Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor for adipogenesis and glucose metabolism, but accumulating evidence demonstrates the involvement of PPARγ in skeletal metabolism as well. PPARγ agonists, the thiazolidinediones, have been widely used for the treatment of type 2 diabetes mellitus owing to their effectiveness in lowering blood glucose levels. However, the use of thiazolidinediones has been associated with bone loss and fractures. Thiazolidinedione-induced alterations in the bone marrow milieu—that is, increased bone marrow adiposity with suppression of osteogenesis—could partially explain the pathogenesis of drug-induced bone loss. Furthermore, several lines of evidence place PPARγ at the center of a regulatory loop between circadian networks and metabolic output. PPARγ exhibits a circadian expression pattern that is magnified by consumption of a high-fat diet. One gene with circadian regulation in peripheral tissues, nocturnin, has been shown to enhance PPARγ activity. Importantly, mice deficient in nocturnin are protected from diet-induced obesity, exhibit impaired circadian expression of PPARγ and have increased bone mass. This Review focuses on new findings regarding the role of PPARγ in adipose tissue and skeletal metabolism and summarizes the emerging role of PPARγ as an integral part of a complex circadian regulatory system that modulates food storage, energy consumption and skeletal metabolism.
Key Points
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Activation of PPARγ is a therapeutic target in type 2 diabetes mellitus
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Activation of PPARγ is a risk factor for osteoporosis
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PPARγ is a key factor in the determination of mesenchymal stem cell fate
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A role for bone marrow adipocytes in skeletal metabolism is emerging
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PPARγ provides a link between the circadian clock system and metabolic output
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References
Tontonoz, P., Hu, E., Graves, R. A., Budavari, A. I. & Spiegelman, B. M. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 8, 1224–1234 (1994).
Tontonoz, P. & Spiegelman, B. M. Fat and beyond: the diverse biology of PPARgamma. Annu. Rev. Biochem. 77, 289–312 (2008).
Kawai, M., Sousa, K. M., MacDougald, O. A. & Rosen, C. J. The many facets of PPARgamma: novel insights for the skeleton. Am. J. Physiol. Endocrinol. Metab. 299, E3–E9 (2010).
Rosen, E. D. & MacDougald, O. A. Adipocyte differentiation from the inside out. Nat. Rev. Mol. Cell Biol. 7, 885–896 (2006).
Iwamoto, Y. et al. Effect of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NIDDM. Diabetes Care 14, 1083–1086 (1991).
Fujiwara, T., Yoshioka, S., Yoshioka, T., Ushiyama, I. & Horikoshi, H. Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes 37, 1549–1558 (1988).
Ciaraldi, T. P., Gilmore, A., Olefsky, J. M., Goldberg, M. & Heidenreich, K. A. In vitro studies on the action of CS-045, a new antidiabetic agent. Metabolism 39, 1056–1062 (1990).
Suter, S. L., Nolan, J. J., Wallace, P., Gumbiner, B. & Olefsky, J. M. Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care 15, 193–203 (1992).
Nolan, J. J., Ludvik, B., Beerdsen, P., Joyce, M. & Olefsky, J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N. Engl. J. Med. 331, 1188–1193 (1994).
Schwartz, A. V. et al. Thiazolidinedione use and bone loss in older diabetic adults. J. Clin. Endocrinol. Metab. 91, 3349–3354 (2006).
Grey, A. et al. The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. J. Clin. Endocrinol. Metab. 92, 1305–1310 (2007).
Kahn, S. E. et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 355, 2427–2443 (2006).
Home, P. D. et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373, 2125–2135 (2009).
Yaturu, S., Bryant, B. & Jain, S. K. Thiazolidinedione treatment decreases bone mineral density in type 2 diabetic men. Diabetes Care 30, 1574–1576 (2007).
Rosen, C. J. The rosiglitazone story--lessons from an FDA Advisory Committee meeting. N. Engl. J. Med. 357, 844–846 (2007).
Aubert, R. E., Herrera, V., Chen, W., Haffner, S. M. & Pendergrass, M. Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes. Metab. 12, 716–721 (2010).
Dormuth, C. R., Carney, G., Carleton, B., Bassett, K. & Wright, J. M. Thiazolidinediones and fractures in men and women. Arch. Intern. Med. 169, 1395–1402 (2009).
