Minireview: The link between fat and bone: does mass beget mass?

Abstract

Osteoporosis is less common in individuals with high fat mass. This putative osteoprotection is likely an adaptive mechanism that allows obese individuals to better carry their increased body mass. Recent studies have focused on hormones that link fat to bone. Adipokines, such as leptin, modulate bone cells through both direct and indirect actions, whereas molecules activating peroxisome proliferator-activated receptor γ drive mesenchymal stem cell differentiation towards adipocytes away from the osteoblastic lineage. There is emerging evidence that bone-derived osteocalcin regulates insulin release and insulin sensitivity and, hence, might indirectly affect fat mass. Despite these molecular connections between fat and bone, animal and human studies call into question a primary role for body fat in determining bone mass. Mice devoid of fat do not have a skeletal phenotype, and in humans, the observed correlations between bone and body mass are not just due to adipose tissue. An improved understanding of the integrative physiology at the fat-bone interface should allow us develop therapies for both osteoporosis and obesity.

Fig. 1.

The role of Wnt signaling in osteoblast and adipocyte differentiation. A, Canonical Wnt signaling resulting in β-catenin activation plays a critical role in mediating the fate of MSC. Wnt10B has been shown to signal through Frizzled and LRP (low-density lipoprotein receptor-related protein) 5/6 to cause β-catenin accumulation and downstream transcription of Wnt target genes. The resulting genetic program impairs adipocyte development while simultaneously augmenting osteoblast development. B, Similar to canonical Wnt signaling, noncanonical Wnt signaling also controls the fate of MSC. Wnt5A signals through JNK (Janus-N-terminal kinase) to promote osteoblastogenesis at the expense of adipocyte differentiation. In a negative feedback loop, adipocytes secrete SFRP5 that acts as a decoy for Wnt5A, thereby preventing signaling. Similar to many other adipokines, SFRP5 (secreted frizzled related protein 5) secretion can alter the extracellular signals nearby MSCs are exposed to, and reinforce differentiation into, similar cell types (e.g. produce more adipocytes). Through this mechanism, clusters of fat, or alternatively, rows of osteoblasts reinforce their own differentiation while inhibiting differentiation into other cell types.