AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Bone Research Article
PDF (5.2 MB)
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Original Article | Open Access

Lipolysis supports bone formation by providing osteoblasts with endogenous fatty acid substrates to maintain bioenergetic status

Ananya Nandy1, Ron C. M. Helderman1, Santosh Thapa1, Shobana Jayapalan1, Alison Richards1, Nikita Narayani1, Michael P. Czech2, Clifford J. Rosen3, Elizabeth Rendina-Ruedy1,4 ( )
Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Maine Medical Center Research Institute, Scarborough, ME, USA
Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA
Show Author Information

Abstract

Bone formation is a highly energy-demanding process that can be impacted by metabolic disorders. Glucose has been considered the principal substrate for osteoblasts, although fatty acids are also important for osteoblast function. Here, we report that osteoblasts can derive energy from endogenous fatty acids stored in lipid droplets via lipolysis and that this process is critical for bone formation. As such, we demonstrate that osteoblasts accumulate lipid droplets that are highly dynamic and provide the molecular mechanism by which they serve as a fuel source for energy generation during osteoblast maturation. Inhibiting cytoplasmic lipolysis leads to both an increase in lipid droplet size in osteoblasts and an impairment in osteoblast function. The fatty acids released by lipolysis from these lipid droplets become critical for cellular energy production as cellular energetics shifts towards oxidative phosphorylation during nutrient-depleted conditions. In vivo, conditional deletion of the ATGL-encoding gene Pnpla2 in osteoblast progenitor cells reduces cortical and trabecular bone parameters and alters skeletal lipid metabolism. Collectively, our data demonstrate that osteoblasts store fatty acids in the form of lipid droplets, which are released via lipolysis to support cellular bioenergetic status when nutrients are limited. Perturbations in this process result in impairment of bone formation, specifically reducing ATP production and overall osteoblast function.

References

1

Feng, X. & McDonald, J. M. Disorders of bone remodeling. Annu. Rev. Pathol. 6, 121–145 (2011).
Crossref Google Scholar
2

Zaidi, M. Skeletal remodeling in health and disease. Nat. Med. 13, 791–801 (2007).
Crossref Google Scholar
3

Iqbal, J., Sun, L. & Zaidi, M. Coupling bone degradation to formation. Nat. Med. 15, 729–731 (2009).
Crossref Google Scholar
4

Andersen, T. L. et al. A physical mechanism for coupling bone resorption and formation in adult human bone. Am. J. Pathol. 174, 239–247 (2009).
Crossref Google Scholar
5

Florencio-Silva, R., Sasso, G. R., Sasso-Cerri, E., Simoes, M. J. & Cerri, P. S. Biology of bone tissue: structure, function, and factors that influence bone cells. Biomed. Res. Int. 2015, 421746 (2015).
Crossref Google Scholar
6

Cutarelli, A. et al. Adenosine triphosphate stimulates differentiation and mineralization in human osteoblast-like Saos-2 cells. Dev. Growth Differ. 58, 400–408 (2016).
Crossref Google Scholar
7

Orimo, H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J. Nippon Med. Sch. 77, 4–12 (2010).
Crossref Google Scholar
8

Orriss, I. R., Burnstock, G. & Arnett, T. R. Purinergic signalling and bone remodelling. Curr. Opin. Pharmacol. 10, 322–330 (2010).
Crossref Google Scholar
9

Young, D. W. et al. SWI/SNF chromatin remodeling complex is obligatory for BMP2-induced, Runx2-dependent skeletal gene expression that controls osteoblast differentiation. J. Cell Biochem. 94, 720–730 (2005).
Crossref Google Scholar
10

Francis, M. J. O. et al. ATPase pumps in osteoclasts and osteoblasts. Int. J. Biochem. Cell Biol. 34, 459–476 (2002).
Crossref Google Scholar
11

Iwayama, T. et al. Osteoblastic lysosome plays a central role in mineralization. Sci. Adv. 5, eaax0672 (2019).
Crossref Google Scholar
12

Cohn, D. V. & Forscher, B. K. Aerobic metabolism of glucose by bone. J. Biolog. Chem. 237, 615–618 (1962).
Crossref Google Scholar
13

