From Takeda California, San Diego, California 92121,
From Takeda California, San Diego, California 92121.
J Biol Chem. 2019 Jun 14;294(24):9567-9575. doi: 10.1074/jbc.RA118.007302. Epub 2019 May 2.
Inhibitors of methionine aminopeptidase 2 (MetAP2) have been shown to reduce body weight in obese mice and humans. The target tissue and cellular mechanism of MetAP2 inhibitors, however, have not been extensively examined. Using compounds with diverse chemical scaffolds, we showed that MetAP2 inhibition decreases body weight and fat mass and increases lean mass in the obese mice but not in the lean mice. Obesity is associated with catecholamine resistance and blunted β-adrenergic receptor signaling activities, which could dampen lipolysis and energy expenditure resulting in weight gain. In the current study, we examined effect of MetAP2 inhibition on brown adipose tissue and brown adipocytes. Norepinephrine increases energy expenditure in brown adipose tissue by providing fatty acid substrate through lipolysis and by increasing expression of uncoupled protein-1 (UCP1). Metabolomic analysis shows that in response to MetAP2 inhibitor treatment, fatty acid metabolites in brown adipose tissue increase transiently and subsequently decrease to basal or below basal levels, suggesting an effect on fatty acid metabolism in this tissue. Treatment of brown adipocytes with MetAP2 inhibitors enhances norepinephrine-induced lipolysis and energy expenditure, and prolongs the activity of norepinephrine to increase ucp1 gene expression and energy expenditure in norepinephrine-desensitized brown adipocytes. In summary, we showed that the anti-obesity activity of MetAP2 inhibitors can be mediated, at least in part, through direct action on brown adipocytes by enhancing β-adrenergic-signaling-stimulated activities.
甲硫氨酸氨肽酶 2（MetAP2）抑制剂已被证明可减少肥胖小鼠和人类的体重。然而，MetAP2 抑制剂的靶组织和细胞机制尚未得到广泛研究。使用具有不同化学结构骨架的化合物，我们表明 MetAP2 抑制可降低肥胖小鼠的体重和脂肪量，增加瘦体重，但对瘦小鼠则没有影响。肥胖与儿茶酚胺抵抗和β-肾上腺素能受体信号转导活性减弱有关，这可能会抑制脂肪分解和能量消耗，导致体重增加。在本研究中，我们研究了 MetAP2 抑制对棕色脂肪组织和棕色脂肪细胞的影响。去甲肾上腺素通过脂肪分解提供脂肪酸底物，并通过增加解偶联蛋白 1（UCP1）的表达来增加棕色脂肪组织的能量消耗。代谢组学分析表明，对 MetAP2 抑制剂治疗的反应中，棕色脂肪组织中的脂肪酸代谢物短暂增加，随后降至基础或低于基础水平，表明对该组织中的脂肪酸代谢有影响。用 MetAP2 抑制剂处理棕色脂肪细胞可增强去甲肾上腺素诱导的脂肪分解和能量消耗，并延长去甲肾上腺素的活性，以增加去甲肾上腺素脱敏的棕色脂肪细胞中 ucp1 基因的表达和能量消耗。总之，我们表明 MetAP2 抑制剂的抗肥胖活性至少部分可以通过增强β-肾上腺素能信号刺激的活性来介导，这种活性可直接作用于棕色脂肪细胞。
