Cordycepin promotes browning of white adipose tissue through an AMP-activated protein kinase(AMPK)-dependent pathway
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摘要
Obesity is a worldwide epidemic. Promoting browning of white adipose tissue(WAT)contributes to increased energy expenditure and hence counteracts obesity. Here we show that cordycepin(Cpn), a natural derivative of adenosine, increases energy expenditure, inhibits weight gain, improves metabolic profile and glucose tolerance, decreases WAT mass and adipocyte size, and enhances cold tolerance in normal and high-fat diet-fed mice. Cpn markedly increases the surface temperature around the inguinal WAT and turns the inguinal fat browner. Further investigations show that Cpn induces the development of brown-like adipocytes in inguinal and, to a less degree, epididymal WAT depots. Cpn also increases the expression of uncoupling protein 1(UCP1) and other thermogenic genes in WAT and3T3-L1 differentiated adipocytes, in which AMP-activated protein kinase(AMPK) plays an important role. Our results provide novel insights into the function of Cpn in regulating energy balance, and suggest a potential utility of Cpn in the treatment of obesity.
Obesity is a worldwide epidemic. Promoting browning of white adipose tissue(WAT)contributes to increased energy expenditure and hence counteracts obesity. Here we show that cordycepin(Cpn), a natural derivative of adenosine, increases energy expenditure, inhibits weight gain, improves metabolic profile and glucose tolerance, decreases WAT mass and adipocyte size, and enhances cold tolerance in normal and high-fat diet-fed mice. Cpn markedly increases the surface temperature around the inguinal WAT and turns the inguinal fat browner. Further investigations show that Cpn induces the development of brown-like adipocytes in inguinal and, to a less degree, epididymal WAT depots. Cpn also increases the expression of uncoupling protein 1(UCP1) and other thermogenic genes in WAT and3T3-L1 differentiated adipocytes, in which AMP-activated protein kinase(AMPK) plays an important role. Our results provide novel insights into the function of Cpn in regulating energy balance, and suggest a potential utility of Cpn in the treatment of obesity.
Obesity is a worldwide epidemic. Promoting browning of white adipose tissue(WAT)contributes to increased energy expenditure and hence counteracts obesity. Here we show that cordycepin(Cpn), a natural derivative of adenosine, increases energy expenditure, inhibits weight gain, improves metabolic profile and glucose tolerance, decreases WAT mass and adipocyte size, and enhances cold tolerance in normal and high-fat diet-fed mice. Cpn markedly increases the surface temperature around the inguinal WAT and turns the inguinal fat browner. Further investigations show that Cpn induces the development of brown-like adipocytes in inguinal and, to a less degree, epididymal WAT depots. Cpn also increases the expression of uncoupling protein 1(UCP1) and other thermogenic genes in WAT and3T3-L1 differentiated adipocytes, in which AMP-activated protein kinase(AMPK) plays an important role. Our results provide novel insights into the function of Cpn in regulating energy balance, and suggest a potential utility of Cpn in the treatment of obesity.
引文
1.Bhupathiraju SN,Hu FB.Epidemiology of obesity and diabetes and their cardiovascular complications.Circ Res 2016;118:1723-35.
2.Wang S,Wu C,Li X,Zhou Y,Zhang Q,Ma F,et al.Syringaresinol-4-O-b-D-glucoside alters lipid and glucose metabolism in HepG2 cells and C2C12 myotubes.Acta Pharm Sin B 2017;7:453-60.
3.Crowley VE,Yeo GS,O'Rahilly S.Obesity therapy:altering the energy intake-and-expenditure balance sheet.Nat Rev Drug Discov2002;1:276-86.
4.Tseng YH,Cypess AM,Kahn CR.Cellular bioenergetics as a targe for obesity therapy.Nat Rev Drug Discov 2010;9:465-82.
5.Kuo T,Chen TC,Lee RA,Thao Nguyen NH,Broughton AE,Zhang Det al.Pik3r1 is required for glucocorticoid-induced perilipin 1 phosphorylation in lipid droplet for adipocyte lipolysis.Diabetes 2017;66:1601-10
6.Yu J,Zhang S,Cui L,Wang W,Na H,Zhu X,et al.Lipid drople remodeling and interaction with mitochondria in mouse brown adipose tissue during cold treatment.Biochim Biophys Acta 2015;1853:918-28
7.Wu J,Bostrom P,Sparks LM,Ye L,Choi JH,Giang AH,et al.Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human.Cell 2012;150:366-76.
