Whey protein hydrolysates improve high-fat-diet-induced obesity by modulating the brain–peripheral axis of GLP-1 through inhibition of DPP-4 function in mice.

OBESITY; BRAIN; GASTROINTESTINAL system; BIOLOGICAL models; BIOMARKERS; INTERLEUKINS; CELL differentiation; PROTEASE inhibitors; BODY weight; HIGH performance liquid chromatography; STAINS & staining (Microscopy); HYPERGLYCEMIA; GLUCAGON-like peptide 1; ANIMAL experimentation; SERUM; WESTERN immunoblotting; ONE-way analysis of variance; LIQUID chromatography; INFLAMMATION; ORAL drug administration; NF-kappa B; CELL survival; ENZYME-linked immunosorbent assay; ADIPONECTIN; DESCRIPTIVE statistics; MASS spectrometry; WHEY proteins; TRANSCRIPTION factors; CELL lines; GLUCOSE tolerance tests; DATA analysis software; MICE; ADIPOSE tissues; INSULIN resistance; PHARMACODYNAMICS

Purpose: Obesity is a growing global health concern. Recent literature indicates a prominent role of glucagon-like peptide-1 (GLP-1) in glucose metabolism and food intake. The synergistic action of GLP-1 in the gut and brain is responsible for its satiety-inducing effect, suggesting that upregulation of active GLP-1 levels could be an alternative strategy to combat obesity. Dipeptidyl peptidase-4 (DPP-4) is an exopeptidase known to inactivate GLP-1, suggesting that its inhibition could be a crucial strategy for effectively extending the half-life of endogenous GLP-1. Peptides derived from partial hydrolysis of dietary proteins are gaining traction due to their inhibitory activity on DPP-4. Methods: Whey protein hydrolysate from bovine milk (bmWPH) was produced using simulated in situ digestion, purified using RP-HPLC, and characterized for DPP-4 inhibition. The antiadipogenic and antiobesity activity of bmWPH was then studied in 3T3-L1 preadipocytes and high-fat diet-induced obesity (HFD) mice model, respectively. Results: The dose-dependent inhibitory effect of bmWPH on the catalytic activity of DPP-4 was observed. Additionally, bmWPH suppressed adipogenic transcription factors and DPP-4 protein levels, leading to a negative effect on preadipocyte differentiation. In an HFD mice model, co-administration of WPH for 20 weeks downregulated adipogenic transcription factors, resulting in a concomitant reduction in whole body weight and adipose tissues. Mice fed with bmWPH also showed a marked reduction in DPP-4 levels in WAT, liver, and serum. Furthermore, HFD mice fed with bmWPH exhibited increased serum and brain GLP levels, which led to a significant decrease in food intake. Conclusion: In conclusion, bmWPH reduces body weight in HFD mice by suppressing appetite through GLP-1, a satiety-inducing hormone, in both the brain and peripheral circulation. This effect is achieved through modulation of both the catalytic and non-catalytic activity of DPP-4. [ABSTRACT FROM AUTHOR]