β_3肾上腺素能受体与肥胖的研究进展
|
摘要
寒冷刺激或激动剂激动β_3肾上腺素能受体能够刺激棕色脂肪的产热作用,并诱导白色脂肪的棕色化转变,提高机体代谢率,增加能量消耗。在肥胖者体内激动β_3肾上腺素能受体,具有改善机体胰岛素抵抗、代谢紊乱和慢性炎症状态的潜力。而胰岛素抵抗、代谢紊乱和慢性炎症状态又被认为是造成肥胖相关不良妊娠结局、影响子代远期健康的核心因素。因此,在妊娠期激动β_3肾上腺素能受体可能对改善妊娠期肥胖对母子两代的不良影响具有潜在治疗价值。但目前有关β_3肾上腺素能受体的治疗方式存在明显的局限性,更多能够特异性激动脂肪组织β_3肾上腺素能受体的方法有待进一步研究。
The activation of β_3 adrenergic receptor via cold stimulation or agonist is capable of promoting the thermogenesis of brown adipose tissue,browning the white adipose tissue,as well as improving the metabolic rate and energy expenditure. The activation of β_3 adrenergic receptor has therapeutic potential on the insulin resistance,metabolic disorders and chronic inflammatory state in people with obesity. Besides,insulin resistance,metabolic disorders and chronic inflammatory state are the core factors that cause the obesity-related adverse pregnancy outcomes and affect the long-term health of the offspring. Thus,the activation of β_3 adrenergic receptor during gestation may have therapeutic potential in improving obesity-related adverse maternal and offspring outcomes. However,there are obvious limitations in the current treatment methods of activating β_3 adrenergic receptor. More methods that can specifically activate β_3 adrenergic receptors in adipose tissue require further research.
The activation of β_3 adrenergic receptor via cold stimulation or agonist is capable of promoting the thermogenesis of brown adipose tissue,browning the white adipose tissue,as well as improving the metabolic rate and energy expenditure. The activation of β_3 adrenergic receptor has therapeutic potential on the insulin resistance,metabolic disorders and chronic inflammatory state in people with obesity. Besides,insulin resistance,metabolic disorders and chronic inflammatory state are the core factors that cause the obesity-related adverse pregnancy outcomes and affect the long-term health of the offspring. Thus,the activation of β_3 adrenergic receptor during gestation may have therapeutic potential in improving obesity-related adverse maternal and offspring outcomes. However,there are obvious limitations in the current treatment methods of activating β_3 adrenergic receptor. More methods that can specifically activate β_3 adrenergic receptors in adipose tissue require further research.
引文
[1] Ng M,Fleming T, Robinson M,et al. Global,regional,and national prevalence of overweight and obesity in children and adults during 1980-2013:A systematic analysis for the Global Burden of Disease Study 2013[J]. Lancet,2014, 384(9945):766-781.
[2] NCD Risk Factor Collaboration(NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014:A pooled analysis of 1698 population-based measurement studies with19·2 million participants[J]. Lancet,2016,387(10026):1377-1396.
[3]Rosenbaum M,Leibel RL. Adaptive thermogenesis in humans[J].Int J Obes(Lond),2010,34 Suppl 1:S47-55.
[4] Muller MJ, Bosy-Westphal A. Adaptive thermogenesis with weight loss in humans[J]. Obesity(Silver Spring),2013, 21(2):218-28.
[5] Denis GV,Obin MS.'Metabolically healthy obesity':Origins and implications[J]. Mol Aspects Med,2013,34(1):59-70.
[6] Bovet P,Chiolero A,Gedeon J. Health Effects of Overweight and Obesity in 195 Countries[J]. N Engl J Med, 2017,377(15):1495 4496.
[7] Afshin A,Forouzanfar MH, Reitsma MB, et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years[J]. N Engl J Med,2017,377(1):13-27.
[8] Liu P,Xu L, Wang Y, et al. Association between perinatal outcomes and maternal pre-pregnancy body mass index[J]. Obes Rev,2016,17(11):1091 4 102.
[9] Catalano PM,Ehrenberg HM. The short-and long-term implications of maternal obesity on the mother and her offspring[J].BJOG,2006,113(10):1126-1133.
