Leptin Improves Fatty Liver Independently of Insulin Sensitization and Appetite Suppression in Hepatocyte-Specific Pten-Deficient Mice with Insulin Hypersensitivity

Abstract

Nonalcoholic fatty liver disease (NAFLD) is recognized as the hepatic component of the metabolic syndrome. Although NAFLD is a major cause of cirrhosis and cancer of the liver of unknown cause, no established pharmacological treatment for NAFLD has been established yet. It has been reported that leptin treatment improved fatty liver dramatically as well as insulin resistance and hyperphagia in patients with lipodystrophy. However, it is unclear whether leptin improves fatty liver independently of these metabolic improvements. We investigated the liver effect of leptin independently of insulin sensitization and appetite suppression using hepatocyte-specific Pten-deficient (AlbCrePtenff) mouse, a model of severe fatty liver with insulin hypersensitivity. Male AlbCrePtenff mice were infused subcutaneously with leptin (20 ng/g/h) for 2 weeks using osmotic minipumps. Leptin infusion effectively reduced liver weight, liver triglyceride content, and glutamate pyruvate transaminase (GPT) concentrations as well as food intake and body weight without the change of plasma insulin concentration in AlbCrePtenff mice. Pair-feeding also reduced body weight but not liver triglyceride content. Pair feeding reduced α1 and α2 AMP-activated protein kinase (AMPK) activities and PGC1α gene expression in the liver, while leptin infusion unchanged them. The present study clearly demonstrated that leptin improve fatty liver independently of insulin sensitization and suppression of food intake. It was suggested that leptin improves fatty liver by stimulation of β-oxidation in the liver. The present study might provide a further understanding on the mechanism of metabolic effect of leptin.

Knockdown of phosphatase and tensin homolog (PTEN) inhibits fatty acid oxidation and reduces very low density lipoprotein assembly and secretion in calf hepatocytes

“…However, incomplete β-oxidation leads to the re-esterification of fatty acids into TG, which is one of the important causes of TG accumulation in the liver. Yamamoto-Kataoka et al (2015) reported that the liver-specific deletion of PTEN in mice enhanced TG accumulation in the liver. Interestingly, we found that PTEN knockdown significantly increased the TG content in calf hepatocytes.…”

Effects of probiotics on nonalcoholic fatty liver disease: a systematic review and meta-analysis

“…83,84 Animal trials, human trials, and reviews seem to support the application of leptin or its efficacy in obesity or NAFLD considering its beneficial effect on IR and liver fat accumulation. 85–90 However, Imajo and colleagues 91 reported that obesity-induced leptin plays a crucial role in NASH progression via enhanced responsivity to endotoxin, and Polyzos and colleagues 92 concluded that a high circulating leptin level was associated with severity of NAFLD. Above all, the effect of leptin on NAFLD still needs further investigation.…”

Hepatic Fat Content Is Associated with Fasting-Induced Fibroblast Growth Factor 21 Secretion in Mice Fed Soy Proteins

“…This result suggests that dietary soy proteins suppress HFHS diet-induced leptin resistance. Although further analysis is needed regarding the relation between leptin resistance and fatty liver (50), it has been demonstrated that serum leptin levels are elevated in patients with fatty liver, independently of the body-mass index and percentage of body fat (51), and leptin improves fatty liver by stimulation of b-oxidation (52). It was reported that leptin suppressed the lipogenic enzyme gene by down-regulating the SREBP1c gene (53), suggesting that in the HFHS-b-conglycinin group the lower leptin resistance was associated with lower expression levels of FAS and ChREBP, which was regulated by SREBP1c.…”