The recruitment of new fat cells through adipogenesis may prevent the development of obesity-related comorbidities. However, adipogenic capacity is markedly reduced in mature adults. This study examined how initiation of high-fat feeding at different phases of adulthood modified adipose tissue (AT) morphology and obesity phenotype in obese and diabetic Zucker Diabetic Sprague Dawley (ZDSD) rats. For this, rodents were provided high-fat diet (HFD) beginning at 63, 84, or 112？d after parturition until termination . At termination, ZDSD rats fed HFD beginning at 63？d after parturition (early adulthood) exhibited greater body fat and lower lean mass without significant changes to energy intake or body weight. Moreover, early high fat feeding increased adipocyte size and number, whereas these effects were absent at 84 or 112？d after parturition. At 126？d after parturition, there were no detectable transcript differences in PPARγ or C/EBPα. However, rodents provided HFD in early adolescence exhibited lower expression of canonical Wnt signaling intermediates. Corresponding with these changes was a marked reduction in AT-specific inflammation, as well as overall improvement in systemic glucose, lipid, and inflammatory homeostasis. Taken together, these data indicate that dietary regulation of adipocyte recruitment in adolescence may represent a major determinant of obesity phenotype. 1. Introduction Obesity is commonly associated with the development of type 2 diabetes mellitus (T2DM) [1]. However, the occurrence of diabetic complications in obese subjects is highly variable. In fact, epidemiological data have indicated that ~30% of the obese population is classified as metabolically healthy but obese (MHO) [2, 3], which is characterized by normal insulin sensitivity and inflammatory profile regardless of excess body fat [4, 5]. Alternatively, there is a subgroup of normal weight subjects that exhibit metabolic dysfunction without increased adiposity [6, 7]. As such, the underlying factors involved in the development of obesity-related disease are poorly understood. Fat cell recruitment is a coordinately regulated process that involves activation of proadipogenic transcription factors, including peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT-enhancer-binding protein-α (C/EBPα) [8, 9], as well as inhibition of antiadipogenic signals, including the canonical Wnt/β-catenin pathway [8, 10]. Thiazolidinediones (TZDs) represent a class of antidiabetic drugs that function through regulation of these pro- and antiadipogenic pathways [11, 12]. Similarly,
References
[1]
S. Smyth and A. Heron, “Diabetes and obesity: the twin epidemics,” Nature Medicine, vol. 12, no. 1, pp. 75–80, 2006.
[2]
J. L. Shea, E. W. Randell, and G. Sun, “The prevalence of metabolically healthy obese subjects defined by BMI and dual-energy X-ray absorptiometry,” Obesity, vol. 19, no. 3, pp. 624–630, 2011.
[3]
R. P. Wildman, P. Muntner, K. Reynolds et al., “The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999–2004),” Archives of Internal Medicine, vol. 168, no. 15, pp. 1617–1624, 2008.
[4]
N. Stefan, K. Kantartzis, J. Machann et al., “Identification and characterization of metabolically benign obesity in humans,” Archives of Internal Medicine, vol. 168, no. 15, pp. 1609–1616, 2008.
[5]
M. J. Shin, Y. J. Hyun, O. Y. Kim, J. Y. Kim, Y. Jang, and J. H. Lee, “Weight loss effect on inflammation and LDL oxidation in metabolically healthy but obese (MHO) individuals: low inflammation and LDL oxidation in MHO women,” International Journal of Obesity, vol. 30, no. 10, pp. 1529–1534, 2006.
[6]
R. Kelishadi, S. R. Cook, M. E. Motlagh et al., “Metabolically obese normal weight and phenotypically obese metabolically normal youths: The CASPIAN Study,” Journal of the American Dietetic Association, vol. 108, no. 1, pp. 82–90, 2008.
[7]
E. Succurro, M. A. Marini, S. Frontoni et al., “Insulin secretion in metabolically obese, but normal weight, and in metabolically healthy but obese individuals,” Obesity, vol. 16, no. 8, pp. 1881–1886, 2008.
[8]
S. E. Ross, N. Hemati, K. A. Longo et al., “Inhibition of adipogenesis by Wnt signaling,” Science, vol. 289, no. 5481, pp. 950–953, 2000.
[9]
M. Kawai, S. Mushiake, K. Bessho, et al., “Wnt/Lrp/beta-catenin signaling suppresses adipogenesis by inhibiting mutual activation of PPARgamma and C/EBPalpha,” Biochemical and Biophysical Research Communications, vol. 363, no. 2, pp. 276–282, 2007.
