AgRP Neurons Require Carnitine Acetyltransferase to Regulate Metabolic Flexibility and Peripheral Nutrient Partitioning

Alex Reichenbach; Romana Stark; Mathieu Mequinion; Raphael R.G. Denis; Jeferson F. Goularte; Rachel E. Clarke; Sarah H. Lockie; Moyra B. Lemus; Greg M. Kowalski; Clinton R. Bruce; Cheng Huang; Ralf B. Schittenhelm; Randall L. Mynatt; Brian J. Oldfield; Matthew J. Watt; Serge Luquet; Zane B. Andrews

doi:10.1016/j.celrep.2018.01.067

Cell Reports (Feb 2018)

AgRP Neurons Require Carnitine Acetyltransferase to Regulate Metabolic Flexibility and Peripheral Nutrient Partitioning

Alex Reichenbach,
Romana Stark,
Mathieu Mequinion,
Raphael R.G. Denis,
Jeferson F. Goularte,
Rachel E. Clarke,
Sarah H. Lockie,
Moyra B. Lemus,
Greg M. Kowalski,
Clinton R. Bruce,
Cheng Huang,
Ralf B. Schittenhelm,
Randall L. Mynatt,
Brian J. Oldfield,
Matthew J. Watt,
Serge Luquet,
Zane B. Andrews

Affiliations

Alex Reichenbach: Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia; Department of Physiology, Monash University, Clayton 3800, VIC, Australia
Romana Stark: Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia; Department of Physiology, Monash University, Clayton 3800, VIC, Australia
Mathieu Mequinion: Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia; Department of Physiology, Monash University, Clayton 3800, VIC, Australia
Raphael R.G. Denis: Université of Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionelle et Adaptative, CNRS UMR 8251, 75205 Paris, France
Jeferson F. Goularte: Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia
Rachel E. Clarke: Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia; Department of Physiology, Monash University, Clayton 3800, VIC, Australia
Sarah H. Lockie: Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia; Department of Physiology, Monash University, Clayton 3800, VIC, Australia
Moyra B. Lemus: Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia; Department of Physiology, Monash University, Clayton 3800, VIC, Australia
Greg M. Kowalski: Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood 3125, VIC, Australia
Clinton R. Bruce: Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood 3125, VIC, Australia
Cheng Huang: Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia; Monash Biomedical Proteomics Facility and Department of Biochemistry, Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia
Ralf B. Schittenhelm: Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia; Monash Biomedical Proteomics Facility and Department of Biochemistry, Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia
Randall L. Mynatt: Gene Nutrient Interactions Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA; Transgenic Core Facility, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA
Brian J. Oldfield: Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia; Department of Physiology, Monash University, Clayton 3800, VIC, Australia
Matthew J. Watt: Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia; Department of Physiology, Monash University, Clayton 3800, VIC, Australia
Serge Luquet: Université of Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionelle et Adaptative, CNRS UMR 8251, 75205 Paris, France
Zane B. Andrews: Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia; Department of Physiology, Monash University, Clayton 3800, VIC, Australia; Corresponding author

DOI: https://doi.org/10.1016/j.celrep.2018.01.067
Journal volume & issue: Vol. 22, no. 7
pp. 1745 – 1759

Abstract

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Summary: AgRP neurons control peripheral substrate utilization and nutrient partitioning during conditions of energy deficit and nutrient replenishment, although the molecular mechanism is unknown. We examined whether carnitine acetyltransferase (Crat) in AgRP neurons affects peripheral nutrient partitioning. Crat deletion in AgRP neurons reduced food intake and feeding behavior and increased glycerol supply to the liver during fasting, as a gluconeogenic substrate, which was mediated by changes to sympathetic output and peripheral fatty acid metabolism in the liver. Crat deletion in AgRP neurons increased peripheral fatty acid substrate utilization and attenuated the switch to glucose utilization after refeeding, indicating altered nutrient partitioning. Proteomic analysis in AgRP neurons shows that Crat regulates protein acetylation and metabolic processing. Collectively, our studies highlight that AgRP neurons require Crat to provide the metabolic flexibility to optimize nutrient partitioning and regulate peripheral substrate utilization, particularly during fasting and refeeding.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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