PuSH - Publication Server of Helmholtz Zentrum München: MTORC2 and AMPK differentially regulate muscle triglyceride content via perilipin 3.

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Kleinert, M. ; Parker, B.L.* ; Chaudhuri, R.* ; Fazakerley, D.J.* ; Serup, A.* ; Thomas, K.C.* ; Krycer, J.R.* ; Sylow, L.* ; Fritzen, A.M.* ; Hoffman, N.J.* ; Jeppesen, J.* ; Schjerling, P.* ; Ruegg, M.A.* ; Kiens, B.* ; James, D.E.* ; Richter, E.A.*

MTORC2 and AMPK differentially regulate muscle triglyceride content via perilipin 3.

Mol. Metab. 5, 646-655 (2016)

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Objective: We have recently shown that acute inhibition of both mTOR complexes (mTORC1 and mTORC2) increases whole-body lipid utilization, while mTORC1 inhibition had no effect. Therefore, we tested the hypothesis that mTORC2 regulates lipid metabolism in skeletal muscle. Methods: Body composition, substrate utilization and muscle lipid storage were measured in mice lacking mTORC2 activity in skeletal muscle (specific knockout of RICTOR (Ric mKO)). We further examined the RICTOR/mTORC2-controlled muscle metabolome and proteome; and performed follow-up studies in other genetic mouse models and in cell culture. Results: Ric mKO mice exhibited a greater reliance on fat as an energy substrate, a re-partitioning of lean to fat mass and an increase in intramyocellular triglyceride (IMTG) content, along with increases in several lipid metabolites in muscle. Unbiased proteomics revealed an increase in the expression of the lipid droplet binding protein Perilipin 3 (PLIN3) in muscle from Ric mKO mice. This was associated with increased AMPK activity in Ric mKO muscle. Reducing AMPK kinase activity decreased muscle PLIN3 expression and IMTG content. AMPK agonism, in turn, increased PLIN3 expression in a FoxO1 dependent manner. PLIN3 overexpression was sufficient to increase triglyceride content in muscle cells. Conclusions: We identified a novel link between mTORC2 and PLIN3, which regulates lipid storage in muscle. While mTORC2 is a negative regulator, we further identified AMPK as a positive regulator of PLIN3, which impacts whole-body substrate utilization and nutrient partitioning.

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