Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

Abstract

fThe Wnt coreceptors Lrp5 and Lrp6 are essential for normal postnatal bone accrual and osteoblast function. In this study, we identify a previously unrecognized skeletal function unique to Lrp5 that enables osteoblasts to oxidize fatty acids. Mice lacking the Lrp5 coreceptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass but also exhibit an increase in body fat with corresponding reductions in energy expenditure. Conversely, mice expressing a high bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt-initiated signals downstream of Lrp5, but not the closely related Lrp6 coreceptor, regulate the activation of ␤-catenin and thereby induce the expression of key enzymes required for fatty acid ␤-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism. Wnt signaling regulates nearly all aspects of osteoblast function, from initial fate specification (1) to the control of osteoclast differentiation (2). In this pathway, low-density-lipoprotein (LDL)-related receptor 5 (Lrp5) and the closely related Lrp6 participate in the stabilization and activation of the transcription factor ␤-catenin by facilitating the interaction of Wnt ligands with frizzled receptors (3, 4). Osteoblasts express all the components of the Wnt/␤-catenin pathway, and most have now been linked with bone development and maintenance in humans and mouse models (5-7). Mutations in the LRP5 gene, in particular, can result in premature and generalized osteoporosis as in the rare condition osteoporosis pseudoglioma (8) or a high-bone-mass phenotype (9, 10) likely due to an increase in the number of mineralizing osteoblasts (11).Like other metabolically active cells, osteoblasts require a supply of energy-rich molecules to fuel the synthesis, deposition, and mineralization of bone matrix (12). When energy input fails to meet demand, normal bone accrual ceases, a phenomenon that is evident clinically by the arrest of longitudinal bone growth and osteopenia observed in undernourished children and adults (13, 14). Therefore, osteoblasts must possess mechanisms to acquire and regulate the utilization of fuel macromolecules, as well as the ability to communicate energy needs with other tissues.Recent studies have delineated a role for the osteoblast in a bone-pancreas endocrine loop that contributes to the regulation of glucose metabolism, as well as bone acquisition. Insulin receptor signaling in the osteoblast regulates the activity of the osteogenic transcription factor Runx2 and is required for the attainment of a mature phenotype as well as normal postnatal bone acquisition (15). In addition, insulin actions regulate the production and bioavailability of osteocalcin (15, 16), a bone-derived hormone that in ...

Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner

“…The development of dyslipidemia in these models further confirms the idea that cells of the osteoblast lineage are significant utilizers of available fatty acids and is suggestive of a redistribution of energy resources when fatty acid utilization is compromised in the osteoblast. In this regard, the current data are entirely compatible with the conclusions of our previous work (24), which reported an increase in adiposity and the development of dyslipidemia in mice lacking the Wnt-signaling coreceptor Lrp5, specifically in osteoblasts and osteocytes. Based on the reduced expression of enzymatic mediators of fatty acid β-oxidation in Lrp5-deficient osteoblasts, we hypothesized that Wnt signaling promotes fatty acid utilization in the osteoblasts and that reductions in Wnt signaling result in reduced lipid utilization and its storage in adipose tissue (24).…”

“…In this regard, the current data are entirely compatible with the conclusions of our previous work (24), which reported an increase in adiposity and the development of dyslipidemia in mice lacking the Wnt-signaling coreceptor Lrp5, specifically in osteoblasts and osteocytes. Based on the reduced expression of enzymatic mediators of fatty acid β-oxidation in Lrp5-deficient osteoblasts, we hypothesized that Wnt signaling promotes fatty acid utilization in the osteoblasts and that reductions in Wnt signaling result in reduced lipid utilization and its storage in adipose tissue (24). The similarities in the metabolic phenotypes of mice deficient for Lrp5 and Cpt2 in osteoblasts and osteocytes lend credence to this idea.…”

“…Histomorphometric studies performed in this sex suggested that the reduction in bone volume was secondary to impairments in mineralization, as the MAR was reduced and parameters of osteoid accumulation were increased. These in vivo data are supported by both the reduced ability of ΔCpt2 osteoblast cultures to form a mineralized matrix and our previous finding of a dramatic increase in fatty acid oxidation as osteoblasts attain a mature phenotype (24). Likewise, these data are consistent with previous studies that reported a linkage between bone mass and the function of CD36 (51) and FFA4 (52), receptors that facilitate fatty acid uptake and are activated by extracellular fatty acids, respectively.…”

“…Initial studies suggested that fatty acid metabolism contributes as little as 40% of the energy yield that cultured osteoblasts derive from the metabolism of glucose (23). However, our previous work demonstrated that fatty acid β-oxidation increases dramatically as osteoblasts mature in vitro and that anabolic Wnt signaling through the low-density lipoprotein-related receptor-5 promotes fatty acid oxidation (24). Similarly, histological and radiotracer studies indicate that bone takes up a significant fraction of postprandial lipoproteins (25), while in vitro studies suggest that high-and low-density lipoproteins are sufficient to maintain osteoblast proliferation under serum-free conditions (26).…”

Lrp5 Has a Wnt-Independent Role in Glucose Uptake and Growth for Mammary Epithelial Cells

“…For example, Lrp5 was cloned as a candidate gene from the IDDM4 locus, which has been linked to genetic susceptibility to diabetes (12). lrp5 Ϫ/Ϫ mice are leaner than wild-type mice and show higher expression levels of key enzymes required for fatty acid ␤-oxidation (13). So far, the only Lrp5 activity not linked to Wnt receptor activity is the binding of ApoE by Lrp5.…”