Skip to main content
SpringerLink
Log in

Diseases of Energy and Lipid Metabolism and Bone: Emerging Therapeutics

  • Chapter
  • First Online:
Bone-Metabolic Functions and Modulators

Part of the book series: Topics in Bone Biology ((TBB,volume 7))

  • 1056 Accesses

Abstract

Lipids constitute a broad group of naturally occurring molecules that function as energy storage organs, as components of cell membranes, and as signaling molecules. Lipids and fatty acids are stored as triglycerides and are the most important source of energy for most organisms. When the body needs energy, lipolysis is initiated in adipocytes, and the triglycerides are hydrolyzed to glycerol and nonesterified fatty acids (NEFAs) [64]. The capacity to store triglycerides makes it possible to maintain energy homeostasis and prevent an abnormal toxic increase in plasma NEFAs. Under normal conditions, fat cells fine-tune the balance between lipogenesis and lipolysis of triglycerides in response to physiological needs. However, changes in lipid storage and metabolism, whether anabolic or catabolic, modulate whole body homeostasis. When fat mass is lacking as in lipoatrophy, there arise complications similar to those in type 2 diabetes, i.e., insulin resistance, dyslipidemia, hyperphagia, and liver steatosis. On the other hand, excessive lipid storage leads to obesity, along with a multitude of manifestations and clinical complications including altered insulin production. Fatty tissue accumulation is a major risk factor for chronic diseases, including the metabolic syndrome, also known as “syndrome X,” a cluster of phenotypes that contribute to elevating the risk of disorders. Symptoms of the metabolic syndrome include insulin resistance, impaired glucose regulation, dyslipidemia, hypertension, central obesity, and microalbuminuria, with insulin resistance the major feature. Between 60% and 90% of type 2 diabetes cases are thought to be due to obesity. Altogether, adipose tissue is essential to maintaining health and in glucose and lipid homeostasis [64].

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ali AA, Weinstein RS, Stewart SA, Parfitt AM, Manolagas SC, Jilka RL. Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology. 2005;146:1226–35.

    Article  PubMed  CAS  Google Scholar 

  2. Aubert RE, Herrera V, Chen W, Haffner SM, Pendergrass M. Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab. 2010;12:716–21.

    Article  PubMed  CAS  Google Scholar 

  3. Bennett CN, Hodge CL, MacDougald OA, Schwartz J. Role of Wnt10b and C/EBPalpha in spontaneous adipogenesis of 243 cells. Biochem Biophys Res Commun. 2003;302:12–6.

    Article  PubMed  CAS  Google Scholar 

  4. Bennett CN, Ross SE, Longo KA, Bajnok L, Hemati N, Johnson KW, Harrison SD, MacDougald OA. Regulation of Wnt signaling during adipogenesis. J Biol Chem. 2002;277:30998–1004.

    Article  PubMed  CAS  Google Scholar 

  5. Berner HS, Lyngstadaas SP, Spahr A, Monjo M, Thommesen L, Drevon CA, Syversen U, Reseland JE. Adiponectin and its receptors are expressed in bone-forming cells. Bone. 2004;35:842–9.

    Article  PubMed  CAS  Google Scholar 

  6. Botolin S, McCabe LR. Bone loss and increased bone adiposity in spontaneous and pharmacologically induced diabetic mice. Endocrinology. 2007;148:198–205.

    Article  PubMed  CAS  Google Scholar 

  7. Bouillon R. Diabetic bone disease. Calcif Tissue Int. 1991;49:155–60.

    Article  PubMed  CAS  Google Scholar 

  8. Bouillon R. Diabetic bone disease Low turnover osteoporosis related to decreased IGF-I production. Verh K Acad Geneeskd Belg. 1992;54:365–91; discussion 391–362.

    PubMed  CAS  Google Scholar 

  9. Bruedigam C, Eijken M, Koedam M, van de Peppel J, Drabek K, Chiba H, van Leeuwen JP. A new concept underlying stem cell lineage skewing that explains the detrimental effects of thiazolidinediones on bone. Stem Cells. 2010;28:916–27.

