Hepatic Lipids as Molecular Targets in Obesity-Associated Insulin Resistance in Rodent Models: A Systematic Review...

Obesity induced by a high-calorie diet (HCD) results in the accumulation of ectopic fat in tissues not typically associated with lipid storage. This accumulation can cause lipotoxicity, a type of cellular stress triggered by the accumulation of lipid intermediates such as diacylglycerols (DAG) and ceramides (Cer) in nonadipose tissues like the liver. The accumulation of these bioactive lipids has been directly linked to the development of insulin resistance induced by a HCD. However, the specific molecular species of lipids associated with such metabolic abnormalities remain poorly defined. In this study, we conducted a systematic review and meta-analysis to consolidate current evidence on how HCDs alter the liver lipidome in rodents. A search was performed in PubMed to identify lipidomic studies on the livers of mice (C57Bl/6) and rats (Wistar and Sprague-Dawley) fed high-calorie diets. We assessed the effect size by calculating the standardized mean difference (SMD) using Hedges' g with a 95% confidence interval. A total of 18 studies were identified. The HCD had a significant effect on insulin resistance (HOMA-IR, p < 0.01) and significantly increased (p < 0.05) hepatic levels of Cer(18:0_18:0), Cer(18:1_18:0), Cer(18:1_20:0), Cer(18:2_20:0), and DAG(16:0_18:1) (p < 0.05). Furthermore, the HCD negatively affected three specific phosphatidylcholine (PC) species and four phosphatidylethanolamine (PE) species containing monounsaturated and polyunsaturated fatty acid chains. These findings may provide valuable insights for targeting the molecular mechanisms underlying tissue-specific insulin resistance, a significant condition in the context of obesity.