FRI025 Succinate Receptor Activation Increases Respiration In Human But Not Murine Brown Adipocytes
FRI025 Succinate Receptor Activation Increases Respiration In Human But Not Murine Brown Adipocytes
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DOI：
10.1210/jendso/bvad114.036
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发表时间：
2023-10-05
影响因子：
4.1
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披露：B.T.麦克尼尔：没有。答：凯尔曼：没有。L.E.拉马奇：没有。K.J.Suchacki：没有。Wakelin：没有。N.M.莫顿：没有。R.H.史汀生：没有。棕色脂肪组织(BAT)是一种产热组织，能产生热量来维持体温。BAT激活是治疗肥胖相关心脏代谢性疾病的潜在治疗靶点。我们对人类原代棕色和白色脂肪细胞进行了RNA测序，并发现编码琥珀酸受体的SUCNR1在棕色和白色脂肪细胞中高度差异表达(20倍)。众所周知，琥珀酸可以增加BAT的产热，而SUCNR1的激活则抑制白色脂肪组织(WAT)的脂解。我们假设SUCNR1的激活增加了人类和小鼠的BAT产热。为了验证这一点，我们研究了琥珀酸和选择性的SUCNR1激动剂顺式环氧琥珀酸(C-ESA)对人和小鼠原代棕色/米色脂肪细胞的影响。此外，我们还测定了Sucnr1基因干扰对对照组或高脂(HFD)饲养12周的小鼠的代谢影响，并测量了在标准室温(21°C)和冷暴露(4°C)下的能量消耗。在人棕色和白色脂肪细胞中，琥珀酸增加了基础呼吸和去甲肾上腺素刺激的呼吸，而C-ESA只增加了人棕色脂肪细胞的基础呼吸，而不改变UCP1的mRNA水平。SUCNR1的激活只减少人白色脂肪细胞中甘油的释放。雄性(但不是雌性)Sucnr1-/-小鼠在HFD后2周表现出糖耐量受损，Sucnr1-/-小鼠在慢性HFD后也观察到更多的脂肪质量。然而，雄性Sucnr1-/-小鼠在21°C和4°C下的能量消耗、活动能力和尾静脉温度都没有变化。此外，Ucp1和Pgc1α在蝙蝠和腹股沟Wat中的表达在不同基因型之间是相似的。Sucnr1缺失对喂食对照饮食的小鼠的脂肪质量或葡萄糖耐量没有影响。在体外，来自Sucnr1-/-小鼠的分化的棕色脂肪细胞在基础和去甲肾上腺素刺激下对Sucnr1+/+脂肪细胞显示出相似的细胞呼吸和Ucp1mRNA水平。琥珀酸和C-ESA不能刺激小鼠棕色或白色脂肪细胞的呼吸。这些数据表明，SUCNR1激活促进了人类棕色脂肪细胞的呼吸，但不能促进小鼠棕色脂肪细胞的呼吸，这突显了除了物种之间的差异外，调节BAT功能的一种新途径。这些数据还揭示了SUCNR1代谢效应在性别上的新差异，尽管Sucnr1缺失保护雌性小鼠免受不利代谢影响的机制尚不清楚。SUCNR1的激活可能是治疗肥胖和相关代谢性疾病的一个新的治疗靶点，但需要在人类中进行进一步的研究，以确定SUCNR1调节BAT产热的具体机制。演示文稿：2023年6月16日星期五
Disclosure: B.T. McNeill: None. A. Kelman: None. L.E. Ramage: None. K.J. Suchacki: None. S.J. Wakelin: None. N.M. Morton: None. R.H. Stimson: None. Brown adipose tissue (BAT) is a thermogenic tissue that generates heat to maintain body temperature. BAT activation is a potential therapeutic target for treating obesity-related cardiometabolic disease. We performed RNA sequencing of human primary brown and white adipocytes and identified SUCNR1, which encodes the succinate receptor, as highly differentially expressed (20-fold) in brown versus white adipocytes. Succinate is known to increase BAT thermogenesis, while SUCNR1 activation inhibits lipolysis in white adipose tissue (WAT). We hypothesized that SUCNR1 activation increases BAT thermogenesis in humans and in mice. To test this, we investigated the effect of succinate and the selective SUCNR1 agonist cis-epoxysuccinic acid (C-ESA) in human and murine primary brown/ beige adipocytes. In addition, we determined the metabolic effects of disruption of Sucnr1 in mice either fed control or a high fat (HFD) for 12 weeks and measured energy expenditure when housed at standard room temperature (21°C) and during cold exposure (4°C). In human brown and white adipocytes, succinate increased basal and noradrenaline-stimulated respiration, while C-ESA increased basal respiration only in human brown adipocytes without altering UCP1 mRNA levels. SUCNR1 activation reduced glycerol release only in human white adipocytes. Male (but not female) Sucnr1-/- mice exhibited impaired glucose tolerance versus Sucnr1+/+ littermates after 2 weeks of HFD, and greater fat mass was also observed in the Sucnr1-/- mice following chronic HFD. However, energy expenditure, locomotor activity and tail vein temperature were unchanged in male Sucnr1-/- mice either at 21°C or 4°C. In addition, expression of Ucp1 and Pgc1α in BAT and inguinal WAT were similar between genotypes. Sucnr1 deletion had no effect on fat mass or glucose tolerance in mice fed a control diet. In vitro, differentiated brown adipocytes from Sucnr1-/- mice demonstrated comparable cellular respiration and Ucp1 mRNA levels both basally and during noradrenaline stimulation to Sucnr1+/+ adipocytes. Succinate and C-ESA did not stimulate respiration in murine brown or white adipocytes. These data reveal that SUCNR1 activation enhances brown adipocyte respiration in human but not murine brown adipocytes, highlighting a novel pathway regulating BAT function in addition to differences between species. These data also reveal novel sex-specific differences in the metabolic effects of SUCNR1, although the mechanisms through which female mice are protected from the adverse metabolic effects of Sucnr1 deletion are unclear. SUCNR1 activation may be a novel therapeutic target to treat obesity and associated metabolic disease, but requires further research in humans to determine the specific mechanisms through which SUCNR1 regulates BAT thermogenesis. Presentation: Friday, June 16, 2023