Hepatic Fatty Acid Oxidation Restrains Systemic Catabolism during Starvation.
The liver is critical for maintaining systemic energy balance during starvation. To understand the role of hepatic fatty acid β-oxidation on this process, we generated mice with a liver-specific knockout of carnitine palmitoyltransferase 2 (Cpt2(L-/-)), an obligate step in mitochondrial long-chain fatty acid β-oxidation. Fasting induced hepatic steatosis and serum dyslipidemia with an absence of circulating ketones, while blood glucose remained normal. Systemic energy homeostasis was largely maintained in fasting Cpt2(L-/-) mice by adaptations in hepatic and systemic oxidative gene expression mediated in part by Pparα target genes including procatabolic hepatokines Fgf21, Gdf15, and Igfbp1. Feeding a ketogenic diet to Cpt2(L-/-) mice resulted in severe hepatomegaly, liver damage, and death with a complete absence of adipose triglyceride stores. These data show that hepatic fatty acid oxidation is not required for survival during acute food deprivation but essential for constraining adipocyte lipolysis and regulating systemic catabolism when glucose is limiting.
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Jieun
J
Lee
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Joseph
J
Choi
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Susanna
S
Scafidi
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: mwolfga1@jhmi.edu.
Michael J
MJ
Wolfgang
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000172:deficiency / Q000378:metabolism; D055423:Diet, Ketogenic; D050171:Dyslipidemias / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005215:Fasting / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D009928:Organ Specificity; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D047493:PPAR alpha / Q000378:metabolism; D013217:Starvation / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D005227:Fatty Acids; D047493:PPAR alpha; D014280:Triglycerides; C116917:acylcarnitine; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine