaglia JA, Rao RR, Chedotal A, Kajimura S, Gygi SP, Spiegelman BM (2016) A secreted slit2 fragment regulates adipose tissue thermogenesis and metabolic function. Cell Metab 23:454–466PubMedPubMedCentralGoogle Scholar
  145. Szillat D, Bukowiecki LJ (1983) Control of brown adipose tissue lipolysis and respiration by adenosine. Am J Physiol 245:E555–E559PubMedGoogle Scholar
  146. Sztalryd C, Xu G, Dorward H, Tansey JT, Contreras JA, Kimmel AR, Londos C (2003) Perilipin A is essential for the translocation of hormone-sensitive lipase during lipolytic activation. J Cell Biol 161:1093–1103PubMedPubMedCentralGoogle Scholar
  147. Tanaka T, Yoshida N, Kishimoto T, Akira S (1997) Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J 16:7432–7443PubMedPubMedCentralGoogle Scholar
  148. Tasken K, Aandahl EM (2004) Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiol Rev 84:137–167PubMedGoogle Scholar
  149. Tiraby C, Langin D (2003) Conversion from white to brown adipocytes: a strategy for the control of fat mass? Trends Endocrinol Metab 14:439–441PubMedGoogle Scholar
  150. Tiraby C, Tavernier G, Lefort C, Larrouy D, Bouillaud F, Ricquier D, Langin D (2003) Acquirement of brown fat cell features by human white adipocytes. J Biol Chem 278:33370–33376PubMedGoogle Scholar
  151. Tsai EJ, Kass DA (2009) Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. Pharmacol Ther 122:216–238PubMedPubMedCentralGoogle Scholar
  152. Uhler MD, Carmichael DF, Lee DC, Chrivia JC, Krebs EG, McKnight GS (1986a) Isolation of cDNA clones coding for the catalytic subunit of mouse cAMP-dependent protein kinase. Proc Natl Acad Sci U S A 83:1300–1304PubMedPubMedCentralGoogle Scholar
  153. Uhler MD, Chrivia JC, McKnight GS (1986b) Evidence for a second isoform of the catalytic subunit of cAMP-dependent protein kinase. J Biol Chem 261:15360–15363PubMedGoogle Scholar
  154. Unelius L, Mohell N, Nedergaard J (1990) Cold acclimation induces desensitization to adenosine in brown fat cells without changing receptor binding. Am J Physiol 258:C818–C826PubMedGoogle Scholar
  155. Vaandrager AB, de Jonge HR (1996) Signalling by cGMP-dependent protein kinases. Mol Cell Biochem 157:23–30PubMedGoogle Scholar
  156. Valladares A, Porras A, Alvarez AM, Roncero C, Benito M (2000) Noradrenaline induces brown adipocytes cell growth via beta-receptors by a mechanism dependent on ERKs but independent of cAMP and PKA. J Cell Physiol 185:324–330PubMedGoogle Scholar
  157. Waldman SA, Rapoport RM, Murad F (1984) Atrial natriuretic factor selectively activates particulate guanylate cyclase and elevates cyclic GMP in rat tissues. J Biol Chem 259:14332–14334PubMedGoogle Scholar
  158. Wernet W, Flockerzi V, Hofmann F (1989) The cDNA of the two isoforms of bovine cGMP-dependent protein kinase. FEBS Lett 251:191–196PubMedGoogle Scholar
  159. Yin W, Mu J, Birnbaum MJ (2003) Role of AMP-activated protein kinase in cyclic AMP-dependent lipolysis in 3T3-L1 adipocytes. J Biol Chem 278:43074–43080PubMedGoogle Scholar
  160. Zhang JW, Klemm DJ, Vinson C, Lane MD (2004) Role of CREB in transcriptional regulation of CCAAT/enhancer-binding protein beta gene during adipogenesis. J Biol Chem 279:4471–4478PubMedGoogle Scholar
  161. Zhang X, Ji J, Yan G, Wu J, Sun X, Shen J, Jiang H, Wang H (2010) Sildenafil promotes adipogenesis through a PKG pathway. Biochem Biophys Res Commun 396:1054–1059PubMedGoogle Scholar
  162. Zoller MJ, Kerlavage AR, Taylor SS (1979) Structural comparisons of cAMP-dependent protein kinases I and II from porcine skeletal muscle. J Biol Chem 254:2408–2412PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Laia Reverte-Salisa
    • 1
  • Abhishek Sanyal
    • 1
  • Alexander Pfeifer
    • 1
    Email author
  1. 1.Institute of Pharmacology and ToxicologyUniversity Hospital Bonn, University of BonnBonnGermany

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