[10] Adane AA, Dobson A,Tooth L, et al. Maternal preconception weight trajectories are associated with offsprings'childhood obesity[J]. Int J Obes(Lond),2018,42(7):12654274.
[11] Fleming TP,Watkins AJ,Velazquez MA,et al. Origins of lifetime health around the time of conception:Causes and consequences[J]. Lancet,2018,391(10132):18424852.
[12] Aye IL, Lager S, Ramirez VI,et al. Increasing maternal body mass index is associated with systemic inflammation in the mother andthe activation of distinct placental inflammatory pathways[J].Biol Reprod,2014,90(6):129.
[13] Challier JC,Basu S,Bintein T,et al. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta[J]. Placenta,2008,29(3):274-281.
[14] King JC. Maternal obesity, metabolism, and pregnancy outcomes[J]. Annu Rev Nutr,2006,26:271-291.
[15] Saben JL,Boudoures AL, Asghar Z,et al. Maternal Metabolic Syndrome Programs Mitochondrial Dysfunction via Germline Changes across Three Genera-tions[J].Cell Rep,2016,16(1):1-8.
[16] Heymsfield SB,Wadden TA. Mechanisms,Pathophysiology,and Management of Obesity[J]. N Engl J Med,2017,376(3):254-266.
[17] Ravussin E, Lillioja S, Anderson TE, et al. Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber[J]. J Clin Invest,1986,78(6):1568-1578·
[18] Ando T,Piaggi P,Bogardus C,et al. VO_2 max is associated with measures of energy expenditure in sedentary condition but does not predict weight change[J]. Metabolism,2019,90:44-51.
[19] Donahoo WT,Levine JA,Melanson EL. Variability in energy expenditure and its components[J]. Curr Opin Clin Nutr Metab Care,2004,7(6):599-605.
[20] Rosenbaum M,Hirsch J,Gallagher DA,et al. Long-term persistence of adaptive thermogenesis in subjects who have maintained a reduced body weight[J]. Am J Clin Nutr,2008,88(4):906-912.
[21] Townsend K, Tseng YH. Brown adipose tissue:Recent insights into development,metabolic function and therapeutic potential[J]. Adipocyte,2012,1(1):13-34.
[22] Kato H,Ohue M,Kato K,et al. Mechanism of amelioration of insulin resistance by beta3-adrenoceptor agonist AJ-9677 in the KK-Ay/Ta diabetic obese mouse model[J]. Diabetes, 2001,50(1):113422.
[23]张金宇,杨毅宁.β_3肾上腺素能受体基因多态性与心血管疾病的研究进展[J].医学综述,2014,20(12):2116-2118.
[24] Nedergaard J, Cannon B. The browning of white adipose tissue:Some burning issues[J].Cell Metab,2014,20(3):396-407.
[25] Tam CS,Lecoultre V, Ravussin E. Brown adipose tissue:Mechanisms and potential therapeutic targets[J]. Circulation,2012,125(22):2782-2791.
[26] Murano I,Barbatelli G,Giordano A,et al. Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ[J]. J Anat,2009,214(1):171-478.
[27] Mattsson CL, Csikasz RI, Chernogubova E,et al.β1-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimatedβ_3-adrenergic receptor-knockout mice via nonshivering thermogenesis[J]. Am J Physiol Endocrinol Metab2011,301(6):E11084118.
[28] Chondronikola M,Volpi E,B(?)rsheim E, et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans[J]. Diabetes, 2014,63(12):4089-4099.
[29] Cannon B,Nedergaard J. Metabolic consequences of the presence or absence of the thermogenic capacity of brown adipose tissue inmice(and probably in humans)[J]. Int J Obes(Lond),2010,34 Suppl 1:S746.
[30] Wijers SL, Schrauwen P, van Baak MA, et al. Beta-adrenergic receptor blockade does not inhibit cold-induced thermogenesis in humans:Possible involvement of brown adipose tissue[J]. J Clin Endocrinol Metab,2011,96(4):E598-605.
[31] van der Lans AA, Hoeks J, Brans B, et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis[J]. J Clin Invest,2013,123(8):3395-3403.
[32] Yoneshiro T,Aita S,Matsushita M,et al. Recruited brown adipose tissue as an antiobesity agent in humans[J]. J Clin Invest,2013,123(8):3404-3408.