Esen, E. et al. WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation. Cell Metab. 17, 745–755 (2013).
Crossref Google Scholar
14

Neuman, W. F., Neuman, M. W. & Brommage, R. Aerobic glycolysis in bone: lactate production and gradients in calvaria. Am. J. Physiol. 234, C41–50 (1978).
Crossref Google Scholar
15

Adamek, G. et al. Fatty acid oxidation in bone tissue and bone cells in culture. Characterization and hormonal influences. Biochem. J. 248, 129–37 (1987).
Crossref Google Scholar
16

Kim, S. P. et al. Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner. JCI Insight 2, e92704 (2017).
Crossref Google Scholar
17

Rendina-Ruedy, E., Guntur, A. R. & Rosen, C. J. Intracellular lipid droplets support osteoblast function. Adipocyte 6, 250–258 (2017).
Crossref Google Scholar
18

VandeKopple, M. J. et al. HILPDA regulates lipid metabolism, lipid droplet abundance, and response to microenvironmental stress in solid tumors. Mol. Cancer Res. 17, 2089–2101 (2019).
Crossref Google Scholar
19

Getiye, Y., Rice, T. A., Phillips, B. D., Carrillo, D. F. & He, G. Dysregulated lipolysis and lipophagy in lipid droplets of macrophages from high fat diet-fed obese mice. J. Cell Mol. Med. 26, 4825–4836 (2022).
Crossref Google Scholar
20

Krueger, K. C., Costa, M. J., Du, H. & Feldman, B. J. Characterization of Cre recombinase activity for in vivo targeting of adipocyte precursor cells. Stem Cell Rep. 3, 1147–1158 (2014).
Crossref Google Scholar
21

Sanchez-Gurmaches, J., Hsiao, W. Y. & Guertin, D. A. Highly selective in vivo labeling of subcutaneous white adipocyte precursors with Prx1-Cre. Stem Cell Rep. 4, 541–550 (2015).
Crossref Google Scholar
22

Bolton, J. G., Patel, S., Lacey, J. H. & White, S. A prospective study of changes in bone turnover and bone density associated with regaining weight in women with anorexia nervosa. Osteoporos Int. 16, 1955–1962 (2005).
Crossref Google Scholar
23

Nussbaum, M., Baird, D., Sonnenblick, M., Cowan, K. & Shenker, I. R. Short stature in anorexia nervosa patients. J. Adolesc. Health Care 6, 453–455 (1985).
Crossref Google Scholar
24

Engelbregt, M. J. et al. Body composition and bone measurements in intra-uterine growth retarded and early postnatally undernourished male and female rats at the age of 6 months: comparison with puberty. Bone 34, 180–186 (2004).
Crossref Google Scholar
25

Boyer, P. M. et al. Bone status in an animal model of chronic sub-optimal nutrition: a morphometric, densitometric and mechanical study. Br. J. Nutr. 93, 663–669 (2005).
Crossref Google Scholar
26

Misra, B. B., Jayapalan, S., Richards, A. K., Helderman, R. C. M. & Rendina-Ruedy, E. Untargeted metabolomics in primary murine bone marrow stromal cells reveals distinct profile throughout osteoblast differentiation. Metabolomics 17, 86 (2021).
Crossref Google Scholar
27

Frey, J. L. et al. Wnt-Lrp5 signaling regulates fatty acid metabolism in the osteoblast. Mol. Cell Biol. 35, 1979–1991 (2015).
Crossref Google Scholar
28

Kevorkova, O. et al. Low-bone-mass phenotype of deficient mice for the cluster of differentiation 36 (CD36). PLoS One 8, e77701 (2013).
Crossref Google Scholar
29

Enlow, D. H., Conklin, J. L. & Bang, S. Observations on the occurrence and the distribution of lipids in compact bone. Clin. Orthop. Relat. Res. 38, 157–69 (1965).
Crossref Google Scholar
30

Kawai, K., Tamaki, A. & Hirohata, K. Steroid-induced accumulation of lipid in the osteocytes of the rabbit femoral head. A histochemical and electron microscopic study. J. Bone. Joint. Surg. Am. 67, 755–63 (1985).
Crossref Google Scholar
31

