Oligomeric peptides LLRLTDL and GYALPCDCL alleviate obesity through HO-1/Nrf2-dependent pathways in high-fat...

The potential antiobesity, anti-inflammatory, and antioxidative stress properties of ark shell-derived LLRLTDL (Bu1) and GYALPCDCL (Bu2) peptides were comprehensively investigated. In bone marrow-derived mesenchymal stem cells, both peptides demonstrated significant antiadipogenic effects by downregulating key adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha, and sterol regulatory element-binding protein 1 and their downstream adipocyte-specific genes, including adipocyte fatty acid-binding protein 2, fatty acid synthase, and lipoprotein lipase. Mechanistically, Bu1 and Bu2 promoted lipolysis through the activation of AMP-activated protein kinase and hormone-sensitive lipase. These peptides also exhibited potent antioxidative stress activity by suppressing reactive oxygen species generation and activating the heme oxygenase-1/Nrf2 signaling pathway, as confirmed through heme oxygenase-1 small interfering RNA silencing. In addition, Bu1 and Bu2 demonstrated robust anti-inflammatory effects by reducing proinflammatory cytokine production and inhibiting mitogen-activated protein kinase signaling pathways. These findings were corroborated in a high-fat diet-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 antioxidative stress effects via heme oxygenase-1/Nrf2 activation. Collectively, these results underline the potential of Bu1 and Bu2 as multitarget therapeutic agents against obesity and related metabolic disorders.