Dokas J, Chadt A, Joost H-G, Al-Hasani H
German Institute for Human Nutrition, Potsdam, Germany.
German Diabetes Center, Leibniz Center for Diabetes Research at the Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Int J Obes (Lond). 2016 Aug;40(8):1242-9. doi: 10.1038/ijo.2016.45. Epub 2016 Mar 22.
Variants in the gene TBC1D1 have been previously associated with obesity-related traits in several species, including humans, mice, rabbits and chicken. While in humans variants in TBC1D1 were linked to obesity, disruption of the Tbc1d1 gene reduced body weight in mice. TBC1D1 has been identified as a regulator of insulin-dependent glucose transport in skeletal muscle, however, its role in energy homeostasis in the obese state remains unclear. The impact of TBC1D1 deficiency on energy homeostasis, glucose and lipid metabolism in an established mouse model of obesity was examined.
Obese leptin (ob/ob)- and Tbc1d1-double-deficient mice (D1KO-ob/ob) were generated by crossing obese B6.V.Lep(ob/ob)-mice with lean Tbc1d1-deficient mice on a C57BL/6J background. Male mice on either standard (SD) or high-fat diet (HFD) were analyzed for body weight, body composition, food intake, voluntary physical activity and energy expenditure by indirect calorimetry. Glucose and insulin tolerance as well as glucose transport and fatty acid oxidation in skeletal muscle were analyzed.
In obese mice, Tbc1d1 deficiency resulted in reduced body weight on both SD and HFD. However, food intake was unchanged on SD or even increased in HFD-fed Tbc1d1-deficient mice without alterations in voluntary physical activity. Despite substantially reduced insulin-stimulated glucose transport and increased fatty acid oxidation in intact isolated skeletal muscle, obese Tbc1d1-deficient mice showed no gross changes in glycemia and glucose tolerance compared with obese controls. Indirect calorimetry revealed that obese Tbc1d1-deficient mice had a decreased respiratory quotient together with increased daily energy expenditure.
In obese leptin-deficient mice, lack of TBC1D1 has no impact on feeding behavior or energy intake but results in increased energy expenditure, altered energy substrate preference with increased fatty acid oxidation and suppression of obesity. TBC1D1 may have an evolutionary conserved role in regulating energy homeostasis in vertebrates.
基因TBC1D1中的变异先前已在包括人类、小鼠、兔子和鸡在内的多个物种中与肥胖相关性状联系起来。虽然在人类中TBC1D1的变异与肥胖有关，但Tbc1d1基因的破坏会降低小鼠的体重。TBC1D1已被确定为骨骼肌中胰岛素依赖性葡萄糖转运的调节因子，然而，其在肥胖状态下能量稳态中的作用仍不清楚。本研究检测了TBC1D1缺陷对已建立的肥胖小鼠模型中能量稳态、葡萄糖和脂质代谢的影响。
通过将肥胖的B6.V.Lep(ob/ob)小鼠与C57BL/6J背景的瘦型Tbc1d1缺陷小鼠杂交，培育出肥胖瘦素（ob/ob）和Tbc1d1双缺陷小鼠（D1KO-ob/ob）。对食用标准（SD）或高脂饮食（HFD）的雄性小鼠进行体重、身体成分、食物摄入量、自主身体活动和通过间接量热法测定的能量消耗分析。分析了葡萄糖和胰岛素耐受性以及骨骼肌中的葡萄糖转运和脂肪酸氧化。
在肥胖小鼠中，Tbc1d1缺陷导致在SD和HFD上体重均降低。然而，在SD上食物摄入量未改变，甚至在喂食HFD的Tbc1d1缺陷小鼠中增加，自主身体活动无变化。尽管在完整分离的骨骼肌中胰岛素刺激的葡萄糖转运显著减少且脂肪酸氧化增加，但肥胖的Tbc1d1缺陷小鼠与肥胖对照组相比，血糖和葡萄糖耐受性没有明显变化。间接量热法显示，肥胖的Tbc1d1缺陷小鼠呼吸商降低，每日能量消耗增加。
在肥胖的瘦素缺陷小鼠中，缺乏TBC1D1对摄食行为或能量摄入没有影响，但会导致能量消耗增加、能量底物偏好改变，脂肪酸氧化增加并抑制肥胖。TBC1D1可能在调节脊椎动物能量稳态中具有进化保守作用。
