Cow's milk increases the activities of human nuclear receptors peroxisome proliferator-activated receptors α and δ and retinoid X receptor α involved in the regulation of energy homeostasis, obesity, and inflammation

The nuclear peroxisome proliferator-activated receptors (PPAR) have been shown to play crucial roles in regulating energy homeostasis including lipid and carbohydrate metabolism, inflammatory responses, and cell proliferation, differentiation, and survival. Because PPAR agonists have the potential to prevent or ameliorate diseases such as hyperlipidemia, diabetes, atherosclerosis, and obesity, we have explored new natural agonists for PPAR. For this purpose, cow's milk was tested for agonistic activity toward human PPAR subtypes using a reporter gene assay. Milk increased human PPARα activity in a dose-dependent manner with a 3.2-fold increase at 0.5% (vol/vol). It also enhanced human PPARδ activity in a dose-dependent manner with an 11.5-fold increase at 0.5%. However, it only slightly affected human PPARγ activity. Ice cream, butter, and yogurt also increased the activities of PPARα and PPARδ, whereas vegetable cream affected activity of PPARδ but not PPARα. Skim milk enhanced the activity of PPAR to a lesser degree than regular milk. Milk and fresh cream increased the activity of human retinoid X receptor (RXR)α as well as PPARα and PPARδ, whereas neither affected vitamin D3 receptor, estrogen receptors α and β, or thyroid receptors α and β. Both milk and fresh cream were shown by quantitative real-time PCR to increase the quantity of mRNA for uncoupling protein 2 (UCP2), an energy expenditure gene, in a dose-dependent manner. The increase in UCP2 mRNA was found to be reduced by treatment with PPARδ-short interfering (si)RNA. This study unambiguously clarified at the cellular level that cow's milk increased the activities of human PPARα, PPARδ, and RXRα. The possible role in enhancing the activities of PPARα, PPARδ, and RXRα, and the health benefits of cow's milk were discussed.