Fatty liver disease is strongly associated with insulin resistance. In order to elucidate the causality of this complex relationship, we studied insulin resistance in a rodent model of fatty liver disease the choline deficient diet (CDD) in which fatty liver occurs without generalised obesity. C57Bl/6 mice were fed a low fat (10% calories as fat, Lo) or isocaloric high fat diet (45% calories as fat, Hi) for 3 weeks; then half of the animals in each group continued either on standard choline supplementation (CS) or on an identical diet deficient in choline (CD) for a further 3 weeks. Insulin resistance was assessed by intraperitoneal glucose tolerance test after an overnight fast. Liver fat was quantified biochemically, and expression of hepatic enzymes involved in lipid metabolism was examined by real-time PCR. CDD induced fatty liver with Lo (liver triglycerides, CS 13.4±2.1, CD 31.6±6.3 μmol/g, P=0.03) or Hi diet (triglycerides, CS 36.8±4.8, CD 59.5±2.1 μmol/g; P=0.006). There was no change in body weight or fat depot size. Choline deficiency significantly improved measures of insulin resistance induced by a high fat diet, despite greater liver fat accumulation (Table 1). mRNA expression of the rate limiting enzyme of phosphatidylcholine synthesis (Pcyt1a) and of enzymes involved in free fatty acid esterification (Acsl1, mGPAM, AGPAT1, DGAT2) was significantly increased. In contrast, the expressions of key enzymes or transcription factors involved in free fatty acid synthesis or oxidation was unaltered. These results suggest that liver fat accumulation per se does not cause insulin resistance. CDD, which increases liver triglyceride accumulation by enhancing free fatty acid esterification, improves insulin resistance, perhaps by shunting potentially toxic FFA towards innocuous storage triglyceride.
|Fasting glucose (mM)||6.1±0.2a||5.6±0.3||7.5±0.3a||6.8±0.2|
|Fasting insulin (pM)||26.9±3.7a||23.4±1.8||337.6±71.6a,b||116.2±17.4b|