Nrf2 induces Ucp1 expression in adipocytes in response to β3-AR stimulation and enhances oxygen consumption in high-fat diet-fed obese mice
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Cold-induced norepinephrine activates β3-adrenergic receptors(β3-AR) to stimulate the kinase cascade and cAMP-responseelement-binding protein, leading to the induction of thermogenicgene expression including uncoupling protein 1 (Ucp1). Here,we showed that stimulation of the β3-AR by its agonists isoproterenoland CL316,243 in adipocytes increased the expressionof Ucp1 and Heme Oxygenase 1 (Hmox1), the principal Nrf2target gene, suggesting the functional interaction of Nrf2 withβ3-AR signaling. The activation of Nrf2 by tert-butylhydroquinoneand reactive oxygen species (ROS) production by glucoseoxidase induced both Ucp1 and Hmox1 expression. The increasedexpression of Ucp1 and Hmox1 was significantly reduced inthe presence of a Nrf2 chemical inhibitor or in Nrf2-deleted(knockout) adipocytes. Furthermore, Nrf2 directly activated theUcp1 promoter, and this required DNA regions located at −3.7 and −2.0 kb of the transcription start site. The CL316,243-induced Ucp1 expression in adipocytes and oxygen consumptionin obese mice were partly compromised in the absence ofNrf2 expression. These data provide additional insight into therole of Nrf2 in β3-AR-mediated Ucp1 expression and energyexpenditure, further highlighting the utility of Nrf2-mediatedthermogenic stimulation as a therapeutic approach to diet-inducedobesity.
Abstract
Cold-induced norepinephrine activates β3-adrenergic receptors(β3-AR) to stimulate the kinase cascade and cAMP-responseelement-binding protein, leading to the induction of thermogenicgene expression including uncoupling protein 1 (Ucp1). Here,we showed that stimulation of the β3-AR by its agonists isoproterenoland CL316,243 in adipocytes increased the expressionof Ucp1 and Heme Oxygenase 1 (Hmox1), the principal Nrf2target gene, suggesting the functional interaction of Nrf2 withβ3-AR signaling. The activation of Nrf2 by tert-butylhydroquinoneand reactive oxygen species (ROS) production by glucoseoxidase induced both Ucp1 and Hmox1 expression. The increasedexpression of Ucp1 and Hmox1 was significantly reduced inthe presence of a Nrf2 chemical inhibitor or in Nrf2-deleted(knockout) adipocytes. Furthermore, Nrf2 directly activated theUcp1 promoter, and this required DNA regions located at −3.7 and −2.0 kb of the transcription start site. The CL316,243-induced Ucp1 expression in adipocytes and oxygen consumptionin obese mice were partly compromised in the absence ofNrf2 expression. These data provide additional insight into therole of Nrf2 in β3-AR-mediated Ucp1 expression and energyexpenditure, further highlighting the utility of Nrf2-mediatedthermogenic stimulation as a therapeutic approach to diet-inducedobesity.
참고문헌 (35)
- Betz MJ, "Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease", Nat Rev Endocrinol, 14, pp.77~87 (2018)
- Chang SH, "Mechanisms underlying UCP1 dependent and independent adipocyte thermogenesis", Obes Rev, 20, pp.241~251 (2019)
- Fedorenko A, "Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria", Cell, 151, pp.400~413 (2012)
- Divakaruni AS, "The regulation and physiology of mitochondrial proton leak", Physiology(Bethesda), 26, pp.192~205 (2011)
- Vitali A, "The adipose organ of obesity-prone C57BL", 6J mice is composed of mixed white and brown adipocytes, 2012, pp.53, 619~629
- Himms-Hagen J, "Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes", Am J Physiol Cell Physiol, 279, pp.C670~C681 (2000)
- Stanford KI, "Exercise effects on white adipose tissue : beiging and metabolic adaptations", Diabetes, 64, pp.2361~2368 (2015)
- Yoneshiro T, "Impact of UCP1 and beta3AR gene polymorphisms on age-related changes in brown adipose tissue and adiposity in humans", Int J Obes(Lond), 37, pp.993~998 (2013)
- Morrison SF, "Central control of brown adipose tissue thermogenesis", Front Endocrinol (Lausanne)., 3, pp.1~19 (2012)
