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.

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.

Composition and structure elucidation of bovine milk glycosaminoglycans and their anti-adipogenic activity via modulation PPAR-γ and C/EBP-α.

The structure function relation of Glycosaminoglycans from bovine milk (bmGAGs) has not been studied in detail. In the present study bmGAGs was isolated and structurally characterized. Chondroitin sulphate was one of the major GAGs present and had 65% of ΔDi-diSB (GlcA(2S)-GalNAc(4S)), followed by 18% of ΔDi-4S(Δ4,5HexUAα1 â†’ 3GalNAc). Further, bmGAGs exhibited a marked anti-adipogenic effect in 3 T3-L1 cells without affecting cell viability at the concentration used. The triglyceride content treated with bmGAGs was significantly decreased as assessed by Oil-Red O staining. Peroxisome proliferator activated receptor γ (PPAR-γ) and CCAAT/enhancer-binding proteins (C/EBPα) the critical transcription factors in adipogenesis showed significant decrease in both gene and protein levels. Sterol regulatory element-binding protein 1c (SREBP-1c) that promotes the adipocyte differentiation by enhancing the activity of PPAR-γ was inversely affected by bmGAGs and the fatty acid synthase (FAS) expression was modulated. Thus, the present work is among the firsts to demonstrate an anti-adipogenic activity of bmGAGs by modulating the adipogenesis-related marker proteins and hence bmGAGs may be used as a supplement/therapeutic in the management of obesity.