Impaired skeletal muscle mitochondrial pyruvate uptake rewires glucose metabolism to drive whole-body leanness

Arpit Sharma, Lalita Oonthonpan, Ryan D. Sheldon, Adam J. Rauckhorst, Zhiyong Zhu, Sean C. Tompkins, Kevin Cho, Wojciech J. Grzesik, Lawrence R. Gray, Diego A. Scerbo, Alvin D. Pewa, Emily M. Cushing, Michael C. Dyle, James E. Cox, Chris Adams, Brandon S. Davies, Richard K. Shields, Andrew W. Norris, Gary Patti, Leonid V. ZingmanEric B. Taylor

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Metabolic cycles are a fundamental element of cellular and organismal function. Among the most critical in higher organisms is the Cori Cycle, the systemic cycling between lactate and glucose. Here, skeletal muscle-specific Mitochondrial Pyruvate Carrier (MPC) deletion in mice diverted pyruvate into circulating lactate. This switch disinhibited muscle fatty acid oxidation and drove Cori Cycling that contributed to increased energy expenditure. Loss of muscle MPC activity led to strikingly decreased adiposity with complete muscle mass and strength retention. Notably, despite decreasing muscle glucose oxidation, muscle MPC disruption increased muscle glucose uptake and whole-body insulin sensitivity. Furthermore, chronic and acute muscle MPC deletion accelerated fat mass loss on a normal diet after high fat diet-induced obesity. Our results illuminate the role of the skeletal muscle MPC as a whole-body carbon flux control point. They highlight the potential utility of modulating muscle pyruvate utilization to ameliorate obesity and type 2 diabetes.

Original languageEnglish
Article numbere45873
JournaleLife
Volume8
DOIs
StatePublished - 1 Jul 2019
Externally publishedYes

Fingerprint

Dive into the research topics of 'Impaired skeletal muscle mitochondrial pyruvate uptake rewires glucose metabolism to drive whole-body leanness'. Together they form a unique fingerprint.

Cite this