- Collins S, "Beta-adrenoceptor signaling networks in adipocytes for recruiting stored fat and energy expenditure", Front Endocrinol (Lausanne), 2, pp.102~ (2011)
- Cypess AM, "Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist", Cell Metab, 21, pp.33~38 (2015)
- Matthias A, "Thermogenic responses in brown fat cells are fully UCP1-dependent. UCP2 or UCP3 do not substitute for UCP1 in adrenergically or fatty scid-induced thermogenesis", J Biol Chem, 275, pp.25073~25081 (2000)
- Inokuma K, "Uncoupling protein 1 is necessary for norepinephrine-induced glucose utilization in brown adipose tissue", Diabetes, 54, pp.1385~1391 (2005)
- Guan XM, "Determination of structural domains for G protein coupling and ligand binding in beta 3-adrenergic receptor", Mol Pharmacol, 48, pp.492~498 (1995)
- Mayr B, "Transcriptional regulation by the phosphorylation-dependent factor CREB", Nat Rev Mol Cell Biol, 2, pp.599~609 (2001)
- Schneider KS, "Emerging role of Nrf2 in adipocytes and adipose biology", Adv Nutr, 4, pp.62~66 (2013)
- Shaw P, "Nrf2-ARE signaling in cellular protection : Mechanism of action and the regulatory mechanisms", J Cell Physiol, 235, pp.3119~3130 (2020)
- Wakabayashi N, "When NRF2 talks, who’s listening?", Antioxid Redox Signal, 13, pp.1649~1663 (2010)
- Hye In Lee, "Dehydrocostus lactone inhibits NFATc1 via regulation of IKK, JNK, and Nrf2, thereby attenuating osteoclastogenesis", BMB Reports, 53(4), pp.218~222 (2020), 생화학분자생물학회[DOI]
- Jaiswal AK, "Nrf2 signaling in coordinated activation of antioxidant gene expression", Free Radic Biol Med, 36, pp.1199~1207 (2004)
- Potashnik R, "IRS1 degradation and increased serine phosphorylation cannot predict the degree of metabolic insulin resistance induced by oxidative stress", Diabetologia, 46, pp.639~648 (2003)
- Elbini Dhouib I, "A minireview on N-acetylcysteine : an old drug with new approaches", Life Sci, 151, pp.359~363 (2016)
- Kulkarni SR, "Fasting induces nuclear factor E2-related factor 2 and ATP-binding Cassette transporters via protein kinase A and Sirtuin-1 in mouse and human", Antioxid Redox Signal, 20, pp.15~30 (2014)
- Astort F, "Role of CREB on heme oxygenase-1 induction in adrenal cells : involvement of the PI3K pathway", J Mol Endocrinol, 57, pp.113~124 (2016)
- Kronke G, "Oxidized phospholipids induce expression of human heme oxygenase-1 involving activation of cAMP-responsive elementbinding protein", J Biol Chem, 278, pp.51006~51014 (2003)
- Mylroie H, "PKCepsilon-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis", Cardiovasc Res, 106, pp.509~519 (2015)
- Tchivileva IE, "Signaling pathways mediating beta3-adrenergic receptor-induced production of interleukin-6 in adipocytes", Mol Immunol, 46, pp.2256~2266 (2009)
- Lindquist JM, "Beta 3-and alpha1-adrenergic Erk1", 2activation is Src-but not Gi-mediated in Brown adipocytes, 2000, pp.275, 22670~22677
- Soeder KJ, "The beta3-adrenergic receptor activates mitogen-activated protein kinase in adipocytes through a Gi-dependent mechanism", J Biol Chem, 274, pp.12017~12022 (1999)
- Gerhardt CC, "Stimulation of the extracellular signal-regulated kinase 1", 2pathway by human beta-3 adrenergic receptor : new pharmacological profile and mechanism of activation, 1999, pp.55, 255~262
- Ye L, "Fat cells directly sense temperature to activate thermogenesis", Proc Natl Acad Sci U S A, 110, pp.12480~12485 (2013)
- Corbi G, "Adrenergic signaling and oxidative stress : a role for sirtuins?", Front Physiol, 4, pp.324~ (2013)
- Takahata Y, "Functional expression of beta2 adrenergic receptors responsible for protection against oxidative stress through promotion of glutathione synthesis after Nrf2 upregulation in undifferentiated mesenchymal C3H10T1", 2 stem cells, 2009, pp.218, 268~275
- Song NJ, "Prdm4induction by the small molecule butein promotes white adipose tissue browning", Nat Chem Biol, 12, pp.479~481 (2016)
- Bahn G, "NRF2", ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer’s models, 2019, pp.116, 12516~12523