    PubMed  CAS  Google Scholar 

  10. Confavreux CB, Levine RL, Karsenty G. A paradigm of integrative physiology, the crosstalk between bone and energy metabolisms. Mol Cell Endocrinol. 2009;310:21–9.

    Article  PubMed  CAS  Google Scholar 

  11. Debiais F. Thiazolidinediones: antidiabetic agents with effects on bone. Joint Bone Spine. 2009;76:221–3.

    Article  PubMed  CAS  Google Scholar 

  12. Dimitri P, Wales JK, Bishop N. Fat and bone in children: differential effects of obesity on bone size and mass according to fracture history. J Bone Miner Res. 2010;25:527–36.

    Article  PubMed  Google Scholar 

  13. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 2000;100:197–207.

    Article  PubMed  CAS  Google Scholar 

  14. Epstein S, Leroith D. Diabetes and fragility fractures – a burgeoning epidemic? Bone. 2008;43:3–6.

    Article  PubMed  CAS  Google Scholar 

  15. Felson DT, Zhang Y, Hannan MT, Anderson JJ. Effects of weight and body mass index on bone mineral density in men and women: the Framingham study. J Bone Miner Res. 1993;8:567–73.

    Article  PubMed  CAS  Google Scholar 

  16. Ferron M, Wei J, Yoshizawa T, Del Fattore A, DePinho RA, Teti A, Ducy P, Karsenty G. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell. 2010;142:296–308.

    Article  PubMed  CAS  Google Scholar 

  17. Forsen T, Eriksson J, Tuomilehto J, Reunanen A, Osmond C, Barker D. The fetal and childhood growth of persons who develop type 2 diabetes. Ann Intern Med. 2000;133:176–82.

    PubMed  CAS  Google Scholar 

  18. Fowlkes JL, Bunn RC, Liu L, Wahl EC, Coleman HN, Cockrell GE, Perrien DS, Lumpkin Jr CK, Thrailkill KM. Runt-related transcription factor 2 (RUNX2) and RUNX2-related osteogenic genes are down-regulated throughout osteogenesis in type 1 diabetes mellitus. Endocrinology. 2008;149:1697–704.

    Article  PubMed  CAS  Google Scholar 

  19. Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D, Faugere MC, Aja S, Hussain MA, Bruning JC, Clemens TL. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell. 2010;142:309–19.

    Article  PubMed  CAS  Google Scholar 

  20. Gimble JM, Zvonic S, Floyd ZE, Kassem M, Nuttall ME. Playing with bone and fat. J Cell Biochem. 2006;98:251–66.

    Article  PubMed  CAS  Google Scholar 

  21. Hadzibegovic I, Miskic B, Cosic V, Prvulovic D, Bistrovic D. Increased bone mineral density in postmenopausal women with type 2 diabetes mellitus. Ann Saudi Med. 2008;28:102–4.

    Article  PubMed  Google Scholar 

  22. Hinoi E, Gao N, Jung DY, Yadav V, Yoshizawa T, Kajimura D, Myers Jr MG, Chua Jr SC, Wang Q, Kim JK, Kaestner KH, Karsenty G. An osteoblast-dependent mechanism contributes to the leptin regulation of insulin secretion. Ann N Y Acad Sci. 2009;1173 Suppl 1:E20–3030.

    Article  PubMed  CAS  Google Scholar 

  23. Hinoi E, Gao N, Jung DY, Yadav V, Yoshizawa T, Myers Jr MG, Chua Jr SC, Kim JK, Kaestner KH, Karsenty G. The sympathetic tone mediates Leptin’s inhibition of insulin secretion by modulating osteocalcin bioactivity. J Cell Biol. 2008;183:1235–42.

    Article  PubMed  CAS  Google Scholar 

  24. Hordon L. Bone disease in diabetes mellitus. In: ­uptodate; 2010. www.uptodate.com/contents/bone-disease-in-diabetes-mellitus.

