Progressive adaptation of hepatic ketogenesis in mice fed a high-fat diet

Abstract

Hepatic ketogenesis provides a vital systemic fuel during fasting because ketone bodies are oxidized by most peripheral tissues and, unlike glucose, can be synthesized from fatty acids via mitochondrial beta-oxidation. Since dysfunctional mitochondrial fat oxidation may be a cofactor in insulin-resistant tissue, the objective of this study was to determine whether diet-induced insulin resistance in mice results in impaired in vivo hepatic fat oxidation secondary to defects in ketogenesis. Ketone turnover (micromol/min) in the conscious and unrestrained mouse was responsive to induction and diminution of hepatic fat oxidation, as indicated by an eightfold rise during the fed (0.50+/-0.1)-to-fasted (3.8+/-0.2) transition and a dramatic blunting of fasting ketone turnover in PPARalpha(-/-) mice (1.0+/-0.1). C57BL/6 mice made obese and insulin resistant by high-fat feeding for 8 wk had normal expression of genes that regulate hepatic fat oxidation, whereas 16 wk on the diet induced expression of these genes and stimulated the function of hepatic mitochondrial fat oxidation, as indicated by a 40% induction of fasting ketogenesis and a twofold rise in short-chain acylcarnitines. Together, these findings indicate a progressive adaptation of hepatic ketogenesis during high-fat feeding, resulting in increased hepatic fat oxidation after 16 wk of a high-fat diet. We conclude that mitochondrial fat oxidation is stimulated rather than impaired during the initiation of hepatic insulin resistance in mice.

Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver

“…Following an overnight fast, unrestrained mice were infused with [3,4-13 C 2 ]acetoacetate and [U- 13 C 4 ]sodium ␤ -hydroxybutyrate as a bolus (8.8 and 6.7 µmol/hr) for 10 min and as a continuous infusion (3.5 and 2.7 µmol/hr) for a further 80 min ( 26 ). At the end of 90 min, approximately 50 µl of blood was collected for LC-MS/MS analysis of ketone turnover ( 26 ).…”

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…In fatty liver disease, hepatic beta-oxidation and ketogenesis are upregulated (Sunny et al 2010, Mannisto et al 2015. Hepatic beta-oxidation in response to lipid accumulation prevents lipotoxicity and supports gluconeogenesis and ketogenesis.…”

“…Like fasting-induced hepatic lipid accumulation, high-fat diet feeding elevates hepatic CPT1 activity and beta-oxidative capacity (StefanovicRacic et al 2008, Sunny et al 2010, Zhang et al 2014, Geisler et al 2016. The acetyl-CoA derived through beta-oxidation can either be oxidized through the TCA cycle or enter ketogenesis.…”

The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism

“…Frozen tissues of 100 mg were used for lipid extraction and measurement by the UTSW Metabolic Core Facility as described previously (36). Carnitine measurements were performed as before (37). Serum insulin was measured using mouse insulin ELISA kits (Millipore).…”