Relative Contribution of Intramyocellular Lipid to Whole-Body Fat Oxidation Is Reduced With Age but Subsarcolemmal Lipid Accumulation and Insulin Resistance Are Only Associated With Overweight Individuals.
Relative Contribution of Intramyocellular Lipid to Whole-Body Fat Oxidation Is Reduced With Age but Subsarcolemmal Lipid Accumulation and Insulin Resistance Are Only Associated With Overweight Individuals.
复制标题
肌细胞内脂质对全身脂肪氧化的相对贡献率随年龄增长而降低，但浆膜下脂质积累和胰岛素抵抗仅与超重个体有关。
DOI：
10.2337/db15-1383
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发表时间：
2016-04
期刊：
影响因子：
7.7
通讯作者：
Stephens FB
中科院分区：
文献类型：
--
作者：
Chee C;Shannon CE;Burns A;Selby AL;Wilkinson D;Smith K;Greenhaff PL;Stephens FB
胰岛素抵抗与肌细胞内脂质（IMCL）蓄积密切相关，两者均与年龄增长相关。IMCL代谢的扰动在多大程度上与衰老过程本身有关仍有待确定。在两个不同的情况下，在50%VO2max下运动1小时期间（[U-13 C]棕榈酸酯输注结合IMCL的电子显微镜检查），测定了年轻瘦（YL）、老年瘦（OL）和老年超重（OO）男性的全身和肌肉胰岛素敏感性（2-脱氧葡萄糖的正常血高胰岛素钳夹）和脂肪利用率。OL表现出与YL相当的IMCL含量和胰岛素敏感性，而OO具有明显的胰岛素抵抗，并且在肌膜下（SSL）区域的IMCL高出2倍以上。事实上，虽然血浆游离脂肪酸的出现和消失率是两倍的YL在OL和OO，SSL只增加运动过程中OO。因此，在老年人中经常观察到的骨骼肌胰岛素抵抗和脂质蓄积可能是由于生活方式因素，而不是通常报告的骨骼肌固有老化。然而，年龄本身似乎会导致加剧脂肪组织脂解，这表明在老年超重个体中可能需要减少肌肉脂质递送和改善脂肪组织功能的策略。2型糖尿病的全球流行在老年人中最为明显，据估计，到2050年，65岁以上的糖尿病患者人数将增加4.5倍。获得与年龄相关的胰岛素抵抗和策略，以提高胰岛素敏感性的机制的见解，随着年龄的增长，显然是必要的。虽然衰老与胰岛素抵抗有关，但年龄本身似乎并不引起胰岛素抵抗。可能导致与年龄相关的胰岛素抵抗的几个因素包括腹部肥胖增加和体力活动减少，沿着肌肉质量下降。值得注意的是，肌细胞内脂质（IMCL）随着年龄的增长而积累，特别是在肌膜下（SSL）区域，并与胰岛素抵抗密切相关。事实上，SSL脂质蓄积与代谢物（如二酰基甘油（DAG）和神经酰胺）的蓄积有关，一些人认为这会导致胰岛素刺激的肌肉葡萄糖摄取受损，但另一些人则不然。然而，它仍然是有争议的，与年龄相关的因素影响IMCL积累。IMCL和相关代谢物的积累可能是由于肌肉脂质递送和氧化之间的不平衡。事实上，研究表明，与年轻人相比，老年人的游离脂肪酸（FFA）氧化减少，尽管全身脂解和血浆FFA可用性在休息时和运动期间在相同的绝对和相对强度下更大。与此相关，一些研究表明，与年龄相关的FFA氧化钝化和IMCL积累增加是肌肉线粒体含量和功能随年龄降低的结果。然而，肥胖增加和习惯性体力活动水平降低也会影响老年人的FFA通量和氧化，迄今为止的研究在调查肌肉IMCL代谢随年龄的变化时没有控制这些因素。因此，我们研究了衰老对全身和骨骼肌脂质代谢的影响，同时对肌肉胰岛素敏感性进行了平行表征，在与估计的习惯性体力活动水平和身体成分相匹配的瘦的年轻人和老年人中进行了研究。为了确定肥胖和减少体力活动对衰老过程的影响，还将老年瘦个体与一组老年超重个体进行了比较。我们假设，与年龄相关的运动过程中骨骼肌FFA输送和氧化之间的不平衡仅在老年超重个体中观察到，这将表现为IMCL氧化减少和IMCL储存增加，特别是在SSL区域，并与骨骼肌胰岛素抵抗相关。
Insulin resistance is closely related to intramyocellular lipid (IMCL) accumulation, and both are associated with increasing age. It remains to be determined to what extent perturbations in IMCL metabolism are related to the ageing process per se. On two separate occasions whole-body and muscle insulin sensitivity (euglycaemic hyperinsulinaemic clamp with 2-deoxyglucose) and fat utilisation during 1 h of exercise at 50% VO2max ([U-13C]palmitate infusion combined with electron microscopy of IMCL) were determined in young lean (YL), old lean (OL), and old overweight (OO) males. OL displayed comparable IMCL content and insulin sensitivity to YL, whereas OO were markedly insulin resistant and had over 2-fold greater IMCL in the subsarcolemmal (SSL) region. Indeed, whereas the plasma free fatty acid rate of appearance and disappearance was twice that of YL in both OL and OO, SSL only increased during exercise in OO. Thus, skeletal muscle insulin resistance and lipid accumulation often observed in older individuals are likely due to lifestyle factors, rather than inherent ageing of skeletal muscle as