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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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. Reichenbach et al. demonstrate that AgRP neurons require carnitine acetyltransferase to regulate peripheral substrate switching from fatty acid to glucose utilization during fasting and the transition to refeeding. This mechanism preserves fatty acids when glucose from food becomes available and maximizes energy conservation for future periods of energy deficit.

Original languageEnglish
Pages (from-to)1745-1759
Number of pages15
JournalCell Reports
Volume22
Issue number7
DOIs
Publication statusPublished - 13 Feb 2018

Keywords

  • acetylation
  • energy availability
  • fasting
  • fatty acid utilization
  • glucose
  • liver
  • metabolism
  • refeeding
  • SNS
  • substrate switch

Cite this

Reichenbach, Alex ; Stark, Romana ; Mequinion, Mathieu ; Denis, Raphael R.G. ; Goularte, Jeferson F. ; Clarke, Rachel E. ; Lockie, Sarah H. ; Lemus, Moyra B. ; Kowalski, Greg M. ; Bruce, Clinton R. ; Huang, Cheng ; Schittenhelm, Ralf B. ; Mynatt, Randall L. ; Oldfield, Brian J. ; Watt, Matthew J. ; Luquet, Serge ; Andrews, Zane B. / AgRP Neurons Require Carnitine Acetyltransferase to Regulate Metabolic Flexibility and Peripheral Nutrient Partitioning. In: Cell Reports. 2018 ; Vol. 22, No. 7. pp. 1745-1759.
@article{33300167db38464689aedbbe1a4da5cb,
title = "AgRP Neurons Require Carnitine Acetyltransferase to Regulate Metabolic Flexibility and Peripheral Nutrient Partitioning",
abstract = "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. Reichenbach et al. demonstrate that AgRP neurons require carnitine acetyltransferase to regulate peripheral substrate switching from fatty acid to glucose utilization during fasting and the transition to refeeding. This mechanism preserves fatty acids when glucose from food becomes available and maximizes energy conservation for future periods of energy deficit.",
keywords = "acetylation, energy availability, fasting, fatty acid utilization, glucose, liver, metabolism, refeeding, SNS, substrate switch",
author = "Alex Reichenbach and Romana Stark and Mathieu Mequinion and Denis, {Raphael R.G.} and Goularte, {Jeferson F.} and Clarke, {Rachel E.} and Lockie, {Sarah H.} and Lemus, {Moyra B.} and Kowalski, {Greg M.} and Bruce, {Clinton R.} and Cheng Huang and Schittenhelm, {Ralf B.} and Mynatt, {Randall L.} and Oldfield, {Brian J.} and Watt, {Matthew J.} and Serge Luquet and Andrews, {Zane B.}",
year = "2018",
month = "2",
day = "13",
doi = "10.1016/j.celrep.2018.01.067",
language = "English",
volume = "22",
pages = "1745--1759",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier",
number = "7",

}

AgRP Neurons Require Carnitine Acetyltransferase to Regulate Metabolic Flexibility and Peripheral Nutrient Partitioning. / Reichenbach, Alex; Stark, Romana; Mequinion, Mathieu; Denis, Raphael R.G.; Goularte, Jeferson F.; Clarke, Rachel E.; Lockie, Sarah H.; Lemus, Moyra B.; Kowalski, Greg M.; Bruce, Clinton R.; Huang, Cheng; Schittenhelm, Ralf B.; Mynatt, Randall L.; Oldfield, Brian J.; Watt, Matthew J.; Luquet, Serge; Andrews, Zane B.

In: Cell Reports, Vol. 22, No. 7, 13.02.2018, p. 1745-1759.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - AgRP Neurons Require Carnitine Acetyltransferase to Regulate Metabolic Flexibility and Peripheral Nutrient Partitioning

AU - Reichenbach, Alex

AU - Stark, Romana

AU - Mequinion, Mathieu

AU - Denis, Raphael R.G.

AU - Goularte, Jeferson F.

AU - Clarke, Rachel E.

AU - Lockie, Sarah H.

AU - Lemus, Moyra B.

AU - Kowalski, Greg M.

AU - Bruce, Clinton R.

AU - Huang, Cheng

AU - Schittenhelm, Ralf B.

AU - Mynatt, Randall L.

AU - Oldfield, Brian J.

AU - Watt, Matthew J.

AU - Luquet, Serge

AU - Andrews, Zane B.

PY - 2018/2/13

Y1 - 2018/2/13

N2 - 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. Reichenbach et al. demonstrate that AgRP neurons require carnitine acetyltransferase to regulate peripheral substrate switching from fatty acid to glucose utilization during fasting and the transition to refeeding. This mechanism preserves fatty acids when glucose from food becomes available and maximizes energy conservation for future periods of energy deficit.

AB - 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. Reichenbach et al. demonstrate that AgRP neurons require carnitine acetyltransferase to regulate peripheral substrate switching from fatty acid to glucose utilization during fasting and the transition to refeeding. This mechanism preserves fatty acids when glucose from food becomes available and maximizes energy conservation for future periods of energy deficit.

KW - acetylation

KW - energy availability

KW - fasting

KW - fatty acid utilization

KW - glucose

KW - liver

KW - metabolism

KW - refeeding

KW - SNS

KW - substrate switch

UR - http://www.scopus.com/inward/record.url?scp=85042025044&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2018.01.067

DO - 10.1016/j.celrep.2018.01.067

M3 - Article

VL - 22

SP - 1745

EP - 1759

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 7

ER -