[33] Ravussin Y, Xiao C, Gavrilova O, et al. Effect of intermittent cold exposure on brown fat activation, obesity,and energy homeostasis in mice[J]. PLoS One,2014,9(1):e85876.
[34] Mele J, Muralimanoharan S,Maloyan A,et al. Impaired mitochondrial function in human placenta with increased maternal adiposity[J]. Am J Physiol Endocrinol Metab, 2014, 307(5):E419-425.
[35] Raj an S,Satish S, Shankar K,et al. Aegeline inspired synthesis of novelβ_3-AR agonist improves insulin sensitivity in vitro and in vivo models of insulin resistance[J].Metabolism,2018,85:1-13.
[36] Shin W, Okamatsu-Ogura Y,Machida K,et al. Impaired adrenergic agonist-dependent beige adipocyte induction in aged mice[J]. Obesity(Silver Spring),2017,25(2):417-423.
[37] Xiao C, Goldgof M, Gavrilova OR, et al.Anti-obesity and metabolic efficacy of theβ_3-adrenergic agonist, CL316243, in mice at thermoneutrality compared to 22℃[J]. Obesity(Silver Spring),2015,23(7):1450-4459.
[38] Seki T,Hosaka K,Lim S,et al. Endothelial PDGF-CC regulates angiogenesis-dependent thermogenesis in beige fat[J]. Nat Commun,2016,7:12152.
[39] Abreu-Vieira G, Xiao C, Gavrilova O, et al. Integration of body temperature into the analysis of energy expenditure in the mouse[J]. Mol Metab,2015,4(6):461-470.
[40] Leitner BP,Huang S,Brychta RJ,et al. Mapping of human brown adipose tissue in lean and obese young men[J]. Proc Natl Acad Sci U S A,2017,114(32):8649-8654.
[41] Tseng YH,Cypess AM,Kahn CR. Cellular bioenergetics as a target for obesity therapy[J]. Nat Rev Drug Discov,2010,9(6):465-482.
[42] Larsen TM,Toubro S,van Baak MA,et al. Effect of a 28-d treatment with L-796568, a novel beta3-adrenergic receptor agonist,on energy expenditure and body composition in obese men[J].Am J Clin Nutr,2002,76(4):780-788.
[43] Cypess AM, Weiner LS, Roberts-Toler C, et al. Activation of human brown adipose tissue by aβ_3-adrenergic receptor agonist[J]. Cell Metab,2015,21(1):33-38.
[44] Lackey DE,Olefsky JM. Regulation of metabolism by the innate immune system[J]. Nat Rev Endocrinol,2016,12(1):15-28.
[45] Nicholas LM,Morrison JL,Rattanatray L,et al. The early origins of obesity and insulin resistance:Timing,programming and mechanisms[J]. Int J Obes(Lond),2016,40(2):229-238.
[46] Hoch D,Gauster M,Hauguel-de Mouzon S,et al. Diabesity-associated oxidative and inflammatory stress signalling in the early human placenta[J]. Mol Aspects Med,2018H[2019-02-10].https://linkinghub.elsevier.com/retrieve/pii/S0098-2997(18)30086-4.[Epub ahead of print Dec. 15,2018].
[47] Ferchaud-Roucher V,Barner K,Jansson T, et al. Maternal obesity results in decreased syncytiotrophoblast synthesis of palmitoleic acid,a fatty acid with anti-inflammatory and insulin-sensitizing properties[J]. FASEB J,2019[2019-02-40]. https://doi. org/10. 1096/fj.201802444R.[Epub ahead of print Feb. 27,2019].
[2] NCD Risk Factor Collaboration(NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014:A pooled analysis of 1698 population-based measurement studies with19·2 million participants[J]. Lancet,2016,387(10026):1377-1396.
[3]Rosenbaum M,Leibel RL. Adaptive thermogenesis in humans[J].Int J Obes(Lond),2010,34 Suppl 1:S47-55.
[4] Muller MJ, Bosy-Westphal A. Adaptive thermogenesis with weight loss in humans[J]. Obesity(Silver Spring),2013, 21(2):218-28.
[5] Denis GV,Obin MS.'Metabolically healthy obesity':Origins and implications[J]. Mol Aspects Med,2013,34(1):59-70.
