@article{2089f2a2b57440b7ac4b0517529d8238,
title = "Impaired skeletal muscle mitochondrial pyruvate uptake rewires glucose metabolism to drive whole-body leanness",
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.",
author = "Arpit Sharma and Lalita Oonthonpan and Sheldon, {Ryan D.} and Rauckhorst, {Adam J.} and Zhiyong Zhu and Tompkins, {Sean C.} and Kevin Cho and Grzesik, {Wojciech J.} and Gray, {Lawrence R.} and Scerbo, {Diego A.} and Pewa, {Alvin D.} and Cushing, {Emily M.} and Dyle, {Michael C.} and Cox, {James E.} and Chris Adams and Davies, {Brandon S.} and Shields, {Richard K.} and Norris, {Andrew W.} and Gary Patti and Zingman, {Leonid V.} and Taylor, {Eric B.}",
note = "Funding Information: We thank the Fraternal Order of Eagles Diabetes Research Center Metabolic Phenotyping Core for assistance with insulin clamps. This work was supported by NIH grants R01 DK104998 and R00 AR059190 (EBT); R01 HD084645 and R01 HD082109 (RKS); R01 DK092412 (LVZ); R35ES028365 (GJP); R01 HL130146 (BSD); T32 HL007344 to Steven Lentz (RDS), F32 DK116522 (RDS), the Carver College of Medicine MSTP grant GM007337 (SCT); T32 HL007638 to Michael Welsh (AJR); ADA 1– 18-PDF-060 (AJR); F32 DK101183 (LRG); T32 DK112751 to E Dale Abel (DAS); P30CA086862 to George Weiner, which contributed to support of core facilities utilized for this research. Funding Information: National Institutes of HealthDK104998 Eric B Taylor National Institutes of HealthAR059190 Eric B Taylor National Institutes of Health HD084645 Richard K Shields National Institutes of Health HD082109 Richard K Shields National Institutes of Health DK092412 Leonid V Zingman National Institutes of Health ES028365 Gary Patti National Institutes of Health HL130146 Brandon S Davies National Institutes of HealthHL007344 Ryan D Sheldon National Institutes of Health DK116522 Ryan D Sheldon National Institutes of Health GM007337 Sean C Tompkins National Institutes of Health HL007638 Adam J Rauckhorst National Institutes of Health DK101183 Lawrence R Gray American Diabetes Association 1-18-PDF-060 Adam J Rauckhorst National Institutes of Health DK112751 Diego A Scerbo The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Publisher Copyright: {\textcopyright} Sharma et al.",
year = "2019",
month = jul,
doi = "10.7554/eLife.45873",
language = "English (US)",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}