8.Dodd GT,Decherf S,Loh K,Simonds SE,Wiede F,Balland E,et al Leptin and insulin act on POMC neurons to promote the browning of white fat.Cell 2015;160:88-104.
9.Wang H,Liu L,Lin JZ,Aprahamian TR,Farmer SR.Browning of white adipose tissue with roscovitine induces a distinct population of UCP1tadipocytes.Cell Metab 2016;24:835-47.
10.Zhang P,Huang C,Fu C,Tian Y,Hu Y,Wang B,et al.Cordycepin(3'-deoxyadenosine)suppressed HMGA2,Twist1 and ZEB1-dependent melanoma invasion and metastasis by targeting miR-33b Oncotarget 2015;6:9834-53.
11.Li X,Zhou Y,Zhang X,Cao X,Wu C,Guo P.Cordycepin stimulates autophagy in macrophages and prevents atherosclerotic plaque formation in ApoE-/-mice.Oncotarget 2017;8:94726-37.
12.Ma L,Zhang S,Du M.Cordycepin from Cordyceps militaris prevents hyperglycemia in alloxan-induced diabetic mice.Nutr Res2015;35:431-9.
13.Guo P,Kai Q,Gao J,Lian ZQ,Wu CM,Wu CA,et al.Cordycepin prevents hyperlipidemia in hamsters fed a high-fat diet via activation of AMP-activated protein kinase.J Pharmacol Sci 2010;113:395-403
14.Wu C,Guo Y,Su Y,Zhang X,Luan H,Zhang X,et al.Cordycepin activates AMP-activated protein kinase(AMPK)via interaction with the gamma1 subunit.J Cell Mol Med 2014;18:293-304.
15.Takahashi S,Tamai M,Nakajima S,Kato H,Johno H,Nakamura T,et al.Blockade of adipocyte differentiation by cordycepin.Br JPharmacol 2012;167:561-75.
16.Wu C,Zhang X,Zhang X,Luan H,Sun G,Sun X,et al.The caffeoylquinic acid-rich Pandanus tectorius fruit extract increases insulin sensitivity and regulates hepatic glucose and lipid metabolism in diabetic db/db mice.J Nutr Biochem 2014;25:412-9.
17.Wu C,Feng J,Wang R,Liu H,Yang H,Rodriguez PL,et al.HRS1acts as a negative regulator of abscisic acid signaling to promote timely germination of Arabidopsis seeds.PLoS One 2012;7:e35764.
18.Shan T,Xiong Y,Zhang P,Li Z,Jiang Q,Bi P,et al.Lkb1 controls brown adipose tissue growth and thermogenesis by regulating the intracellular localization of CRTC3.Nat Commun 2016;7:12205.
19.Bi P,Shan T,Liu W,Yue F,Yang X,Liang XR,et al.Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity.Nat Med 2014;20:911-8.
20.Petruzzelli M,Schweiger M,Schreiber R,Campos-Olivas R,Tsoli M,Allen J,et al.A switch from white to brown fat increases energy expenditure in cancer-associated cachexia.Cell Metab 2014;20:433-47.
21.Tomas E,Stanojevic V,McManus K,Khatri A,Everill P,Bachovchin WW,et al.GLP-1(32-36)amide pentapeptide increases basal energy expenditure and inhibits weight gain in obese mice.Diabetes2015;64:2409-19.
22.Li J,Zhong L,Wang F,Zhu H.Dissecting the role of AMP-activated protein kinase in human diseases.Acta Pharm Sin B 2017;7:249-59.
23.Shan T,Liang X,Bi P,Kuang S.Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1a-Fndc5pathway in muscle.FASEB J 2013;27:1981-9.
24.Hui X,Gu P,Zhang J,Nie T,Pan Y,Wu D,et al.Adiponectin enhances cold-induced browning of subcutaneous adipose tissue via promoting M2 macrophage proliferation.Cell Metab 2015;22:279-90.
25.Lee HJ,Lee JO,Kim N,Kim JK,Kim HI,Lee YW,et al.Irisin,a novel nyokine,regulates glucose uptake in skeletal muscle cells via AMPK.Mol Endocrinol 2015;29:873-81.
26.Gaidhu MP,Frontini A,Hung S,Pistor K,Cinti S,Ceddia RB.Chronic AMP-kinase activation with AICAR reduces adiposity by remodeling adipocyte metabolism and increasing leptin sensitivity.JLipid Res 2011;52:1702-11.
27.Beiroa D,Imbernon M,Gallego R,Senra A,Herranz D,Villarroya F,et al.GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK.Diabetes 2014;63:3346-58.
28.Lone J,Choi JH,Kim SW,Yun JW.Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes.J Nutr Biochem2016;27:193-202.
29.Zhang Z,Zhang H,Li B,Meng X,Wang J,Zhang Y,et al.Berberine activates thermogenesis in white and brown adipose tissue.Nat Commun 2014;5:5493.
30.Hardie GD.Regulation of AMP-activated protein kinase by natural and synthetic activators.Acta Pharm Sin B 2016;6:1-19.
31.Wong YY,Moon A,Duffin R,Barthet-Barateig A,Meijer HA,Clemens MJ,et al.Cordycepin inhibits protein synthesis and cell adhesion through effects on signal transduction.J Biol Chem2010;285:2610-21.
32.Gnad T,Scheibler S,von Kugelgen I,Scheele C,Kilic A,Glode A,et al.Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors.Nature 2014;516:395-9.
33.Leu SF,Poon SL,Pao HY,Huang BM.The in vivo and in vitro stimulatory effects of cordycepin on mouse leydig cell steroidogenesis.Biosci Biotechnol Biochem 2011;75:723-31.
34.Cao ZP,Dai D,Wei PJ,Han YY,Guan YQ,Li HH,et al.Effects of cordycepin on spontaneous alternation behavior and adenosine receptors expression in hippocampus.Physiol Behav 2018;184:135-42.
2.Wang S,Wu C,Li X,Zhou Y,Zhang Q,Ma F,et al.Syringaresinol-4-O-b-D-glucoside alters lipid and glucose metabolism in HepG2 cells and C2C12 myotubes.Acta Pharm Sin B 2017;7:453-60.
3.Crowley VE,Yeo GS,O'Rahilly S.Obesity therapy:altering the energy intake-and-expenditure balance sheet.Nat Rev Drug Discov2002;1:276-86.
4.Tseng YH,Cypess AM,Kahn CR.Cellular bioenergetics as a targe for obesity therapy.Nat Rev Drug Discov 2010;9:465-82.
5.Kuo T,Chen TC,Lee RA,Thao Nguyen NH,Broughton AE,Zhang Det al.Pik3r1 is required for glucocorticoid-induced perilipin 1 phosphorylation in lipid droplet for adipocyte lipolysis.Diabetes 2017;66:1601-10
6.Yu J,Zhang S,Cui L,Wang W,Na H,Zhu X,et al.Lipid drople remodeling and interaction with mitochondria in mouse brown adipose tissue during cold treatment.Biochim Biophys Acta 2015;1853:918-28
7.Wu J,Bostrom P,Sparks LM,Ye L,Choi JH,Giang AH,et al.Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human.Cell 2012;150:366-76.
8.Dodd GT,Decherf S,Loh K,Simonds SE,Wiede F,Balland E,et al Leptin and insulin act on POMC neurons to promote the browning of white fat.Cell 2015;160:88-104.
9.Wang H,Liu L,Lin JZ,Aprahamian TR,Farmer SR.Browning of white adipose tissue with roscovitine induces a distinct population of UCP1tadipocytes.Cell Metab 2016;24:835-47.
10.Zhang P,Huang C,Fu C,Tian Y,Hu Y,Wang B,et al.Cordycepin(3'-deoxyadenosine)suppressed HMGA2,Twist1 and ZEB1-dependent melanoma invasion and metastasis by targeting miR-33b Oncotarget 2015;6:9834-53.
11.Li X,Zhou Y,Zhang X,Cao X,Wu C,Guo P.Cordycepin stimulates autophagy in macrophages and prevents atherosclerotic plaque formation in ApoE-/-mice.Oncotarget 2017;8:94726-37.
12.Ma L,Zhang S,Du M.Cordycepin from Cordyceps militaris prevents hyperglycemia in alloxan-induced diabetic mice.Nutr Res2015;35:431-9.
13.Guo P,Kai Q,Gao J,Lian ZQ,Wu CM,Wu CA,et al.Cordycepin prevents hyperlipidemia in hamsters fed a high-fat diet via activation of AMP-activated protein kinase.J Pharmacol Sci 2010;113:395-403
14.Wu C,Guo Y,Su Y,Zhang X,Luan H,Zhang X,et al.Cordycepin activates AMP-activated protein kinase(AMPK)via interaction with the gamma1 subunit.J Cell Mol Med 2014;18:293-304.
15.Takahashi S,Tamai M,Nakajima S,Kato H,Johno H,Nakamura T,et al.Blockade of adipocyte differentiation by cordycepin.Br JPharmacol 2012;167:561-75.
16.Wu C,Zhang X,Zhang X,Luan H,Sun G,Sun X,et al.The caffeoylquinic acid-rich Pandanus tectorius fruit extract increases insulin sensitivity and regulates hepatic glucose and lipid metabolism in diabetic db/db mice.J Nutr Biochem 2014;25:412-9.
17.Wu C,Feng J,Wang R,Liu H,Yang H,Rodriguez PL,et al.HRS1acts as a negative regulator of abscisic acid signaling to promote timely germination of Arabidopsis seeds.PLoS One 2012;7:e35764.
18.Shan T,Xiong Y,Zhang P,Li Z,Jiang Q,Bi P,et al.Lkb1 controls brown adipose tissue growth and thermogenesis by regulating the intracellular localization of CRTC3.Nat Commun 2016;7:12205.
19.Bi P,Shan T,Liu W,Yue F,Yang X,Liang XR,et al.Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity.Nat Med 2014;20:911-8.
20.Petruzzelli M,Schweiger M,Schreiber R,Campos-Olivas R,Tsoli M,Allen J,et al.A switch from white to brown fat increases energy expenditure in cancer-associated cachexia.Cell Metab 2014;20:433-47.
21.Tomas E,Stanojevic V,McManus K,Khatri A,Everill P,Bachovchin WW,et al.GLP-1(32-36)amide pentapeptide increases basal energy expenditure and inhibits weight gain in obese mice.Diabetes2015;64:2409-19.
22.Li J,Zhong L,Wang F,Zhu H.Dissecting the role of AMP-activated protein kinase in human diseases.Acta Pharm Sin B 2017;7:249-59.
23.Shan T,Liang X,Bi P,Kuang S.Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1a-Fndc5pathway in muscle.FASEB J 2013;27:1981-9.
24.Hui X,Gu P,Zhang J,Nie T,Pan Y,Wu D,et al.Adiponectin enhances cold-induced browning of subcutaneous adipose tissue via promoting M2 macrophage proliferation.Cell Metab 2015;22:279-90.
25.Lee HJ,Lee JO,Kim N,Kim JK,Kim HI,Lee YW,et al.Irisin,a novel nyokine,regulates glucose uptake in skeletal muscle cells via AMPK.Mol Endocrinol 2015;29:873-81.
26.Gaidhu MP,Frontini A,Hung S,Pistor K,Cinti S,Ceddia RB.Chronic AMP-kinase activation with AICAR reduces adiposity by remodeling adipocyte metabolism and increasing leptin sensitivity.JLipid Res 2011;52:1702-11.
27.Beiroa D,Imbernon M,Gallego R,Senra A,Herranz D,Villarroya F,et al.GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK.Diabetes 2014;63:3346-58.
28.Lone J,Choi JH,Kim SW,Yun JW.Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes.J Nutr Biochem2016;27:193-202.
29.Zhang Z,Zhang H,Li B,Meng X,Wang J,Zhang Y,et al.Berberine activates thermogenesis in white and brown adipose tissue.Nat Commun 2014;5:5493.
30.Hardie GD.Regulation of AMP-activated protein kinase by natural and synthetic activators.Acta Pharm Sin B 2016;6:1-19.
31.Wong YY,Moon A,Duffin R,Barthet-Barateig A,Meijer HA,Clemens MJ,et al.Cordycepin inhibits protein synthesis and cell adhesion through effects on signal transduction.J Biol Chem2010;285:2610-21.
32.Gnad T,Scheibler S,von Kugelgen I,Scheele C,Kilic A,Glode A,et al.Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors.Nature 2014;516:395-9.
33.Leu SF,Poon SL,Pao HY,Huang BM.The in vivo and in vitro stimulatory effects of cordycepin on mouse leydig cell steroidogenesis.Biosci Biotechnol Biochem 2011;75:723-31.
34.Cao ZP,Dai D,Wei PJ,Han YY,Guan YQ,Li HH,et al.Effects of cordycepin on spontaneous alternation behavior and adenosine receptors expression in hippocampus.Physiol Behav 2018;184:135-42.