Chen Sing-Young, Beretta Martina, Alexopoulos Stephanie J, Shah Divya P, Olzomer Ellen M, Hargett Stefan R, Childress Elizabeth S, Salamoun Joseph M, Aleksovska Isabella, Roseblade Ariane, Cranfield Charles, Rawling Tristan, Quinlan Kate G R, Morris Margaret J, Tucker Simon P, Santos Webster L, Hoehn Kyle L
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
Metabolism. 2021 Apr;117:154724. doi: 10.1016/j.metabol.2021.154724. Epub 2021 Feb 4.
Mitochondrial uncouplers decrease caloric efficiency and have potential therapeutic benefits for the treatment of obesity and related metabolic disorders. Herein we investigate the metabolic and physiologic effects of a recently identified small molecule mitochondrial uncoupler named SHC517 in a mouse model of diet-induced obesity.
SHC517 was administered as an admixture in food. The effect of SHC517 on in vivo energy expenditure and respiratory quotient was determined by indirect calorimetry. A dose-finding obesity prevention study was performed by starting SHC517 treatment concomitant with high fat diet for a period of 12 days. An obesity reversal study was performed by feeding mice western diet for 4 weeks prior to SHC517 treatment for 7 weeks. Biochemical assays were used to determine changes in glucose, insulin, triglycerides, and cholesterol. SHC517 concentrations were determined by mass spectrometry.
SHC517 increased lipid oxidation without affecting body temperature. SHC517 prevented diet-induced obesity when administered at 0.05% and 0.1% w/w in high fat diet and reversed established obesity when tested at the 0.05% dose. In the obesity reversal model, SHC517 restored adiposity to levels similar to chow-fed control mice without affecting food intake or lean body mass. SHC517 improved glucose tolerance and fasting glucose levels when administered in both the obesity prevention and obesity reversal modes.
SHC517 is a mitochondrial uncoupler with potent anti-obesity and insulin sensitizing effects in mice. SHC517 reversed obesity without altering food intake or compromising lean mass, effects that are highly sought-after in anti-obesity therapeutics.
线粒体解偶联剂可降低热量效率，对肥胖症及相关代谢紊乱的治疗具有潜在的益处。在此，我们在饮食诱导肥胖的小鼠模型中研究了一种最近鉴定出的名为SHC517的小分子线粒体解偶联剂的代谢和生理作用。
将SHC517作为食物中的混合物给药。通过间接测热法测定SHC517对体内能量消耗和呼吸商的影响。通过在高脂饮食开始时同时进行SHC517治疗12天，开展了一项剂量探索性肥胖预防研究。在SHC517治疗7周之前，先给小鼠喂食西方饮食4周，开展了一项肥胖逆转研究。采用生化分析方法测定葡萄糖、胰岛素、甘油三酯和胆固醇的变化。通过质谱法测定SHC517的浓度。
SHC517可增加脂质氧化，而不影响体温。在高脂饮食中以0.05%和0.1% w/w的剂量给药时，SHC517可预防饮食诱导的肥胖，以0.05%的剂量进行测试时，可逆转已形成的肥胖。在肥胖逆转模型中，SHC517可将肥胖程度恢复到与正常饮食喂养的对照小鼠相似的水平，而不影响食物摄入量或瘦体重。在肥胖预防和肥胖逆转模式下给药时，SHC517均可改善葡萄糖耐量和空腹血糖水平。
SHC517是一种线粒体解偶联剂，在小鼠中具有强大的抗肥胖和胰岛素增敏作用。SHC517可逆转肥胖，而不改变食物摄入量或损害瘦体重，这些作用是抗肥胖治疗中非常需要的。
