mTOR signaling in adipose tissue influences systemic lipid metabolism
Authors: Paolella Lauren M. , Tran Cassie , Chellappa Karthikeyani , Mukherjee Sarmistha , Davis James G. , Wilson Aisha , Edouard Edwige , Shewale Swapnil , Rader Daniel J. , Baur Joseph A. 
Published: June 2021

Rapamycin, a fungicidal macrolide, has been shown to increase life span and delay the onset of age related diseases across several model organisms. However, rapamycin treatment leads to metabolic dysregulation including glucose intolerance and hyperlipidemia, which limits its potential utility as an anti‐ageing agent. Rapamycin treatment increases serum triglycerides in human patients by 95%, and while it influences the expression of multiple proteins involved in lipid handling in liver and adipose tissue, the precise mechanism by which rapamycin treatment causes hypertriglyceridemia is not known

Rapamycin is an allosteric inhibitor of mTOR (mechanistic target of rapamycin), a serine/threonine protein kinase that functions as a master regulator of cellular growth and metabolism. mTOR exists in two distinct protein complexes, mTORC1 (characterized by the presence of raptor) and mTORC2 (characterized by the presence of rictor), with each complex phosphorylating a distinct set of effector proteins. Rapamycin acutely inhibits mechanistic target of rapamycin complex I (mTORC1), but can also inhibit mTORC2 under chronic conditions. Tissue specific disruption of mTORC1 or mTORC2 has revealed that each complex has different effects on whole body glucose and lipid homeostasis in different organs. Genetic ablation of either mTORC1 or mTORC2 in hepatocytes fails to phenocopy the effects of rapamycin treatment, suggesting that mTOR signaling in another tissue is responsible for rapamycin‐induced hypertriglyceridemia.

LPL hydrolyzes the TG in VLDL into FFA for uptake into adipose tissue. In addition, mTORC1 has been shown to inhibit lipolysis and therefore the releases of FFA into plasma. Using adipose specific raptor knockout mice, we show that TG clearance is delayed and LPL gene expression and genes related to LPL processing are altered in the absence of mTORC1 signaling. The decrease in TG clearance can be a result of the decrease in adipose tissue LPL synthesis due to decreased mRNA and/or decreases secretion of active LPL into the blood. This can result in decreased rate of VLDL‐TG hydrolysis and slower clearance of plasma TG, leading to a buildup of TG levels in the blood. In addition, upon refeeding, these KO mice have increased serum TG and FFA, suggesting a failure to suppress lipolysis. Based off phosphoproteomics analysis, phosphorylation of ATGL, the rate limiting enzyme in lipolysis, is increased with loss of mTORC1 in adipose tissue, thus increasing activity of ATGL. ATGL‐Raptor double knockout mice were generated. The DKO mice, upon refeeding, phenocopy control mice serum TG and FFA. This suggest that with loss of mTORC1 there is an increase in lipolysis in adipose tissue when lipolysis should be inhibited, which leads to increased release of FFA and uptake into the liver. This increase leads to an increase in liver TG for increased VLDL‐TG secretion. Decreased LPL activity and increased lipolysis in adipose can both increase plasma TG levels. We hypothesize that inhibition of mTORC1 signaling in adipose tissue is the major driver of hyperlipidemia caused by rapamycin.

Support or Funding Information

This work was supported by grants from the National Institutes of Health (R01‐AG‐043483 and R01‐DK‐098656 to J.A.B.)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.