  25. Hsu YH, Venners SA, Terwedow HA, Feng Y, Niu T, Li Z, Laird N, Brain JD, Cummings SR, Bouxsein ML, Rosen CJ, Xu X. Relation of body composition, fat mass, and serum lipids to osteoporotic fractures and bone mineral density in Chinese men and women. Am J Clin Nutr. 2006;83:146–54.

    PubMed  CAS  Google Scholar 

  26. Inzerillo AM, Epstein S. Osteoporosis and diabetes mellitus. Rev Endocr Metab Disord. 2004;5:261–8.

    Article  PubMed  Google Scholar 

  27. Jara A, Bover J, Felsenfeld AJ. Development of ­secondary hyperparathyroidism and bone disease in diabetic rats with renal failure. Kidney Int. 1995;47:1746–51.

    Article  PubMed  CAS  Google Scholar 

  28. Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T. Adiponectin is associated with changes in bone markers during glycemic control in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2009;94:3031–7.

    Article  PubMed  CAS  Google Scholar 

  29. Karsenty G. Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab. 2006;4:341–8.

    Article  PubMed  CAS  Google Scholar 

  30. Kawai M, Devlin MJ, Rosen CJ. Fat targets for skeletal health. Nat Rev Rheumatol. 2009;5:365–72.

    Article  PubMed  Google Scholar 

  31. Kawai M, Rosen CJ. Bone: adiposity and bone accrual-still an established paradigm? Nat Rev Endocrinol. 2010;6:63–4.

    Article  PubMed  Google Scholar 

  32. Kawai M, Sousa KM, MacDougald OA, Rosen CJ. The many facets of PPARgamma: novel insights for the skeleton. Am J Physiol Endocrinol Metab. 2010;299:E3–99.

    Article  PubMed  CAS  Google Scholar 

  33. Kellinsalmi M, Parikka V, Risteli J, Hentunen T, Leskela HV, Lehtonen S, Selander K, Vaananen K, Lehenkari P. Inhibition of cyclooxygenase-2 down-regulates osteoclast and osteoblast differentiation and favours adipocyte formation in vitro. Eur J Pharmacol. 2007;572:102–10.

    Article  PubMed  CAS  Google Scholar 

  34. Lecka-Czernik B. Bone loss in diabetes: use of antidiabetic thiazolidinediones and secondary osteoporosis. Curr Osteoporos Rep. 2010;8(4):178–84.

    Article  PubMed  Google Scholar 

  35. Lecka-Czernik B, Ackert-Bicknell C, Adamo ML, Marmolejos V, Churchill GA, Shockley KR, Reid IR, Grey A, Rosen CJ. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by rosiglitazone suppresses components of the insulin-like growth factor regulatory system in vitro and in vivo. Endocrinology. 2007;148:903–11.

    Article  PubMed  CAS  Google Scholar 

  36. Lee NK, Karsenty G. Reciprocal regulation of bone and energy metabolism. Trends Endocrinol Metab. 2008;19:161–6.

    Article  PubMed  CAS  Google Scholar 

  37. Liu LF, Shen WJ, Zhang ZH, Wang LJ, Kraemer FB. Adipocytes decrease Runx2 expression in osteoblastic cells: roles of PPARgamma and adiponectin. J Cell Physiol. 2010;225:837–45.

    Article  PubMed  CAS  Google Scholar 

  38. Lu H, Kraut D, Gerstenfeld LC, Graves DT. Diabetes interferes with the bone formation by affecting the expression of transcription factors that regulate ­osteoblast differentiation. Endocrinology. 2003;144:346–52.

    Article  PubMed  CAS  Google Scholar 

  39. Magni P, Dozio E, Galliera E, Ruscica M, Corsi MM. Molecular aspects of adipokine-bone interactions. Curr Mol Med. 2010;10:522–32.

    PubMed  CAS  Google Scholar 

  40. Martin A, David V, Malaval L, Lafage-Proust MH, Vico L, Thomas T. Opposite effects of leptin on bone metabolism: a dose-dependent balance related to energy intake and insulin-like growth factor-I pathway. Endocrinology. 2007;148:3419–25.

