High-fat diet overfeeding promotes nondetrimental liver steatosis in female mice.

High-fat diet (HFD) feeding or leptin-deficient mice are extensively used as models resembling features of human nonalcoholic fatty liver disease (NAFLD). The concurrence of experimental factors as fat content and source or total caloric intake leads to prominent differences in the development of the hepatic steatosis and related disturbances. In this work, we characterized the hepatic lipid accumulation induced by HFD in wild-type (WT) and ob/ ob mice with the purpose of differentiating adaptations to HFD from those specific of increased overfeeding due to leptin deficiency-associated hyperphagia. Given that most published works have been done in male models, we used female mice with the aim of increasing the body of evidence regarding NAFLD in female subjects. HFD promoted liver lipid accumulation only in the hyperphagic strain. Nevertheless, a decrease of lipid droplet-associated cholesteryl ester (CE) in both WT and obese animals was observed. These changes were accompanied by an improvement in the profile of lipoproteins that transport cholesterol and liver function markers in plasma from ob/ ob mice and a lower hepatic index. Using primary hepatocytes from female mice, overaccumulation of CE induced by 0.4 mM oleic acid reversed in the presence of a specific Takeda G protein-coupled bile acid receptor agonist. Nevertheless, hepatocytes from male mice were not responsive. This study suggests that enterohepatic circulation of bile acids might be one of the factors that can affect sex dimorphism in NAFLD development, which underlines the importance of including female models in the NAFLD research field. NEW & NOTEWORTHY This work provides new insight into the use of high-fat diet as a model to induce nonalcoholic fatty liver disease in wild-type and ob/ ob female mice. We show that high-fat diet induces steatosis only in ob/ ob mice while, surprisingly, several health indicators improve. Noteworthy, experiments with primary hepatocytes from male and female mice show that they express Takeda G protein-coupled bile acid receptor and that it and bile acid enterohepatic circulation might be accountable for sex dimorphism in nonalcoholic fatty liver disease development.

Alternate day fasting (ADF) with a high-fat diet produces similar weight loss and cardio-protection as ADF with a low-fat diet.

UNLABELLED: Alternate day fasting (ADF) with a low-fat (LF) diet is effective for weight loss and cardio-protection. However, the applicability of these findings is questionable as the majority of Americans consume a high-fat (HF) diet. OBJECTIVE: The goal of this study was to determine if these beneficial changes in body weight and coronary heart disease (CHD) risk can be reproduced if an HF background diet is used in place of an LF diet during ADF. METHODS: Thirty-two obese subjects were randomized to an ADF-HF (45% fat) or ADF-LF diet (25% fat), which consisted of two phases: 1) a 2-week baseline weight maintenance period, and 2) an 8-week ADF weight loss period. All food was provided during the study. RESULTS: Body weight was reduced (P<0.0001) by ADF-HF (4.8%±1.1%) and by ADF-LF (4.2%±0.8%). Fat mass decreased (P<0.0001) by ADF-HF (5.4±1.5 kg) and ADF-LF (4.2±0.6 kg). Fat free mass remained unchanged. Waist circumference decreased (P<0.001) by ADF-HF (7.2±1.5 cm) and ADF-LF (7.3±0.9 cm). LDL cholesterol and triacylglycerol concentrations were reduced (P<0.001) by both interventions (ADF-HF: 18.3%±4.6%, 13.7%±4.8%; and ADF-LF: 24.8%±2.6%, 14.3%±4.4%). HDL cholesterol, blood pressure, and heart rate remained unchanged. There were no between-group differences for any parameter. CONCLUSION: These findings suggest that an ADF-HF diet is equally as effective as an ADF-LF diet in helping obese subjects lose weight and improve CHD risk factors.