Wang, Y. et al. Alcohol-induced adipogenesis in bone and marrow: a possible mechanism for osteonecrosis. Clin. Orthop. Rel. Res. 410, 213–224 (2003).
Crossref Google Scholar
32

McGee-Lawrence, M. E. et al. Hdac3 deficiency increases marrow adiposity and induces lipid storage and glucocorticoid metabolism in osteochondroprogenitor cells. J. Bone Miner. Res. 31, 116–128 (2016).
Crossref Google Scholar
33

Chen, S. & Huang, X. Cytosolic lipolysis in non-adipose tissues: energy provision and beyond. FEBS J. 289, 7385–7398 (2022).
Crossref Google Scholar
34

Schott, M. B. et al. Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes. J. Cell Biol. 218, 3320–3335 (2019).
Crossref Google Scholar
35

Arnold, P. K. & Finley, L. W. S. Regulation and function of the mammalian tricarboxylic acid cycle. J. Biol. Chem. 299, 102838 (2023).
Crossref Google Scholar
36

Inigo, M., Deja, S. & Burgess, S. C. Ins and outs of the TCA cycle: the central role of anaplerosis. Annu. Rev. Nutr. 41, 19–47 (2021).
Crossref Google Scholar
37

Cotter, D. G., Schugar, R. C. & Crawford, P. A. Ketone body metabolism and cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol. 304, H1060–76 (2013).
Crossref Google Scholar
38

Carley, A. N. et al. Short-chain fatty acids outpace ketone oxidation in the failing heart. Circulation 143, 1797–1808 (2021).
Crossref Google Scholar
39

Puchalska, P. & Crawford, P. A. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 25, 262–284 (2017).
Crossref Google Scholar
40

Halestrap, A. P. Pyruvate and ketone-body transport across the mitochondrial membrane. Exchange properties, pH-dependence and mechanism of the carrier. Biochem. J. 172, 377–87 (1978).
Crossref Google Scholar
41

Hardie, D. G. Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 144, 5179–5183 (2003).
Crossref Google Scholar
42

Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 (2018).
Crossref Google Scholar
43

Lin, S. C. & Hardie, D. G. AMPK: sensing glucose as well as cellular energy status. Cell Metab. 27, 299–313 (2018).
Crossref Google Scholar
44

Guntur, A. R., Le, P. T., Farber, C. R. & Rosen, C. J. Bioenergetics during calvarial osteoblast differentiation reflect strain differences in bone mass. Endocrinology 155, 1589–1595 (2014).
Crossref Google Scholar
45

Marvyn, P. M., Bradley, R. M., Mardian, E. B., Marks, K. A. & Duncan, R. E. Data on oxygen consumption rate, respiratory exchange ratio, and movement in C57BL/6J female mice on the third day of consuming a high-fat diet. Data Brief 7, 472–475 (2016).
Crossref Google Scholar
46

Fuchs, C. D. et al. Hepatocyte-specific deletion of adipose triglyceride lipase (adipose triglyceride lipase/patatin-like phospholipase domain containing 2) ameliorates dietary induced steatohepatitis in mice. Hepatology 75, 125–139 (2022).
Crossref Google Scholar
47

Haemmerle, G. et al. ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1. Nat. Med. 17, 1076–1085 (2011).
Crossref Google Scholar
48

Bezaire, V. et al. Contribution of adipose triglyceride lipase and hormone-sensitive lipase to lipolysis in hMADS adipocytes. J. Biol. Chem. 284, 18282–18291 (2009).
Crossref Google Scholar
49

Pettersson, U. S., Walden, T. B., Carlsson, P. O., Jansson, L. & Phillipson, M. Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PLoS One 7, e46057 (2012).
Crossref Google Scholar
50

Palmisano, B. T., Zhu, L. & Stafford, J. M. Role of estrogens in the regulation of liver lipid metabolism. Adv. Exp. Med. Biol. 1043, 227–256 (2017).
Crossref Google Scholar
51

Althaher, A. R. An overview of hormone-sensitive lipase (HSL). Sci. World J. 2022, 1964684 (2022).
Crossref Google Scholar
52

de, L. II et al. Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. Osteoporos Int. 16, 1713–1720 (2005).
Crossref Google Scholar
53

