Effects of Short-Term Energy Limitation at Different Levels With Normal Protein Intake on Hepatic Lipid Metabolism and the Gut Microbiota in Overweight/Obese Mice.

Abstract

This study investigated the sex-specific effects of graded short-term energy limitation (EL) with normal protein intake on hepatic lipid metabolism and the gut microbiota in overweight/obese mice. Mice were allocated to a normal control (NC) group, a high-fat diet model (MC) group, and groups receiving 20%, 30% or 40% EL (n&#x2009;=&#x2009;8 per group). All mice underwent blood biochemistry, liver biochemistry, histological, liver metabolomic, and fecal microbiota community genomic analyses. Relative to the NC group, both male and female MC mice developed varying degrees of insulin resistance, dyslipidaemia, and sex hormone dysregulation. However, disrupted hepatic lipid metabolism was detected solely in male mice, in association with changes in key lipid-metabolizing enzymes and metabolites; female mice showed only disturbed total cholesterol (TC) metabolism, which was linked to alterations in the cholesterol synthesis rate-limiting enzyme HMGCR. With normal protein intake, 20%, 30%, and 40% EL reduced hepatic triglyceride and TC synthesis in overweight/obese male mice by suppressing the expression of the key lipogenic enzyme DGAT and the activities of ACC and HMGCR (p&#x2009;<&#x2009;0.05). An effect on the lipolytic enzymes CPT1 and CYP7A1 was detected only at 30% EL (p&#x2009;<&#x2009;0.05), and hepatic metabolite profiles varied with the degree of EL. In female mice, only 40% EL significantly decreased TC synthesis by inhibiting both HMGCR expression and enzymatic activity (p&#x2009;<&#x2009;0.05). Furthermore, irrespective of sex, short-term EL (all levels) with normal protein intake reduced the gut Firmicutes/Bacteroidetes ratio in overweight/obese mice (p&#x2009;<&#x2009;0.05). In conclusion, graded short-term EL with adequate protein intake exerts differential effects on hepatic lipid metabolism and the gut microbiota in overweight/obese mice, with pronounced sex-specific differences.