    Article  PubMed  CAS  Google Scholar 

  41. Mastrandrea LD, Wactawski-Wende J, Donahue RP, Hovey KM, Clark A, Quattrin T. Young women with type 1 diabetes have lower bone mineral density that persists over time. Diabetes Care. 2008;31:1729–35.

    Article  PubMed  Google Scholar 

  42. McCabe LR. Understanding the pathology and mechanisms of type I diabetic bone loss. J Cell Biochem. 2007;102:1343–57.

    Article  PubMed  CAS  Google Scholar 

  43. McDonough AK, Rosenthal RS, Cao X, Saag KG. The effect of thiazolidinediones on BMD and osteoporosis. Nat Clin Pract Endocrinol Metab. 2008;4:507–13.

    Article  PubMed  CAS  Google Scholar 

  44. Melton 3rd LJ, Riggs BL, Leibson CL, Achenbach SJ, Camp JJ, Bouxsein ML, Atkinson EJ, Robb RA, Khosla S. A bone structural basis for fracture risk in diabetes. J Clin Endocrinol Metab. 2008;93:4804–9.

    Article  PubMed  CAS  Google Scholar 

  45. Pei L, Tontonoz P. Fat’s loss is bone’s gain. J Clin Invest. 2004;113:805–6.

    PubMed  CAS  Google Scholar 

  46. Raisz L. Pathogenesis of osteoporosis; 2010. www.mdconsult.com.

  47. Reid IR. Fat and bone. Arch Biochem Biophys. 2010;503(1):20–7.

    Article  PubMed  CAS  Google Scholar 

  48. Riserus U, Willett WC, Hu FB. Dietary fats and prevention of type 2 diabetes. Prog Lipid Res. 2009;48:44–51.

    Article  PubMed  CAS  Google Scholar 

  49. Rosen CJ. Revisiting the rosiglitazone story – lessons learned. N Engl J Med. 2010;363:803–6.

    Article  PubMed  CAS  Google Scholar 

  50. Rosen CJ. The rosiglitazone story – lessons from an FDA Advisory Committee meeting. N Engl J Med. 2007;357:844–6.

    Article  PubMed  CAS  Google Scholar 

  51. Rosen CJ, Bouxsein ML. Mechanisms of disease: is osteoporosis the obesity of bone? Nat Clin Pract Rheumatol. 2006;2:35–43.

    Article  PubMed  CAS  Google Scholar 

  52. Rosen CJ, Klibanski A. Bone, fat, and body composition: evolving concepts in the pathogenesis of osteoporosis. Am J Med. 2009;122:409–14.

    Article  PubMed  CAS  Google Scholar 

  53. Rosen CJ, Motyl KJ. No bones about it: insulin modulates skeletal remodeling. Cell. 2010;142:198–200.

    Article  PubMed  CAS  Google Scholar 

  54. Schafer AL, Vittinghoff E, Lang TF, Sellmeyer DE, Harris TB, Kanaya AM, Strotmeyer ES, Cawthon PM, Cummings SR, Tylavsky FA, Scherzinger AL, Schwartz AV. Fat infiltration of muscle, diabetes, and clinical fracture risk in older adults. J Clin Endocrinol Metab. 2010;95(11):E368–37272. Epub 2010 Jul 28.

    Article  PubMed  Google Scholar 

  55. Schwartz AV, Sellmeyer DE. Diabetes, fracture, and bone fragility. Curr Osteoporos Rep. 2007;5:105–11.

    Article  PubMed  Google Scholar 

  56. Schwartz AV, Sellmeyer DE. Effect of thiazolidinediones on skeletal health in women with Type 2 diabetes. Expert Opin Drug Saf. 2008;7:69–78.

    Article  PubMed  CAS  Google Scholar 

  57. Shi Y, Yadav VK, Suda N, Liu XS, Guo XE, Myers Jr MG, Karsenty G. Dissociation of the ­neuronal regulation of bone mass and energy metabolism by leptin in vivo. Proc Natl Acad Sci USA. 2008;105:20529–33.