[10]
C. N. Bennett, S. E. Ross, K. A. Longo et al., “Regulation of Wnt signaling during adipogenesis,” The Journal of Biological Chemistry, vol. 277, no. 34, pp. 30998–31004, 2002.
[11]
B. Gustafson, B. Eliasson, and U. Smith, “Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: a link with osteogenesis,” Diabetologia, vol. 53, no. 3, pp. 536–540, 2010.
[12]
D. Luand and D. A. Carson, “Repression of beta-catenin signaling by PPAR gamma ligands,” European Journal of Pharmacology, vol. 636, no. 1–3, pp. 198–202, 2010.
[13]
A. Vidal-Puig, M. Jimenez-Li？an, B. B. Lowell et al., “Regulation of PPAR γ gene expression by nutrition and obesity in rodents,” Journal of Clinical Investigation, vol. 97, no. 11, pp. 2553–2561, 1996.
[14]
J. R. Chen, O. P. Lazarenko, X. Wu, et al., “Obesity reduces bone density associated with activation of PPARgamma and suppression of Wnt/beta-catenin in rapidly growing male rats,” PLoS ONE, vol. 5, no. 10, Article ID e13704, 2010.
[15]
I. Karagiannides, T. Tchkonia, D. E. Dobson et al., “Altered expression of C/EBP family members results in decreased adipogenesis with aging,” American Journal of Physiology, vol. 280, no. 6, pp. R1772–R1780, 2001.
[16]
B. M. Schipper, K. G. Marra, W. Zhang, A. D. Donnenberg, and J. P. Rubin, “Regional anatomic and age effects on cell function of human adipose-derived stem cells,” Annals of Plastic Surgery, vol. 60, no. 5, pp. 538–544, 2008.
[17]
K. L. Spalding, E. Arner, P. O. Westermark et al., “Dynamics of fat cell turnover in humans,” Nature, vol. 453, no. 7196, pp. 783–787, 2008.
[18]
J. L. Knittle, K. Timmers, and F. Ginsberg-Fellner, “The growth of adipose tissue in children and adolescents. Cross-sectional and longitudinal studies of adipose cell number and size,” Journal of Clinical Investigation, vol. 63, no. 2, pp. 239–246, 1979.
[19]
J. B. Prins and S. O'Rahilly, “Regulation of adipose cell number in man,” Clinical Science, vol. 92, no. 1, pp. 3–11, 1997.
[20]
A. Okuno, H. Tamemoto, K. Tobe et al., “Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats,” Journal of Clinical Investigation, vol. 101, no. 6, pp. 1354–1361, 1998.
[21]
S. Sugii, P. Olson, D. D. Sears, et al., “PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 52, pp. 22504–22509, 2009.
[22]
P. D. Berk, S. L. Zhou, C. L. Kiang, D. Stump, M. Bradbury, and L. M. Isola, “Uptake of long chain free fatty acids is selectively up-regulated in adipocytes of zucker rats with genetic obesity and non-insulin-dependent diabetes mellitus,” The Journal of Biological Chemistry, vol. 272, no. 13, pp. 8830–8835, 1997.
[23]
R. Peterson, “The Zucker Diabetic fatty (ZDF) rat—lessons from a leptin receptor defect diabetic model,” in Animal Models of Diabetes, Frontiers in Research, E. Shafrir, Ed., pp. 103–118, CRC Press, Boca Raton, Fla, USA, 2008.
[24]
B. Wagoner, D. B. Hausman, and R. B. S. Harris, “Direct and indirect effects of leptin on preadipocyte proliferation and differentiation,” American Journal of Physiology, vol. 290, no. 6, pp. R1557–R1564, 2006.
[25]
S. Reinwald, R. G. Peterson, M. R. Allen, and D. B. Burr, “Skeletal changes associated with the onset of type 2 diabetes in the ZDF and ZDSD rodent models,” American Journal of Physiology, vol. 296, no. 4, pp. E765–E774, 2009.
[26]
P. C. Hughes and J. M. Tanner, “The assessment of skeletal maturity in the growing rat,” Journal of Anatomy, vol. 106, no. 2, pp. 371–402, 1970.
[27]
J. N. Artaza, S. Bhasin, C. Mallidis, W. Taylor, K. Ma, and N. F. Gonzalez-Cadavid, “Endogenous expression and localization of myostatin and its relation to myosin heavy chain distribution in C2C12 skeletal muscle cells,” Journal of Cellular Physiology, vol. 190, no. 2, pp. 170–179, 2002.
[28]
B. Gustafson and U. Smith, “Cytokines promote Wnt signaling and inflammation and impair the normal differentiation and lipid accumulation in 3T3-L1 preadipocytes,” The Journal of Biological Chemistry, vol. 281, no. 14, pp. 9507–9516, 2006.
[29]
J. L. Shea, E. W. Randell, and G. Sun, “The prevalence of metabolically healthy obese subjects defined by BMI and dual-energy X-ray absorptiometry,” Obesity, vol. 19, no. 3, pp. 624–630, 2011.
[30]
E. A. Sims, “Characterization of the syndromes of obesity,” in Diabetes Mellitus and Obesity, B. N. Brodoff and S. J. Bleicher, Eds., pp. 219–226, Williams & Wilkins, London, UK, 1982.
[31]
G. V. Denisand and M. S. Obin, “‘Metabolically healthy obesity’: origins and implications,” Molecular Aspects of Medicine, vol. 34, no. 1, pp. 59–70, 2013.
[32]
J. Y. Kim, E. Van De Wall, M. Laplante et al., “Obesity-associated improvements in metabolic profile through expansion of adipose tissue,” Journal of Clinical Investigation, vol. 117, no. 9, pp. 2621–2637, 2007.
[33]
C. J. De Souza, M. Eckhardt, K. Gagen et al., “Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance,” Diabetes, vol. 50, no. 8, pp. 1863–1871, 2001.
[34]
B. Gustafson and U. Smith, “Activation of canonical wingless-type MMTV integration site family (Wnt) signaling in mature adipocytes increases β-catenin levels and leads to cell dedifferentiation and insulin resistance,” The Journal of Biological Chemistry, vol. 285, no. 18, pp. 14031–14041, 2010.
[35]
T. B. Koenen, C. J. Tack, J. M. Kroese et al., “Pioglitazone treatment enlarges subcutaneous adipocytes in insulin-resistant patients,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 11, pp. 4453–4457, 2009.
[36]
T. McLaughlin, A. Sherman, P. Tsao et al., “Enhanced proportion of small adipose cells in insulin-resistant vs insulin-sensitive obese individuals implicates impaired adipogenesis,” Diabetologia, vol. 50, no. 8, pp. 1707–1715, 2007.
[37]
E. Fabbrini, F. Magkos, B. S. Mohammed et al., “Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 36, pp. 15430–15435, 2009.
[38]
B. Srdic, E. Stokic, A. Korac, et al., “Morphological characteristics of abdominal adipose tissue in normal-weight and obese women of different metabolic profiles,” Experimental and Clinical Endocrinology & Diabetes, vol. 118, no. 10, pp. 713–718, 2010.
[39]
G. P. Ravelli, Z. A. Stein, and M. W. Susser, “Obesity in young men after famine exposure in utero and early infancy,” The New England Journal of Medicine, vol. 295, no. 7, pp. 349–353, 1976.
[40]
M. F. Rolland Cachera, M. Deheeger, and F. Bellisle, “Adiposity rebound in children: a simple indicator for predicting obesity,” American Journal of Clinical Nutrition, vol. 39, no. 1, pp. 129–135, 1984.
[41]
C. G. Brook, J. K. Lloyd, and O. H. Wolf, “Relation between age of onset of obesity and size and number of adipose cells,” British Medical Journal, vol. 2, no. 5804, pp. 25–27, 1972.
[42]
E. Pouteau, S. Turner, O. Aprikian et al., “Time course and dynamics of adipose tissue development in obese and lean Zucker rat pups,” International Journal of Obesity, vol. 32, no. 4, pp. 648–657, 2008.
[43]
K. Hotta, N. L. Bodkin, T. A. Gustafson, S. Yoshioka, H. K. Ortmeyer, and B. C. Hansen, “Age-related adipose tissue mRNA expression of ADD1/SREBP1, PPARγ, lipoprotein lipase, and GLUT4 glucose transporter in rhesus monkeys,” Journals of Gerontology A, vol. 54, no. 5, pp. B183–B188, 1999.
[44]
X. Yang, P. A. Jansson, I. Nagaev, et al., “Evidence of impaired adipogenesis in insulin resistance,” Biochemical and Biophysical Research Communications, vol. 317, no. 4, pp. 1045–1051, 2004.
[45]
P. Isakson, A. Hammarstedt, B. Gustafson, and U. Smith, “Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor-α, and inflammation,” Diabetes, vol. 58, no. 7, pp. 1550–1557, 2009.
[46]
B. Gustafson, S. Gogg, S. Hedjazifar, et al., “Inflammation and impaired adipogenesis in hypertrophic obesity in man,” American Journal of Physiology, vol. 297, no. 5, pp. E999–E1003, 2009.