[6] Bovet P,Chiolero A,Gedeon J. Health Effects of Overweight and Obesity in 195 Countries[J]. N Engl J Med, 2017,377(15):1495 4496.
[7] Afshin A,Forouzanfar MH, Reitsma MB, et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years[J]. N Engl J Med,2017,377(1):13-27.
[8] Liu P,Xu L, Wang Y, et al. Association between perinatal outcomes and maternal pre-pregnancy body mass index[J]. Obes Rev,2016,17(11):1091 4 102.
[9] Catalano PM,Ehrenberg HM. The short-and long-term implications of maternal obesity on the mother and her offspring[J].BJOG,2006,113(10):1126-1133.
[10] Adane AA, Dobson A,Tooth L, et al. Maternal preconception weight trajectories are associated with offsprings'childhood obesity[J]. Int J Obes(Lond),2018,42(7):12654274.
[11] Fleming TP,Watkins AJ,Velazquez MA,et al. Origins of lifetime health around the time of conception:Causes and consequences[J]. Lancet,2018,391(10132):18424852.
[12] Aye IL, Lager S, Ramirez VI,et al. Increasing maternal body mass index is associated with systemic inflammation in the mother andthe activation of distinct placental inflammatory pathways[J].Biol Reprod,2014,90(6):129.
[13] Challier JC,Basu S,Bintein T,et al. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta[J]. Placenta,2008,29(3):274-281.
[14] King JC. Maternal obesity, metabolism, and pregnancy outcomes[J]. Annu Rev Nutr,2006,26:271-291.
[15] Saben JL,Boudoures AL, Asghar Z,et al. Maternal Metabolic Syndrome Programs Mitochondrial Dysfunction via Germline Changes across Three Genera-tions[J].Cell Rep,2016,16(1):1-8.
[16] Heymsfield SB,Wadden TA. Mechanisms,Pathophysiology,and Management of Obesity[J]. N Engl J Med,2017,376(3):254-266.
[17] Ravussin E, Lillioja S, Anderson TE, et al. Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber[J]. J Clin Invest,1986,78(6):1568-1578·
[18] Ando T,Piaggi P,Bogardus C,et al. VO_2 max is associated with measures of energy expenditure in sedentary condition but does not predict weight change[J]. Metabolism,2019,90:44-51.
[19] Donahoo WT,Levine JA,Melanson EL. Variability in energy expenditure and its components[J]. Curr Opin Clin Nutr Metab Care,2004,7(6):599-605.
[20] Rosenbaum M,Hirsch J,Gallagher DA,et al. Long-term persistence of adaptive thermogenesis in subjects who have maintained a reduced body weight[J]. Am J Clin Nutr,2008,88(4):906-912.
[21] Townsend K, Tseng YH. Brown adipose tissue:Recent insights into development,metabolic function and therapeutic potential[J]. Adipocyte,2012,1(1):13-34.
[22] Kato H,Ohue M,Kato K,et al. Mechanism of amelioration of insulin resistance by beta3-adrenoceptor agonist AJ-9677 in the KK-Ay/Ta diabetic obese mouse model[J]. Diabetes, 2001,50(1):113422.
[23]张金宇,杨毅宁.β_3肾上腺素能受体基因多态性与心血管疾病的研究进展[J].医学综述,2014,20(12):2116-2118.
[24] Nedergaard J, Cannon B. The browning of white adipose tissue:Some burning issues[J].Cell Metab,2014,20(3):396-407.
[25] Tam CS,Lecoultre V, Ravussin E. Brown adipose tissue:Mechanisms and potential therapeutic targets[J]. Circulation,2012,125(22):2782-2791.
[26] Murano I,Barbatelli G,Giordano A,et al. Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ[J]. J Anat,2009,214(1):171-478.
[27] Mattsson CL, Csikasz RI, Chernogubova E,et al.β1-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimatedβ_3-adrenergic receptor-knockout mice via nonshivering thermogenesis[J]. Am J Physiol Endocrinol Metab2011,301(6):E11084118.
[28] Chondronikola M,Volpi E,B(?)rsheim E, et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans[J]. Diabetes, 2014,63(12):4089-4099.
[29] Cannon B,Nedergaard J. Metabolic consequences of the presence or absence of the thermogenic capacity of brown adipose tissue inmice(and probably in humans)[J]. Int J Obes(Lond),2010,34 Suppl 1:S746.
