The potential anti-obesity, anti-inflammatory, and anti-oxidative stress properties of ark shell-derived LLRLTDL (Bu1) and GYALPCDCL (Bu2) peptides were comprehensively investigated. In bone marrow-de Show more
The potential anti-obesity, anti-inflammatory, and anti-oxidative stress properties of ark shell-derived LLRLTDL (Bu1) and GYALPCDCL (Bu2) peptides were comprehensively investigated. In bone marrow-derived mesenchymal stem cells (BMMSCs), both peptides demonstrated significant anti-adipogenic effects by downregulating key adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma (PPAR-γ), CCAAT/enhancer-binding protein alpha (C/EBPα), and sterol regulatory element-binding protein 1 (SREBP-1) and their downstream adipocyte-specific genes including adipocyte fatty acid-binding protein 2 (aP2), fatty acid synthase (FAS), and lipoprotein lipase (LPL). Mechanistically, Bu1 and Bu2 promoted lipolysis through the activation of AMP-activated protein kinase (AMPK) and hormone-sensitive lipase (HSL). These peptides also exhibited potent anti-oxidative stress activity by suppressing reactive oxygen species generation and activating the HO-1/Nrf2 signaling pathway, as confirmed through HO-1 siRNA silencing. In addition, Bu1 and Bu2 demonstrated robust anti-inflammatory effects by reducing pro-inflammatory cytokine production and inhibiting MAPK signaling pathways. These findings were corroborated in a high-fat diet (HFD)-induced mouse model, where oral administration of Bu1 and Bu2 resulted in significant reductions in body weight, weight gain, and adipose tissue accumulation, along with decreased expression of adipogenic transcription factors and genes while improving serum cholesterol levels, and exhibited anti-oxidative stress effects via HO-1/Nrf2 activation. Collectively, these results underline the potential of Bu1 and Bu2 as multi-target therapeutic agents against obesity and related metabolic disorders. Show less