Hepatic Fatty Acid Oxidation Restrains Systemic Catabolism during Starvation

Abstract

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 (Cpt2L−/−), 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 Cpt2L−/− 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 Cpt2L−/− 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.

Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

“…(Figure 1H). Previously, we had shown significant alterations in serum acylcarnitines in Cpt2 L−/− mice in response to a 24hr fast or feeding a ketogenic diet (Lee et al, 2016b). HFD-fed Cpt2 L−/− mice exhibited a dramatic suppression of free carnitine and acetyl-carnitine in both blood (Figure 1I) and urine (Figure 1J).…”

“…Previously, we showed that Cpt2 L−/− mice were relatively normal under carbohydrate-fed conditions, but the exposure of the liver to a high burden of free fatty acids via prolonged fasting or a ketogenic diet elicited profound cellular and physiological adaptations (Lee et al, 2016b). Since hepatic fatty acid oxidation is central to systemic energy balance, we were interested in how feeding a chronic lipid-rich diet to Cpt2 L−/− mice would affect systemic metabolic dysfunction.…”

“…Cpt2 L−/− mice were relatively normal under carbohydrate-fed conditions, but fasting resulted in hepatic steatosis and serum dyslipidemia with an absence of circulating ketone bodies. Feeding a ketogenic diet to Cpt2 L−/− mice resulted in severe hepatomegaly, liver damage and death with a complete absence of adipose triglyceride stores (Lee et al, 2016b). As expected, hepatic fatty acid oxidation was a critical adaptation to fasting.…”

Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner

“…The generation of mice in which exon 4 of the mouse Cpt2 gene is flanked by loxP sequences was previously described (35,36). To generate osteoblast-and osteocyte-specific KO, Cpt2 lox/lox mice were crossed with Osteocalcin-Cre (Oc-Cre TG/+ ) mice (37).…”

“…To characterize the requirement for fatty acid β-oxidation during bone formation, we generated mice in which the Cpt2 gene that encodes Cpt2 was selectively disrupted in osteoblasts and osteocytes. Cpt2 lox/lox mice in which exon 4 is flanked by loxP sites (35,36) were crossed with Oc-Cre mice (37) ). Both male and female ΔCpt2 mice were born at the expected Mendelian frequency, exhibited 70% reductions in Cpt2 mRNA levels in skeletal tissue (Figure 2A) with normal expression levels in other metabolic tissues (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.92704DS1), and maintained normal body weights ( Figure 2B).…”