Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Endocrinology. 2021 Jul 1;162(7). doi: 10.1210/endocr/bqab062.
Circulating branched chain amino acid (BCAA) levels are elevated in obese humans and genetically obese rodents. However, the relationship of BCAAs to insulin resistance in diet-induced obese mice, a commonly used model to study glucose homeostasis, is still ill-defined. Here we examined how high-fat high-sucrose (HFHS) or high-fat diet (HFD) feeding, with or without BCAA supplementation in water, alters the metabolome in serum/plasma and tissues in mice and whether raising circulating BCAA levels worsens insulin resistance and glucose intolerance. Neither HFHS nor HFD feeding raised circulating BCAA levels in insulin-resistant diet-induced obese mice. BCAA supplementation raised circulating BCAA and branched-chain α-keto acid levels and C5-OH/C3-DC acylcarnitines (AC) in muscle from mice fed an HFHS diet or HFD, but did not worsen insulin resistance. A set of short- and long-chain acyl CoAs were elevated by diet alone in muscle, liver, and white adipose tissue (WAT), but not increased further by BCAA supplementation. HFD feeding reduced valine and leucine oxidation in WAT but not in muscle. BCAA supplementation markedly increased valine oxidation in muscle from HFD-fed mice, while leucine oxidation was unaffected by diet or BCAA treatment. Here we establish an extensive metabolome database showing tissue-specific changes in mice on 2 different HFDs, with or without BCAA supplementation. We conclude that mildly elevating circulating BCAAs and a subset of ACs by BCAA supplementation does not worsen insulin resistance or glucose tolerance in mice. This work highlights major differences in the effects of BCAAs on glucose homeostasis in diet-induced obese mice versus data reported in obese rats and in humans.
循环支链氨基酸（BCAA）水平在肥胖人群和遗传性肥胖啮齿动物中升高。然而，BCAA 与饮食诱导肥胖小鼠（一种常用于研究葡萄糖稳态的模型）的胰岛素抵抗之间的关系仍未明确。在这里，我们研究了高脂肪高蔗糖（HFHS）或高脂肪饮食（HFD）喂养，以及在水中补充 BCAA，如何改变小鼠血清/血浆和组织中的代谢组学，以及提高循环 BCAA 水平是否会加重胰岛素抵抗和葡萄糖不耐受。HFHS 或 HFD 喂养均未升高胰岛素抵抗的饮食诱导肥胖小鼠的循环 BCAA 水平。BCAA 补充提高了 HFHS 饮食或 HFD 喂养小鼠的循环 BCAA 和支链α-酮酸水平以及 C5-OH/C3-DC 酰基辅酶 A（AC）在肌肉中的水平，但不会加重胰岛素抵抗。单独的饮食增加了一组短链和长链酰基辅酶 A 在肌肉、肝脏和白色脂肪组织（WAT）中的水平，但 BCAA 补充并没有进一步增加。HFD 喂养减少了 WAT 中缬氨酸和亮氨酸的氧化，但在肌肉中没有增加。BCAA 补充显著增加了 HFD 喂养小鼠肌肉中缬氨酸的氧化，而亮氨酸的氧化不受饮食或 BCAA 处理的影响。在这里，我们建立了一个广泛的代谢组学数据库，显示了在两种不同的 HFD 喂养小鼠中，组织特异性的变化，以及是否补充 BCAA。我们得出结论，BCAA 补充轻度升高循环 BCAA 和一组 AC 不会加重小鼠的胰岛素抵抗或葡萄糖耐量。这项工作突出了在饮食诱导肥胖小鼠中，BCAA 对葡萄糖稳态的影响与肥胖大鼠和人类报告的数据之间存在显著差异。
