Bad milk leads to bald mice

Breast isn’t always best, according to research showing that milk-producing mammary cells lacking a hormone called PPAR γ produce milk that is toxic to their pups, causing inflammation and hair loss.

PPAR γ is a vital part of the mechanism that regulates fat-cell formation, and also suppresses inflammatory responses. Hereditary disorders involving PPAR γ generally cause disturbances of fat metabolism leading to obesity, and insulin resistance associated with type 2 diabetes. 

Ronald Evans and his team from the Salk Institute in La Jolla, California, US, hope that understanding the role of PPAR γ could help to understand what roles lipid metabolites and inflammation play in alopecia and other skin disorders, and develop new drugs to prevent and treat these diseases.

Milk lipids provide not only calories, but also essential fatty acids and their derivatives that regulate development of newborns. Yet PPAR γ ’s role in providing healthy milk is unknown. So Evans and his team bred mice which lacked PPAR γ only in their haematopoietic and endothelial cells. 

Mice bred totally devoid of PPAR γ cannot bear pups: the embryos die in the womb due to defects in placenta, cardiac and fat tissue development. While Evan’s mutant mice gave birth to normal pups, the mother’s milk caused inflammation, hair loss and retarded growth. ’These symptoms reverse when the pups are fostered on normal milk, weaned onto solid food, or even treated with an anti-inflammatory like aspirin,’ said Evans.

Essential protection

The pups also recovered their hair if they were given the anti-inflammatory aspirin. This, Evans thinks, shows the pups’ inflammatory response involved the enzymes COX-1 and -2. COX 1 is already known to be inhibited when aspirin is used for blood thining. ’There were high levels of inflammatory lipids in the maternal milk, due to increased expression of lipid oxidation enzymes in the lactating mammary gland,’ said Evans. ’So, maternal PPAR γ  is essential for protecting development of the new-born.’

PPAR γ regulates transcription of the genes controlling carbohydrate, lipid, and protein metabolism. Each PPAR combines with a short DNA nucleotide sequence called a retinoid X receptor, which hooks onto specific regions of the DNA target gene. In the case of PPAR γ , binding the ligand prostaglandin PGJ2 allows it to up- or down-regulate target gene transcription of lipid metabolism. 

The RXR part of the combination also binds other receptor proteins, such as the vitamin D receptor. This has recently been implicated in some people’s lack of response to aspirin’s blood-thinning properties (see Chemistry World August 2007, p22), since aspirin-resistant patients have raised levels of a vitamin D-binding protein (DBP).

’Given the known binding of vitamin D receptors by PPAR γ -attached RXR, and a potential link between DBP in regulating fasting insulin levels, this could further implicate PPAR γ deficiency in the inflammatory response,’ Yihong Wan, one of Evans’ senior researchers.

’From a basic scientist’s point of view, PPAR γ sure seems like a bottomless pit of surprises,’ commented Yaacov Barak, a geneticist who studies the role of PPAR γ at Jackson Laboratory, Bar Harbor, Maine.

Lionel Milgrom