Shockley, K. R. et al. PPARgamma2 nuclear receptor controls multiple regulatory pathways of osteoblast differentiation from marrow mesenchymal stem cells. J. Cell Biochem. 106, 232–246 (2009).
Lecka-Czernik, B. et al. 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 148, 903–911 (2007).
Green, C. B., Takahashi, J. S. & Bass, J. The meter of metabolism. Cell 134, 728–742 (2008).
Yang, X. et al. Nuclear receptor expression links the circadian clock to metabolism. Cell 126, 801–810 (2006).
Green, C. B. et al. Loss of nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity. Proc. Natl Acad. Sci. USA 104, 9888–9893 (2007).
Rosen, E. D. & Spiegelman, B. M. PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth. J. Biol. Chem. 276, 37731–37734 (2001).
Braissant, O., Foufelle, F., Scotto, C., Dauça, M. & Wahli, W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 137, 354–366 (1996).
Xu, H. E. et al. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol. Cell 3, 397–403 (1999).
Forman, B. M. et al. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83, 803–812 (1995).
Kubota, N. et al. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol. Cell 4, 597–609 (1999).
Akune, T. et al. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J. Clin. Invest. 113, 846–855 (2004).
Darlington, G. J., Ross, S. E. & MacDougald, O. A. The role of C/EBP genes in adipocyte differentiation. J. Biol. Chem. 273, 30057–30060 (1998).
Cheng, S. L., Shao, J. S., Charlton-Kachigian, N., Loewy, A. P. & Towler, D. A. MSX2 promotes osteogenesis and suppresses adipogenic differentiation of multipotent mesenchymal progenitors. J. Biol. Chem. 278, 45969–45977 (2003).
Ichida, F. et al. Reciprocal roles of MSX2 in regulation of osteoblast and adipocyte differentiation. J. Biol. Chem. 279, 34015–34022 (2004).
Mori, T. et al. Role of Krüppel-like factor 15 (KLF15) in transcriptional regulation of adipogenesis. J. Biol. Chem. 280, 12867–12875 (2005).
Oishi, Y. et al. Krüppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation. Cell Metab. 1, 27–39 (2005).
Gupta, R. K. et al. Transcriptional control of preadipocyte determination by Zfp423. Nature 464, 619–623 (2010).
Banerjee, S. S. et al. The Krüppel-like factor KLF2 inhibits peroxisome proliferator-activated receptor-gamma expression and adipogenesis. J. Biol. Chem. 278, 2581–2584 (2003).
Tong, Q., Tsai, J., Tan, G., Dalgin, G. & Hotamisligil, G. S. Interaction between GATA and the C/EBP family of transcription factors is critical in GATA-mediated suppression of adipocyte differentiation. Mol. Cell Biol. 25, 706–715 (2005).
Guan, H. P., Ishizuka, T., Chui, P. C., Lehrke, M. & Lazar, M. A. Corepressors selectively control the transcriptional activity of PPARgamma in adipocytes. Genes Dev. 19, 453–461 (2005).
Takada, I. et al. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat. Cell Biol. 9, 1273–1285 (2007).
Hu, E., Kim, J. B., Sarraf, P. & Spiegelman, B. M. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science 274, 2100–2103 (1996).
Camp, H. S. & Tafuri, S. R. Regulation of peroxisome proliferator-activated receptor gamma activity by mitogen-activated protein kinase. J. Biol. Chem. 272, 10811–10816 (1997).
Hosooka, T. et al. Dok1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPAR-gamma phosphorylation. Nat. Med. 14, 188–193 (2008).
Yamashita, D. et al. The transactivating function of peroxisome proliferator-activated receptor gamma is negatively regulated by SUMO conjugation in the amino-terminal domain. Genes Cells 9, 1017–1029 (2004).
Hauser, S. et al. Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation. J. Biol. Chem. 275, 18527–18533 (2000).
Floyd, Z. E. & Stephens, J. M. Interferon-gamma-mediated activation and ubiquitin-proteasome-dependent degradation of PPARgamma in adipocytes. J. Biol. Chem. 277, 4062–4068 (2002).
