valyl-prolyl-proline and Insulin-Resistance

There is great interest in developing naturally derived compounds, especially bioactive peptides with potential insulin sensitizing effects and/or preventing insulin resistance. Previously, we showed adipogenic and insulin mimetic actions of IPP (Ile-Pro-Pro) and VPP (Val-Pro-Pro), the milk-derived tripeptides on cultured preadipocytes, in addition to their previously characterized antihypertensive and anti-inflammatory functions. However, the effect of these peptides on insulin signaling is not known. Therefore, we examined IPP and VPP effects on insulin signaling in preadipocytes, a well-established model for studying insulin signaling. Our results suggested both peptides enhanced insulin signaling and contributed toward the prevention of insulin resistance in the presence of tumor necrosis factor (TNF). Inhibition of inflammatory mediator NF-kB under TNF stimulation was a likely contributor to the prevention of insulin resistance. VPP further enhanced the expression of glucose transporter 4 (GLUT4) in adipocytes and restored glucose uptake in TNF-treated adipocytes. Our data suggested the potential of these peptides in the management of conditions associated with impairments in insulin signaling.

Topics: Adipocytes; Adipogenesis; Animals; Cattle; Glucose; Glucose Transporter Type 4; Insulin; Insulin Resistance; Mice; Milk; NF-kappa B; NIH 3T3 Cells; Oligopeptides; Tumor Necrosis Factor-alpha

This study aimed to examine the effects of Val-Pro-Pro (VPP), a food-derived peptide with an angiotensin-converting enzyme (ACE) inhibitory property, on obesity-linked insulin resistance, and adipose inflammation in vivo and in vitro.. C57BL/6J mice were fed high-fat high-sucrose diet and VPP (0.1% in water) for 4 months. For in vitro analysis, coculture of 3T3-L1 adipocytes overexpressing either ACE (3T3-ACE) or green fluorescent protein (3T3-GFP) and RAW264 macrophages was conducted with VPP. In diet-induced obese mice, VPP improved insulin sensitivity, concomitant with a significant decrease in tumor necrosis factor α (TNF-α) and IL-1β expression in adipose tissue, with a tendency (p = 0.06) toward decreased CC chemokine ligand 5 expression. Additionally, VPP administration inhibited macrophage accumulation and activation in fat tissues. In vitro, VPP attenuated TNF-α mRNA induced by ACE overexpression in 3T3-L1 adipocytes. TNF-α and IL-1β expression decreased following VPP treatment of RAW264 macrophage and 3T3-ACE adipocyte cocultures, but not in RAW264-3T3-GFP adipocyte cocultures.. Our data suggest that VPP inhibits adipose inflammation in the interaction between adipocytes and macrophages, acting as an ACE inhibitor, thereby improving obesity-related insulin resistance. Thus, ingestion of VPP may be a viable protective and therapeutic strategy for insulin resistance and obesity-associated adipose inflammation.

Topics: Adipocytes; Animals; Cells, Cultured; Coculture Techniques; Diet, High-Fat; Gene Expression Regulation; Insulin Resistance; Macrophages; Male; Mice, Inbred C57BL; Milk; Obesity; Oligopeptides; Panniculitis; Peptidyl-Dipeptidase A; Tumor Necrosis Factor-alpha