[30] Wijers SL, Schrauwen P, van Baak MA, et al. Beta-adrenergic receptor blockade does not inhibit cold-induced thermogenesis in humans:Possible involvement of brown adipose tissue[J]. J Clin Endocrinol Metab,2011,96(4):E598-605.
[31] van der Lans AA, Hoeks J, Brans B, et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis[J]. J Clin Invest,2013,123(8):3395-3403.
[32] Yoneshiro T,Aita S,Matsushita M,et al. Recruited brown adipose tissue as an antiobesity agent in humans[J]. J Clin Invest,2013,123(8):3404-3408.
[33] Ravussin Y, Xiao C, Gavrilova O, et al. Effect of intermittent cold exposure on brown fat activation, obesity,and energy homeostasis in mice[J]. PLoS One,2014,9(1):e85876.
[34] Mele J, Muralimanoharan S,Maloyan A,et al. Impaired mitochondrial function in human placenta with increased maternal adiposity[J]. Am J Physiol Endocrinol Metab, 2014, 307(5):E419-425.
[35] Raj an S,Satish S, Shankar K,et al. Aegeline inspired synthesis of novelβ_3-AR agonist improves insulin sensitivity in vitro and in vivo models of insulin resistance[J].Metabolism,2018,85:1-13.
[36] Shin W, Okamatsu-Ogura Y,Machida K,et al. Impaired adrenergic agonist-dependent beige adipocyte induction in aged mice[J]. Obesity(Silver Spring),2017,25(2):417-423.
[37] Xiao C, Goldgof M, Gavrilova OR, et al.Anti-obesity and metabolic efficacy of theβ_3-adrenergic agonist, CL316243, in mice at thermoneutrality compared to 22℃[J]. Obesity(Silver Spring),2015,23(7):1450-4459.
[38] Seki T,Hosaka K,Lim S,et al. Endothelial PDGF-CC regulates angiogenesis-dependent thermogenesis in beige fat[J]. Nat Commun,2016,7:12152.
[39] Abreu-Vieira G, Xiao C, Gavrilova O, et al. Integration of body temperature into the analysis of energy expenditure in the mouse[J]. Mol Metab,2015,4(6):461-470.
[40] Leitner BP,Huang S,Brychta RJ,et al. Mapping of human brown adipose tissue in lean and obese young men[J]. Proc Natl Acad Sci U S A,2017,114(32):8649-8654.
[41] Tseng YH,Cypess AM,Kahn CR. Cellular bioenergetics as a target for obesity therapy[J]. Nat Rev Drug Discov,2010,9(6):465-482.
[42] Larsen TM,Toubro S,van Baak MA,et al. Effect of a 28-d treatment with L-796568, a novel beta3-adrenergic receptor agonist,on energy expenditure and body composition in obese men[J].Am J Clin Nutr,2002,76(4):780-788.
[43] Cypess AM, Weiner LS, Roberts-Toler C, et al. Activation of human brown adipose tissue by aβ_3-adrenergic receptor agonist[J]. Cell Metab,2015,21(1):33-38.
[44] Lackey DE,Olefsky JM. Regulation of metabolism by the innate immune system[J]. Nat Rev Endocrinol,2016,12(1):15-28.
[45] Nicholas LM,Morrison JL,Rattanatray L,et al. The early origins of obesity and insulin resistance:Timing,programming and mechanisms[J]. Int J Obes(Lond),2016,40(2):229-238.
[46] Hoch D,Gauster M,Hauguel-de Mouzon S,et al. Diabesity-associated oxidative and inflammatory stress signalling in the early human placenta[J]. Mol Aspects Med,2018H[2019-02-10].https://linkinghub.elsevier.com/retrieve/pii/S0098-2997(18)30086-4.[Epub ahead of print Dec. 15,2018].
[47] Ferchaud-Roucher V,Barner K,Jansson T, et al. Maternal obesity results in decreased syncytiotrophoblast synthesis of palmitoleic acid,a fatty acid with anti-inflammatory and insulin-sensitizing properties[J]. FASEB J,2019[2019-02-40]. https://doi. org/10. 1096/fj.201802444R.[Epub ahead of print Feb. 27,2019].