A genetic basis for the "Adonis" phenotype of low adiposity and strong bones

Toll receptors in Drosophila contribute to host defense and establish the body plan. Mammalian homologues of Toll, the Toll-like receptors (TLRs), are thought to function only in host defense. Here, we report that mice harboring mutations in TLR4 or in CD14, a co-receptor for TLR4, have an "ideal" body plan consisting of increased bone mineral content, density, and size as well as decreased body fat. These mutant mice live long lives, have normal activity and fertility, and show no evidence of infection. Unlike many strains of caged wild-type mice, they do not become obese. Although all mice continue to gain body fat, bone content, and overall weight, the difference in bone content and body fat between mutant and wild-type mice increases with age. Thus, defects in TLR4/CD14 complex generate an "Adonis" phenotype, characterized by this ideal body type, and this function could potentially be exploited for the treatment of osteoporosis and obesity.