《細胞》棕色脂肪中的BCAA-氮通量控制代謝健康不依賴于產熱功能

2024年4月22日,來自美國霍華德休斯醫學研究所Shingo Kajimura團隊在《細胞》雜志上發表了標題為“BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.”的研究成果,發現棕色脂肪中的BCAA-氮通量控制代謝健康不依賴于產熱功能。

 

據介紹,棕色脂肪組織BAT)具有產熱作用。嚙齒動物研究表明,BAT產熱增強與能量消耗增加、體重減輕和葡萄糖穩態改善密切相關。然而,人類BAT對2型糖尿病具有保護作用,與體重無關。這種分離的機制尚不清楚。

棕色脂肪組織(BAT)

研究人員報道了BAT中支鏈氨基酸(BCAA)的線粒體分解代謝受損,通過刪除線粒體BCAA載體(MBC),在不影響能量消耗和體重的情況下引起全身胰島素抵抗。棕色脂肪細胞在線粒體中分解代謝BCAA,作為非必需氨基酸和谷胱甘肽生物合成的氮供體。BAT中線粒體BCAA氮通量受損導致氧化應激增加,肝臟胰島素信號傳導減少,循環BCAA來源代謝產物減少。高脂肪飲食減弱了BAT中BCAA氮通量和代謝產物的合成,而冷激活的BAT增強了合成。

 

棕色脂肪組織(BAT)中支鏈氨基酸(BCAA)的代謝獨立于能耗和體重,其作為含氮代謝物的氮供體而非TCA循環燃料調節代謝健康。BCAA衍生的含氮代謝物可調節全身氧化還原平衡及葡萄糖穩態,其減少會導致胰島素抵抗。這一發現揭示了BAT代謝益處的新機制,并為研究復雜代謝生物學問題提供了新工具。這一種代謝產物介導的途徑,BAT通過該途徑控制產熱作用之外的代謝健康。

 

Highlights

  • BCAA is a key nitrogen source for synthesizing non-essential amino acids and GSH
  • Mitochondrial BCAA import via MBC is required for BCAA-derived metabolite synthesis
  • Reduced synthesis of BCAA-derived metabolites in BAT results in insulin resistance
  • Obesity impairs BCAA-nitrogen flux and BCAA-derived metabolite synthesis in BAT

Summary

Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

 

文章來源:

Anthony R.P. Verkerke, Dandan Wang et al, BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.DOI: 10.1016/j.cell.2024.03.030,Cell:最新IF:66.85

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