Akazawa, S., Sun, F., Ito, M., Kawasaki, E. & Eguchi, K. Efficacy of troglitazone on body fat distribution in type 2 diabetes. Diabetes Care 23, 1067–1071 (2000).
Shadid, S. & Jensen, M. D. Effects of pioglitazone versus diet and exercise on metabolic health and fat distribution in upper body obesity. Diabetes Care 26, 3148–3152 (2003).
Okuno, A. et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J. Clin. Invest. 101, 1354–1361 (1998).
Gavrilova, O. et al. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J. Biol. Chem. 278, 34268–34276 (2003).
Hevener, A. L. et al. Muscle-specific Pparg deletion causes insulin resistance. Nat. Med. 9, 1491–1497 (2003).
Norris, A. W. et al. Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. J. Clin. Invest. 112, 608–618 (2003).
Rosen, C. J. Bone remodeling, energy metabolism, and the molecular clock. Cell Metab. 7, 7–10 (2008).
Hinoi, E. et al. The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity. J. Cell Biol. 183, 1235–1242 (2008).
Lee, N. K. et al. Endocrine regulation of energy metabolism by the skeleton. Cell 130, 456–469 (2007).
Fulzele, K. et al. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142, 309–319 (2010).
Ferron, M. et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 142, 296–308 (2010).
Lecka-Czernik, B. Bone as a target of type 2 diabetes treatment. Curr. Opin. Investig. Drugs 10, 1085–1090 (2009).
Habib, Z. A. et al. Thiazolidinedione use and the longitudinal risk of fractures in patients with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 95, 592–600 (2010).
Lecka-Czernik, B. et al. Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPARgamma2. J. Cell Biochem. 74, 357–371 (1999).
Wan, Y., Chong, L. W. & Evans, R. M. PPAR-gamma regulates osteoclastogenesis in mice. Nat. Med. 13, 1496–1503 (2007).
Sottile, V., Seuwen, K. & Kneissel, M. Enhanced marrow adipogenesis and bone resorption in estrogen-deprived rats treated with the PPARgamma agonist BRL49653 (rosiglitazone). Calcif. Tissue Int. 75, 329–337 (2004).
Li, M. et al. Surface-specific effects of a PPAR-gamma agonist, darglitazone, on bone in mice. Bone 39, 796–806 (2006).
Wei, W. et al. PGC1beta mediates PPARgamma activation of osteoclastogenesis and rosiglitazone-induced bone loss. Cell Metab. 11, 503–516 (2010).
Lazarenko, O. P. et al. Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology 148, 2669–2680 (2007).
Bendixen, A. C. et al. IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor gamma 1. Proc. Natl Acad. Sci. USA 98, 2443–2448 (2001).
Hounoki, H. et al. Activation of peroxisome proliferator-activated receptor gamma inhibits TNF-alpha-mediated osteoclast differentiation in human peripheral monocytes in part via suppression of monocyte chemoattractant protein-1 expression. Bone 42, 765–774 (2008).
Ackert-Bicknell, C. L. et al. Strain-specific effects of rosiglitazone on bone mass, body composition, and serum insulin-like growth factor-I. Endocrinology 150, 1330–1340 (2009).
Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259–263 (2009).
Botolin, S. & McCabe, L. R. Inhibition of PPARgamma prevents type I diabetic bone marrow adiposity but not bone loss. J. Cell Physiol. 209, 967–976 (2006).
Justesen, J. et al. Mice deficient in 11beta-hydroxysteroid dehydrogenase type 1 lack bone marrow adipocytes, but maintain normal bone formation. Endocrinology 145, 1916–1925 (2004).
Sheng, M. H. et al. Histomorphometric studies show that bone formation and bone mineral apposition rates are greater in C3H/HeJ (high-density) than C57BL/6J (low-density) mice during growth. Bone 25, 421–429 (1999).
Kawai, M. & Rosen, C. J. Insulin-like growth factor-I and bone: lessons from mice and men. Pediatr. Nephrol. 24, 1277–1285 (2009).
Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259–263 (2009).
Zvonic, S., Floyd, Z. E., Mynatt, R. L. & Gimble, J. M. Circadian rhythms and the regulation of metabolic tissue function and energy homeostasis. Obesity (Silver Spring) 15, 539–543 (2007).