usually reported. However, age per se appears to cause exacerbated adipose tissue lipolysis, suggesting that strategies to reduce muscle lipid delivery and improve adipose tissue function may be warranted in older overweight individuals. The global prevalence of type 2 diabetes is most apparent in older people, and it is estimated that the number of people over 65 years of age with diabetes will have increased 4.5 fold by 2050. Gaining mechanistic insight of age related insulin resistance and strategies to improve insulin sensitivity with age are clearly warranted. Although ageing is associated with insulin resistance, age per se does not appear to cause insulin resistance. Several factors that likely contribute to age related insulin resistance include increased abdominal adiposity and reduced physical activity, along with declines in muscle mass. Of note, intramyocellular lipid (IMCL) accumulates with age, particularly in subsarcolemmal (SSL) regions, and has been strongly associated with insulin resistance. Indeed, SSL lipid accumulation has been linked to the accumulation of metabolites, such as diacylglycerol (DAG) and ceramide, thought by some, but not others, to contribute to impaired insulin-stimulated muscle glucose uptake. Nevertheless, it remains contentious as to which factors associated with age influence IMCL accumulation. The accumulation of IMCL and associated metabolites likely result from an imbalance between muscle lipid delivery and oxidation. Indeed, studies have demonstrated reduced free fatty acid (FFA) oxidation in older people compared to young, despite whole-body lipolysis and plasma FFA availability being greater at rest and during exercise at the same absolute and relative intensities. Linked to this, several studies have suggested age related blunting of FFA oxidation and increased IMCL accumulation are a result of reduced muscle mitochondrial content and function with age. However, increased adiposity and reduced habitual levels of physical activity also affect FFA flux and oxidation in older individuals, and studies to date have not controlled for these factors when investigating changes in muscle IMCL metabolism with age. Therefore, we investigated the effect of ageing on whole-body and skeletal muscle lipid metabolism, with parallel characterization of muscle insulin sensitivity, in lean young and older individuals matched for estimated habitual physical activity levels and body composition. To determine the effect of adiposity and reduced physical activity on the ageing process, the older lean individuals were also compared to a group of older overweight individuals matched for lean mass. We hypothesized that an age-associated imbalance between FFA delivery and oxidation in skeletal muscle during exercise would only be observed in older overweight individuals, which would manifest as reduced IMCL oxidation and increased IMCL storage, particularly in the SSL region, and be associated with skeletal muscle insulin resistance.