mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3

Maximilian Kleinert; Benjamin L Parker; Rima Chaudhuri; Daniel J Fazakerley; Annette Karen Lundbeck Serup; Kristen C Thomas; James R. Krycer; Lykke Sylow; Andreas Mæchel Fritzen; Nolan J Hoffman; Jacob Fuglsbjerg Jeppesen; Peter Schjerling; Markus A Ruegg; Bente Kiens; David E James; Erik Richter

doi:10.1016/j.molmet.2016.06.007

mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3

Maximilian Kleinert, Benjamin L Parker, Rima Chaudhuri, Daniel J Fazakerley, Annette Karen Lundbeck Serup, Kristen C Thomas, James R. Krycer, Lykke Sylow, Andreas Mæchel Fritzen, Nolan J Hoffman, Jacob Fuglsbjerg Jeppesen, Peter Schjerling, Markus A Ruegg, Bente Kiens, David E James, Erik Richter

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Abstract

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.

Original language	English
Journal	Molecular Metabolism
Volume	5
Issue number	8
Pages (from-to)	646-655
Number of pages	10
ISSN	2212-8778
DOIs	https://doi.org/10.1016/j.molmet.2016.06.007
Publication status	Published - 1 Aug 2016

Keywords

PLIN3
RICTOR
mTOR
Metabolism
Akt

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Kleinert et al_Molecular Metabolism_2016_Vol 5(8)_646-655Final published version, 1.21 MBLicence: CC BY

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Kleinert, M., Parker, B. L., Chaudhuri, R., Fazakerley, D. J., Serup, A. K. L., Thomas, K. C., Krycer, J. R., Sylow, L., Fritzen, A. M., Hoffman, N. J., Jeppesen, J. F., Schjerling, P., Ruegg, M. A., Kiens, B., James, D. E., & Richter, E. (2016). mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3. Molecular Metabolism, 5(8), 646-655. https://doi.org/10.1016/j.molmet.2016.06.007

Kleinert, M, Parker, BL, Chaudhuri, R, Fazakerley, DJ, Serup, AKL, Thomas, KC, Krycer, JR, Sylow, L , Fritzen, AM, Hoffman, NJ, Jeppesen, JF, Schjerling, P, Ruegg, MA, Kiens, B, James, DE & Richter, E 2016, 'mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3', Molecular Metabolism, vol. 5, no. 8, pp. 646-655. https://doi.org/10.1016/j.molmet.2016.06.007

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title = "mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3",

abstract = "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.",

keywords = "PLIN3, RICTOR, mTOR, Metabolism, Akt",

author = "Maximilian Kleinert and Parker, {Benjamin L} and Rima Chaudhuri and Fazakerley, {Daniel J} and Serup, {Annette Karen Lundbeck} and Thomas, {Kristen C} and Krycer, {James R.} and Lykke Sylow and Fritzen, {Andreas M{\ae}chel} and Hoffman, {Nolan J} and Jeppesen, {Jacob Fuglsbjerg} and Peter Schjerling and Ruegg, {Markus A} and Bente Kiens and James, {David E} and Erik Richter",

note = "CURIS 2016 NEXS 270",

year = "2016",

month = aug,

day = "1",

doi = "10.1016/j.molmet.2016.06.007",

language = "English",

volume = "5",

pages = "646--655",

journal = "Molecular Metabolism",

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TY - JOUR

T1 - mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3

AU - Kleinert, Maximilian

AU - Parker, Benjamin L

AU - Chaudhuri, Rima

AU - Fazakerley, Daniel J

AU - Serup, Annette Karen Lundbeck

AU - Thomas, Kristen C

AU - Krycer, James R.

AU - Sylow, Lykke

AU - Fritzen, Andreas Mæchel

AU - Hoffman, Nolan J

AU - Jeppesen, Jacob Fuglsbjerg

AU - Schjerling, Peter

AU - Ruegg, Markus A

AU - Kiens, Bente

AU - James, David E

AU - Richter, Erik

N1 - CURIS 2016 NEXS 270

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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.

AB - 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.

KW - PLIN3

KW - RICTOR

KW - mTOR

KW - Metabolism

KW - Akt

U2 - 10.1016/j.molmet.2016.06.007

DO - 10.1016/j.molmet.2016.06.007

M3 - Journal article

C2 - 27656402

SN - 2212-8778

VL - 5

SP - 646

EP - 655

JO - Molecular Metabolism

JF - Molecular Metabolism

IS - 8

ER -

mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3

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Keywords

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