Ponnusamy Suriyan, Tran Quynh T, Harvey Innocence, Smallwood Heather S, Thiyagarajan Thirumagal, Banerjee Souvik, Johnson Daniel L, Dalton James T, Sullivan Ryan D, Miller Duane D, Bridges Dave, Narayanan Ramesh
Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
FASEB J. 2017 Jan;31(1):266-281. doi: 10.1096/fj.201600787RR. Epub 2016 Oct 12.
Most satiety-inducing obesity therapeutics, despite modest efficacy, have safety concerns that underscore the need for effective peripherally acting drugs. An attractive therapeutic approach for obesity is to optimize/maximize energy expenditure by increasing energy-utilizing thermogenic brown adipose tissue. We used in vivo and in vitro models to determine the role of estrogen receptor β (ER-β) and its ligands on adipose biology. RNA sequencing and metabolomics were used to determine the mechanism of action of ER-β and its ligands. Estrogen receptor β (ER-β) and its selective ligand reprogrammed preadipocytes and precursor stem cells into brown adipose tissue and increased mitochondrial respiration. An ER-β-selective ligand increased markers of tricarboxylic acid-dependent and -independent energy biogenesis and oxygen consumption in mice without a concomitant increase in physical activity or food consumption, all culminating in significantly reduced weight gain and adiposity. The antiobesity effects of ER-β ligand were not observed in ER-β-knockout mice. Serum metabolite profiles of adult lean and juvenile mice were comparable, while that of adult obese mice was distinct, indicating a possible impact of obesity on age-dependent metabolism. This phenotype was partially reversed by ER-β-selective ligand. These data highlight a new role for ER-β in adipose biology and its potential to be a safer alternative peripheral therapeutic target for obesity.-Ponnusamy, S., Tran, Q. T., Harvey, I., Smallwood, H. S., Thiyagarajan, T., Banerjee, S., Johnson, D. L., Dalton, J. T., Sullivan, R. D., Miller, D. D., Bridges, D., Narayanan, R. Pharmacologic activation of estrogen receptor β increases mitochondrial function, energy expenditure, and brown adipose tissue.
大多数诱导饱腹感的肥胖治疗药物，尽管疗效一般，但都存在安全问题，这凸显了对有效外周作用药物的需求。一种有吸引力的肥胖治疗方法是通过增加利用能量的产热棕色脂肪组织来优化/最大化能量消耗。我们使用体内和体外模型来确定雌激素受体β（ER-β）及其配体在脂肪生物学中的作用。RNA测序和代谢组学被用于确定ER-β及其配体的作用机制。雌激素受体β（ER-β）及其选择性配体将前脂肪细胞和前体干细胞重编程为棕色脂肪组织，并增加线粒体呼吸。一种ER-β选择性配体增加了小鼠三羧酸依赖性和非依赖性能量生物合成及氧气消耗的标志物，而身体活动或食物消耗并未随之增加，所有这些最终导致体重增加和肥胖显著减少。在ER-β基因敲除小鼠中未观察到ER-β配体的抗肥胖作用。成年瘦小鼠和幼年小鼠的血清代谢物谱具有可比性，而成年肥胖小鼠的血清代谢物谱则不同，这表明肥胖可能对年龄依赖性代谢有影响。这种表型被ER-β选择性配体部分逆转。这些数据突出了ER-β在脂肪生物学中的新作用及其作为肥胖更安全外周治疗靶点的潜力。-庞努萨米，S.，陈，Q.T.，哈维，I.，斯莫尔伍德，H.S.，蒂亚加拉扬，T.，班纳吉，S.，约翰逊，D.L.，道尔顿，J.T.，沙利文，R.D.，米勒，D.D.，布里奇斯，D.，纳拉亚南，R.雌激素受体β的药理学激活增加线粒体功能、能量消耗和棕色脂肪组织。