Janghorbani, M., Feskanich, D., Willett, W. C. & Hu, F. Prospective study of diabetes and risk of hip fracture: the Nurses’ Health Study. Diabetes Care 29, 1573–1578 (2006).
Crossref Google Scholar
54

Melton, L. J. 3rd, Leibson, C. L., Achenbach, S. J., Therneau, T. M. & Khosla, S. Fracture risk in type 2 diabetes: update of a population-based study. J. Bone Miner. Res. 23, 1334–1342 (2008).
Crossref Google Scholar
55

Jepsen, K. J. & Schlecht, S. H. Biomechanical mechanisms: resolving the apparent conundrum of why individuals with type Ⅱ diabetes show increased fracture incidence despite having normal BMD. J. Bone Miner. Res. 29, 784–786 (2014).
Crossref Google Scholar
56

Nicodemus, K. K. & Folsom, A. R. Iowa Women’s Health Study. Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care 24, 1192–7 (2001).
Crossref Google Scholar
57

Anagnostis, P., Florentin, M., Livadas, S., Lambrinoudaki, I. & Goulis, D. G. Bone health in patients with dyslipidemias: an underestimated aspect. Int. J. Mol. Sci. 23, 1639 (2022).
Crossref Google Scholar
58

Hughes, D. et al. Gaucher disease in bone: from pathophysiology to practice. J. Bone Miner. Res. 34, 996–1013 (2019).
Crossref Google Scholar
59

Wasserstein, M., Godbold, J. & McGovern, M. M. Skeletal manifestations in pediatric and adult patients with Niemann Pick disease type B. J. Inherit. Metab. Dis. 36, 123–127 (2013).
Crossref Google Scholar
60

Sitnick, M. T. et al. Skeletal muscle triacylglycerol hydrolysis does not influence metabolic complications of obesity. Diabetes 62, 3350–3361 (2013).
Crossref Google Scholar
61

Lighton, J. R. B. Measuring Metabolic Rates: A Manual for Scientists. Oxford: Oxford University Press (2008).
Crossref
62

Maridas, D. E., Rendina-Ruedy, E., Le, P. T. & Rosen, C. J. Isolation, culture, and differentiation of bone marrow stromal cells and osteoclast progenitors from mice. J. Vis. Exp. 56750 (2018).
Crossref Google Scholar
63

Phinney DG, K. G., Isaacson, R. L. & Prockop, D. J. Plastic adherent stromal cells from the bone marrow of commonly used strains of inbred mice: variations in yield, growth, and differentiation. J. Cell Biochem. 72, 570–585 (1999).
Crossref Google Scholar
64

Sun S, G. Z. et al. Isolation of mouse marrow mesenchymal progenitors by a novel and reliable method. Stem Cells 21, 527–535 (2003).
Crossref Google Scholar
65
Jonason, J. H. & O’Keefe, R. J. Isolation and culture of neonatal mouse calvarial osteoblasts, in Skeletal Development and Repair: Methods and Protocols. (ed. M. J. Hilton) 295-305 (Humana Press, Totowa, NJ; 2014).
Crossref
66

Bligh, E. G. & Dyer, W. J. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 911–917 (1959).
Crossref Google Scholar
67

Rambold, A. S., Cohen, S. & Lippincott-Schwartz, J. Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev. Cell 32, 678–692 (2015).
Crossref Google Scholar
68

Dempster, D. W. et al. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J. Bone Miner. Res. 28, 2–17 (2013).
Crossref Google Scholar
69

Parfitt, A. M. et al. Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J. Bone Miner. Res. 2, 595–610 (1987).
Crossref Google Scholar
Bone Research
Volume 11,
December 2023
Article number: 62
DOI: 10.1038/s41413-023-00297-2
Cite this article:
Nandy A, Helderman RCM, Thapa S, et al. Lipolysis supports bone formation by providing osteoblasts with endogenous fatty acid substrates to maintain bioenergetic status. Bone Research, 2023, 11: 62. https://doi.org/10.1038/s41413-023-00297-2

117

Views

1

Downloads

3

Crossref

1

Web of Science

1

Scopus

Altmetrics
Received: 15 May 2023
Revised: 18 September 2023
Accepted: 22 September 2023
Published: 24 November 2023
© The Author(s) 2023

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Return