Decreased Hepatic Triglyceride Content in Obese Male Mice Fed a Ketogenic Diet is Due to a Reduction in Lipid Anabolism Associated with Lower Insulin Signaling

The efficacy of ketogenic diets (KD) in inducing weight loss is well documented, but the changes in peripheral and hepatic insulin sensitivity and their associated effects on fatty acid anabolism remain to be elucidated. The present study examined the impact of a chow diet (CD) versus a one-month KD on peripheral and hepatic insulin sensitivity in male mice with obesity due to two months on a high-fat diet. The subsequent effect of instauration of one-month CD in both subgroups was also investigated. KD mice presented higher weight, serum leptin and high-molecular weight adiponectin levels along with reduced HOMA-IR index. Phosphorylation of STAT3 was increased, while the phosphorylation of insulin receptor, Akt and cAMP response element-binding protein, the activation of ATP citrate lyase and levels of fatty acid synthase, were reduced in KD mice. After instauration of CD in both subgroups, those mice previously fed KD exhibited lower HOMA-IR index and serum and hepatic triglycerides. These findings suggest that KD intervention improves peripheral insulin sensitivity through the reduction in hepatic insulin signaling that inhibits fatty acid anabolism, thereby reducing hepatic triglyceride content.