Dual function of Lactobacillus kefiri DH5 in preventing high‐fat‐diet‐induced obesity: direct reduction of cholesterol and upregulation of PPAR‐α in adipose tissue

Scope Kefir consumption inhibits the development of obesity and non‐alcoholic fatty liver disease (NALFD) in mice fed 60% high‐fat diet (HFD). To identify the key contributor of this effect, we isolated lactic acid bacteria (LAB) from kefir and examined their anti‐obesity properties from in vitro screening and in vivo validation. Methods and results Thirteen kefir LAB isolates were subjected to survivability test using artificial gastrointestinal environment and cholesterol‐reducing assay. Lactobacillus kefiri DH5 showed 100% survivability in gastrointestinal environments and reduced 51.6% of cholesterol; thus, this strain was selected for in vivo experiment. Compared to the HFD‐saline group, the HFD‐DH5 group showed significantly lower body weight (34.68 versus 31.10 g; p < 0.001), epididymal adipose tissue weight (1.39 versus 1.05 g; p < 0.001), blood triglyceride (38.2 versus 31.0 mg/dL; p < 0.01) and LDL‐cholesterol levels (19.4 versus 15.7 mg/dL; p < 0.01). In addition, L. kefiri DH5 administration significantly modulated gut microbiota of HFD‐fed mice. The hepatic steatosis was significantly milder (Lesion score, 2.1 versus 1.2; p < 0.001) and adipocyte diameter was significantly smaller (65.1 versus 42.2 μm; p < 0.001) in the HFD‐DH5 group. L. kefiri DH5 upregulated PPAR‐α, FABP4, and CPT1 expression in the epididymal adipose tissues (2.29‐, 1.77‐, and 2.05‐fold change, respectively), suggesting a reduction in adiposity by stimulating fatty acid oxidation. Conclusion L. kefiri DH5 exerts anti‐obesity effects by direct reduction of cholesterol in the lumen and upregulation of PPAR‐α gene in adipose tissues. The proposed dual mechanism underlying the anti‐obesity and anti‐non‐alcoholic fatty liver disease (NAFLD) effects of L. kefiri DH5 in high‐fat diet (HFD)‐fed mice was explored. A large proportion of the orally administered L. kefiri DH5 remains active and viable in the gastrointestinal tract and exerts potent anti‐obesity effects in HFD‐fed mice via a dual mechanism: (i) direct reduction of excessive cholesterol in the lumen to decrease overall fat influx, and (ii) upregulation of genes encoding PPAR‐α, CPT1, and FABP4 in adipose tissue to increase fatty acid oxidation.