Wan et al. created tissue-specific knockout mice deficient in peroxisome proliferator-activated receptor γ (PPARγ), which is a transcription factor regulated by fatty acids, some prostaglandins, and components of oxidized low-density lipoprotein particles and which regulates lipid biosynthesis. The mice were deficient in PPARγ in the hematopoietic and endothelial tissues. Pups nursed from mothers deficient in PPARγ exhibited growth retardation and hair loss that was completely reversed after the pups were weaned. Furthermore, pups deficient in PPARγ fostered by a wild-type mother did not exhibit these abnormalities, and wild-type pups fostered with the PPARγ-deficient mothers exhibited hair loss and low weight until weaning, confirming that the problem was maternal. Investigation of the skin of the pups nursed by the PPARγ-deficient mothers showed the formation of follicular cysts, which appeared to result from an inflammatory response that was characterized by leukocyte infiltration, elevated expression, and abundance of inflammatory cytokines and cyclooxygenase (COX-1 and COX-2). Hair loss was partially prevented if the pups were treated with aspirin, a COX inhibitor. Inflammation was also noted in the livers of the pups nursed by the PPARγ-deficient mothers. Histological analysis of the mammary tissue of the PPARγ-deficient mice showed increased lipid accumulation. Transcription analysis revealed that the PPARγ-deficient mammary glands exhibited decreased expression of homeobox genes and matrix metalloproteinases involved in mammary gland development. The expression of genes encoding two lipid oxidation enzymes that are involved in the production of inflammatory lipids was elevated in the mutant mice. When a mouse macrophage cell line was exposed to milk from the PPARγ-deficient mice in the presence of lipoprotein lipase, which is involved in lipid digestion, the cells increased production of inflammatory mediators. Furthermore, the skin from the mouse pups fed by the PPARγ-deficient mice exhibited an altered lipid profile compared with pups fed by wild-type mice, and mass analysis suggested that one group of lipids present in the skin of pups fed by the PPARγ-deficient mice was oxidized free fatty acids. Investigation of the gene expression of the macrophages from the mutant mice, which do not express PPARγ in the macrophages but do in the epithelial cells and adipocytes in the mammary gland, revealed that the macrophages had elevated expression of genes encoding enzymes that produce PPAΡγ ligands. The authors propose that these ligands activated PPARγ in the epithelial and adipocyte tissue of the mammary gland, leading to excessive production of inflammatory lipids.
Y. Wan, A. Saghatelian, L.-W. Chong, C.-L. Zhang, B. F. Cravatt, R. M. Evans, Maternal PPARγ protects nursing neonates by suppressing the production of inflammatory milk. Genes Dev. 21, 1895-1908 (2007). [Abstract] [Full Text]