Fu, L., Patel, M. S., Bradley, A., Wagner, E. F. & Karsenty G. The molecular clock mediates leptin-regulated bone formation. Cell 122, 803–815 (2005).
Turek, F. W. et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 1043–1045 (2005).
Rudic, R. D. et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol. 2, e377 (2004).
Oishi, K. et al. Disrupted fat absorption attenuates obesity induced by a high-fat diet in Clock mutant mice. FEBS Lett. 580, 127–130 (2006).
Holmbäck, U. et al. Endocrine responses to nocturnal eating--possible implications for night work. Eur. J. Nutr. 42, 75–83 (2003).
Cirelli, C. The genetic and molecular regulation of sleep: from fruit flies to humans. Nat. Rev. Neurosci. 10, 549–560 (2009).
Balsalobre, A. et al. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289, 2344–2347 (2000).
Ralph, M. R., Foster, R. G., Davis, F. C. & Menaker, M. Transplanted suprachiasmatic nucleus determines circadian period. Science 247, 975–978 (1990).
Gallego, M. & Virshup, D. M. Post-translational modifications regulate the ticking of the circadian clock. Nat. Rev. Mol. Cell Biol. 8, 139–148 (2007).
Preitner, N. et al. The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260 (2002).
Kornmann, B., Schaad, O., Bujard, H., Takahashi, J. S. & Schibler, U. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol. 5, e34 (2007).
Evans, R. M., Barish, G. D. & Wang, Y. X. PPARs and the complex journey to obesity. Nat. Med. 10, 355–361 (2004).
Anan, F. et al. Pioglitazone shift circadian rhythm of blood pressure from non-dipper to dipper type in type 2 diabetes mellitus. Eur. J. Clin. Invest. 37, 709–714 (2007).
Liu, C., Li, S., Liu, T., Borjigin, J. & Lin, J. D. Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism. Nature 447, 477–481 (2007).
Green, C. B. & Besharse, J. C. Identification of a novel vertebrate circadian clock-regulated gene encoding the protein nocturnin. Proc. Natl Acad. Sci. USA 93, 14884–14888 (1996).
Wang, Y. et al. Rhythmic expression of nocturnin mRNA in multiple tissues of the mouse. BMC Dev. Biol. 1, 9 (2001).
Garbarino-Pico, E. et al. Immediate early response of the circadian polyA ribonuclease nocturnin to two extracellular stimuli. RNA 13, 745–755 (2007).
Baggs, J. E. & Green, C. B. Nocturnin, a deadenylase in Xenopus laevis retina: a mechanism for posttranscriptional control of circadian-related mRNA. Curr. Biol. 13, 189–198 (2003).
Dupressoir, A. et al. Identification of four families of yCCR4- and Mg2+-dependent endonuclease-related proteins in higher eukaryotes, and characterization of orthologs of yCCR4 with a conserved leucine-rich repeat essential for hCAF1/hPOP2 binding. BMC Genomics 2, 9 (2001).
Tucker, M. et al. The transcription factor associated Ccr4 and Caf1 proteins are components of the major cytoplasmic mRNA deadenylase in Saccharomyces cerevisiae. Cell 104, 377–386 (2001).
Kawai, M. et al. A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-gamma nuclear translocation. Proc. Natl Acad. Sci. USA 107, 10508–10513 (2010).
Cao, S. X., Dhahbi, J. M., Mote, P. L. & Spindler, S. R. Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice. Proc. Natl Acad. Sci. USA 98, 10630–10635 (2001).
Kawai, M. et al. Nocturnin: a circadian target of Pparg-induced adipogenesis. Ann. NY Acad. Sci. 1192, 131–138 (2010).
Massiera, F. et al. A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations. J. Lipid Res. 51, 2352–2361 (2010).
Acknowledgements
C. J. Rosen is supported by NIH grants R24DK084970 and AR45433.
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M. Kawai and C. J. Rosen contributed equally to researching the data for the article, discussions of the content, writing of the article and reviewing and/or editing of the manuscript before submission.
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Kawai, M., Rosen, C. PPARγ: a circadian transcription factor in adipogenesis and osteogenesis. Nat Rev Endocrinol 6, 629–636 (2010). https://doi.org/10.1038/nrendo.2010.155
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DOI: https://doi.org/10.1038/nrendo.2010.155
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