    Article  PubMed  CAS  Google Scholar 

  58. Shinoda Y, Yamaguchi M, Ogata N, Akune T, Kubota N, Yamauchi T, Terauchi Y, Kadowaki T, Takeuchi Y, Fukumoto S, Ikeda T, Hoshi K, Chung UI, Nakamura K, Kawaguchi H. Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways. J Cell Biochem. 2006;99:196–208.

    Article  PubMed  CAS  Google Scholar 

  59. Sonnett TE, Levien TL, Gates BJ, Robinson JD, Campbell RK. Diabetes mellitus, inflammation, ­obesity: proposed treatment pathways for current and future therapies. Ann Pharmacother. 2010;44:701–11.

    Article  PubMed  CAS  Google Scholar 

  60. Takeda S. Bone and development, topics in bone biology. London: Springer; 2010.

    Google Scholar 

  61. Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G. Leptin regulates bone formation via the sympathetic nervous system. Cell. 2002;111:305–17.

    Article  PubMed  CAS  Google Scholar 

  62. Urs S, Venkatesh D, Tang Y, Henderson T, Yang X, Friesel RE, Rosen CJ, Liaw L. Sprouty1 is a critical regulatory switch of mesenchymal stem cell lineage allocation. FASEB J. 2010;24:3264–73.

    Article  PubMed  CAS  Google Scholar 

  63. von Muhlen D, Safii S, Jassal SK, Svartberg J, ­Barrett-Connor E. Associations between the ­metabolic ­syndrome and bone health in older men and women: the Rancho Bernardo Study. Osteoporos Int. 2007;18:1337–44.

    Article  Google Scholar 

  64. Wang P, Mariman E, Renes J, Keijer J. The secretory function of adipocytes in the physiology of white ­adipose tissue. J Cell Physiol. 2008;216:3–13.

    Article  PubMed  CAS  Google Scholar 

  65. WHO. Diet and physical activity. www.who.int/­dietphysicalactivity/en/.

  66. Zhao LJ, Jiang H, Papasian CJ, Maulik D, Drees B, Hamilton J, Deng HW. Correlation of obesity and osteoporosis: effect of fat mass on the determination of osteoporosis. J Bone Miner Res. 2008;23:17–29.

    Article  PubMed  CAS  Google Scholar 

  67. Zhao LJ, Liu YJ, Liu PY, Hamilton J, Recker RR, Deng HW. Relationship of obesity with osteoporosis. J Clin Endocrinol Metab. 2007;92:1640–6.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME, 04074, USA

    Sumithra K. Urs Ph.D.

  2. Clinical and Translational Research, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME, 04074, USA

    Clifford J. Rosen M.D.

Authors
  1. Sumithra K. Urs Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clifford J. Rosen M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Clifford J. Rosen M.D. .

Editor information

Editors and Affiliations

  1. Health Center, Dept. Pharmacology, University of Connecticut, Farmington Ave. 263, Farmington, 06030-6125, Connecticut, USA

    Felix Bronner

  2. , Department of Biochemistry and Cell Biol, Rice University, 6100 Main Street, Houston, 77005, Texas, USA

    Mary C. Farach-Carson

  3. , General Hospital, University of Southampton, Southampton, SO16 6YD, United Kingdom

    Helmtrud I. Roach

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag London

About this chapter

Cite this chapter

Urs, S.K., Rosen, C.J. (2012). Diseases of Energy and Lipid Metabolism and Bone: Emerging Therapeutics. In: Bronner, F., Farach-Carson, M., Roach, H. (eds) Bone-Metabolic Functions and Modulators. Topics in Bone Biology, vol 7. Springer, London. https://doi.org/10.1007/978-1-4471-2745-1_8

Download citation

  • DOI: https://doi.org/10.1007/978-1-4471-2745-1_8

  • Published:

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-4471-2744-4

  • Online ISBN: 978-1-4471-2745-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation