We have demonstrated acute differential effects of dietary protein sources on postprandial low-grade inflammation after a high-fat meal in obese non-diabetic subjects. Of particular interest we observed that MCP-1 and CCL5/RANTES displayed acute postprandial responses to the test meals. MCP-1 was initially suppressed and CCL5/RANTES initially increased after consumption of the test meals. For both cytokines no significant differences between meals were evident at peak values after 60 min. However, whey-meal was associated with a different overall response after 240 min compared to the other protein meals. MCP-1 was suppressed to a smaller extent after whey-meal compared to cod-meal and gluten-meal. CCL5/RANTES iAUC-240 min was smaller after the whey-meal compared to the other meals - in particular compared to cod-meal and casein-meal.
Several studies have demonstrated postprandial adherence of Apo B to monocytes and activation of monocytes in response to an oral fat loading test in healthy subjects [19
]. The activation of monocytes is important for the endothelial adhesion of monocytes and subsequent transmigration across the endothelial wall where the monocytes differentiate into macrophages [43
]. However, this process is further enhanced when oxidized LDL and chylomicron remnant particles are taken up by residing macrophages inside the vessel wall. These macrophages activate the endothelium to produce MCP-1 which in mice resulted in further localized recruitment and tissue infiltration of monocytes [44
]. In the endothelial wall the phagocytosis of oxidized lipoproteins by macrophages precedes the development of atherosclerotic plaques. Consequently any means to reduce endothelial adhesion of monocytes may reduce the progression of atherosclerotic plaques.
The CCL5/RANTES response was significantly smaller after whey meal compared to the cod and casein meals. Krohn et al
] demonstrated reduction of neointimal thickening and macrophage infiltration in CCL5/RANTES knock-out mice. These findings are consistent with the CCL5/RANTES antagonist study of Braunersreuther et al
] who also demonstrated that deficiency of the CCL5/RANTES receptor protects Apo E -/- mice from diet induced atherosclerosis [47
]. The finding of up-regulated CCL5/RANTES in human atherosclerotic plaques [48
] corroborates with the association demonstrated between CCL5/RANTES and unstable angina pectoris [49
] and myocardial infarction [50
]. While CCL5/RANTES is thought to be crucial to monocyte recruitment during development of atherosclerosis [51
] high density lipoprotein may partly cause its cardioprotective effect by reducing circulating levels of CCL5/RANTES [52
]. Furthermore, high levels of CCL5/RANTES had a positive correlation to the development of T2DM in humans [53
In the present study cod protein and gluten induced significantly lower concentrations of MCP-1 compared to whey protein. The mechanism of action is not known. However, in the cod-meal the total quantity of n-3 fatty acids was 752 mg, which may contribute to the anti-inflammatory effects via interaction with the pro-inflammatory transcription factor i.e. nuclear factor kappa beta (NF-κB) [54
]. However, since gluten does not contain any n-3 fatty acids it may be speculated that cod and gluten do not share particular MCP-1 lowering properties. MCP-1 may be higher after whey meal due to whey specific properties e.g. higher insulin response as discussed later.
Research on the immunomodulatory properties of milk proteins has traditionally been focusing on the antimicrobial effects of T-cells, macrophages and the innate immune response [56
]. The availability of immunomodulatory peptides is not solely depending on the dietary composition but also varies depending on the specific enzymatic digestion of milk components in the intestinal tractus [57
]. Aihara et al
] demonstrated that the casein and whey derived tri-peptide valyl-prolyl-proline modulates monocyte adhesion to inflamed endothelia in vitro
via attenuation of the pro-inflammatory c-Jun N-terminal kinases (JNK) pathway. Interestingly, the casein subunit "α s1" is expressed by monocytes in vitro
] promoting a pro-inflammatory cytokine response. Furthermore, Zemel et al
] demonstrated reduced levels of MCP-1 after a dairy rich diet but not after a soy rich diet in a 28 day intervention period. These observations support that circulating peptides from a dairy product rich diet may at least in part be responsible for the differential cytokine responses observed after the four meals in the present study.
Whey protein reduces postprandial lipaemia more than cod, gluten and casein [39
]. However, we could not demonstrate any correlation between postprandial lipaemia and the inflammatory markers.
Euglycemic hyperinsulineamia has been found to inhibit NF-κB and reduce concentrations of MCP-1 in obese subjects after 2 h and 4 h of insulin infusion [60
]. As whey protein is more insulinotropic than cod protein, gluten and casein this mechanism would imply a larger suppression of MCP-1 after the whey meal compared to the other meals. However, we have demonstrated a positive correlation between postprandial insulin and MCP-1 as well as a negative correlation between postprandial insulin and CCL5/RANTES. This is in accordance with our findings that the MCP-1 iAUC-240 min for the whey meal was larger compared to the other meals and that the CCL5/RANTES iAUC-240 min was smaller after whey meal. Other studies have demonstrated anti-inflammatory properties of insulin infusion on both MCP-1 and CCL5/RANTES [62
]. We cannot explain the opposing effects of whey meal on MCP-1 and CCL5/RANTES in our study.