Since the identification of causative mutations in Lrp5 in osteoporosis-pseudoglioma and the high bone mass syndrome, the low-density lipoprotein receptor-related protein 5 (Lrp5) has been firmly linked with osteoblast function in humans and animal models. In the previous funding period, we demonstrated that Wnt/b-catenin signaling through Lrp5 regulates long-chain fatty acid utilization by the osteoblast. Thus, transgenic mice lacking Lrp5 specifically in the osteoblast exhibited an increase in adipose tissue mass and developed a dyslipidemia in addition to the expected low bone mass phenotype. Moreover, genetic ablation of Cpt2, an obligate enzyme in long chain fatty acid catabolism, in the osteoblast impairs bone acquisition and led to an increase in serum lipids. Together, these data suggest that bone is a site of significant fatty acid utilization and that the regulation of osteoblast metabolism by Lrp5 contributes to both bone accrual and whole body energy balance. In this renewal application we will use genetic mouse models to (1) determine the mechanism by which fatty acids are acquired by the osteoblast and (2) assess the metabolic substrate requirements that are necessary for Wnt-stimulated bone formation. We hypothesize that fatty acid uptake will require the actions of Slc27a1 and/or CD36 and that inhibition of fatty acid utilization will be sufficient to inhibit the Wnt-induced increase in bone formation associated with Sost deficiency or expression of a Lrp5 high bone mass allele. These studies will further our understanding of the metabolic requirements of bone formation, the contribution of bone to metabolism, and the mechanisms by which Wnt/b-catenin signaling govern skeletal homeostasis.

Public Health Relevance

This project investigates the molecular mechanism by which the osteoblast acquires fatty acids to be used to fuel normal and Wnt/b-catenin stimulated bone formation and thereby contributes to whole body energy balance. Completion of this work may ultimately lead to the development of novel approaches for the treatment of both osteopenia and metabolic dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK099134-06A1
Application #
9732985
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Malozowski, Saul N
Project Start
2013-07-24
Project End
2023-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Frey, Julie L; Kim, Soohyun P; Li, Zhu et al. (2018) ?-Catenin Directs Long-Chain Fatty Acid Catabolism in the Osteoblasts of Male Mice. Endocrinology 159:272-284
Moorer, Megan C; Riddle, Ryan C (2018) Regulation of Osteoblast Metabolism by Wnt Signaling. Endocrinol Metab (Seoul) 33:318-330
Kushwaha, Priyanka; Wolfgang, Michael J; Riddle, Ryan C (2018) Fatty acid metabolism by the osteoblast. Bone 115:8-14
Riddle, Ryan C; Clemens, Thomas L (2017) Bone Cell Bioenergetics and Skeletal Energy Homeostasis. Physiol Rev 97:667-698
Kim, Soohyun P; Li, Zhu; Zoch, Meredith L et al. (2017) Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner. JCI Insight 2:
Lee, Jieun; Choi, Joseph; Selen Alpergin, Ebru S et al. (2017) Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance. Cell Rep 20:655-667
Kim, Soohyun P; Frey, Julie L; Li, Zhu et al. (2017) Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes. Proc Natl Acad Sci U S A 114:E11238-E11247
Kim, Soohyun P; Frey, Julie L; Li, Zhu et al. (2017) Lack of Lrp5 Signaling in Osteoblasts Sensitizes Male Mice to Diet-Induced Disturbances in Glucose Metabolism. Endocrinology 158:3805-3816
Zoch, Meredith L; Abou, Diane S; Clemens, Thomas L et al. (2016) In vivo radiometric analysis of glucose uptake and distribution in mouse bone. Bone Res 4:16004
Zoch, Meredith L; Clemens, Thomas L; Riddle, Ryan C (2016) New insights into the biology of osteocalcin. Bone 82:42-9

Showing the most recent 10 out of 16 publications