Lipid Activates mTORC1 and mTORC2 in the Absorption of Dietary Triglycerides

Abstract

Mechanistic target of rapamycin (mTOR) senses amino acids; however, its role in lipid metabolism is less established. Organismal lipid requirements are largely met through dietary intake. How nutrient sensing mechanisms in gut interface with dietary fat remains unclear. Here we reveal fundamental and cooperative roles for mTOR complexes 1 and 2 (mTORC1/2) in absorption of dietary triglycerides. Dietary lipid activates mTORC1/2 signaling in gut. Hyperactivating mTORC1 by deleting Tsc1 is sufficient to promote triglyceride absorption and metabolic disease in high fat-fed mice. Conversely, blocking mTORC1/2 by deleting Raptor or Rictor each decreases triglyceride absorption. Loss of Raptor sequesters lipid in Golgi in enterocytes and suppresses triglyceride secretion, while Rictor mice show reduced triglycerides in enterocytes and circulation. Lipidomics in Rictor-null enterocytes revealed accumulation of diacylglycerols and funneling of absorbed fatty acids into phospholipids supporting triglyceride synthesis failure. Targeting mTOR signaling in gut may help counter hypertriglyceridemia and prevent cardiometabolic diseases.