Abstract
Obesity and obesity-related illnesses are global epidemics impacting the health of adults and children. The purpose of the present work is to evaluate a genetically intact obese mouse model that more accurately reflects the impact of aging on diet-induced obesity and type 2 diabetes in humans. Male C57Bl/6J mice consumed either a control diet or one in which 60% kcal were due to lard beginning at 5–6 weeks of age. Body weight and fat measurements were obtained and necropsy performed at 15, 20, 30, and 40 weeks of age. Serum chemistry, histopathology, gene expression of the liver, and renal and hepatic function were also evaluated. In concert with significant increases in percent body fat and weight, mice fed the high-fat versus control diet had significantly increased levels of serum cholesterol. At ages 20 and 30 weeks, serum glucose was significantly higher in obese versus controls, while serum insulin levels were ≥4-fold higher in obese mice at ages 30 and 40 weeks. The effect of age exacerbated the effects of consuming a high-fat diet. In addition to being hyperinsulinemic and leptin resistant, older obese mice exhibited elevated hepatic PAI-1 and downregulation of GLUT4, G6PC, IGFBP-1, and leptin receptor mRNA in the liver, steatosis with subsequent inflammation, glomerular mesangial proliferation, elevated serum ALT, AST, and BUN, and increased numbers of pancreatic islets.
Similar content being viewed by others
References
World Health Organization, Joint WHO/FAO Expert Consultation on Diet, Nutrition, and the Prevention of Chronic Diseases (World Health Organization, Geneva, 2003)
D.M. Muoio, C.B. Newgard, Annu. Rev. Biochem. 75, 367–401 (2006)
P. Poirier, T.D. Giles, G.A. Bray, Y. Hong, J.S. Stern, F.X. Pi-Sunyer, R.H. Eckel, Arterioscler. Thromb. Vasc. Biol. 26(5), 968–976 (2006)
R. Wolk, V.K. Somers, Diabetes Obes. Metab. 8(3), 250–260 (2006)
J.A. Meyerhardt, D. Niedzwiecki, D. Hollis, L.B. Saltz, R.J. Mayer, H. Nelson, R. Whittom, A. Hantel, J. Thomas, C.S. Fuchs, J. Clin. Oncol. 26(25), 4109–4115 (2008)
E.E. Calle, M.J. Thun, Oncogene 23(38), 6365–6378 (2004)
F. Bianchini, R. Kaaks, H. Vainio, Lancet Oncol. 3(9), 565–574 (2002)
G. Reaven, Diabetes Care 26(2), 539–540 (2003)
G. Wilcox, Clin. Biochem. Rev. 26(2), 19–39 (2005)
M. Bullo, P. Garcia-Lorda, I. Megias, J. Salas-Salvado, Obes. Res. 11(4), 525–531 (2003)
T. McLaughlin, F. Abbasi, C. Lamendola, L. Liang, G. Reaven, P. Schaaf, P. Reaven, Circulation 106(23), 2908–2912 (2002)
L. Roytblat, M. Rachinsky, A. Fisher, L. Greemberg, Y. Shapira, A. Douvdevani, S. Gelman, Obes. Res. 8(9), 673–675 (2000)
J.S. Yudkin, C.D. Stehouwer, J.J. Emeis, S.W. Coppack, Arterioscler. Thromb. Vasc. Biol. 19(4), 972–978 (1999)
J.S. Yudkin, S.W. Coppack, K. Bulmer, A. Rawesh, V. Mohamed-Ali, Thromb. Res. 96(1), 1–9 (1999)
A. Dey, A.I. Cederbaum, Hepatology 45(6), 1355–1365 (2007)
Z. Wang, S.D. Hall, J.F. Maya, L. Li, A. Asghar, J.C. Gorski, Br. J. Clin. Pharmacol. 55(1), 77–85 (2003)
K. Yoshinari, S. Takagi, J. Sugatani, M. Miwa, Biol. Pharm. Bull. 29(8), 1634–1638 (2006)
M. Rossmeisl, J.S. Rim, R.A. Koza, L.P. Kozak, Diabetes 52(8), 1958–1966 (2003)
S. Cinti, Prostaglandins Leukot. Essent. Fatty Acids 73(1), 9–15 (2005)
M.W. Schwartz, R.L. Prigeon, S.E. Kahn, M. Nicolson, J. Moore, A. Morawiecki, E.J. Boyko, D. Porte Jr., Diabetes Care 20(9), 1476–1481 (1997)
T. Jiang, Z. Wang, G. Proctor, S. Moskowitz, S.E. Liebman, T. Rogers, M.S. Lucia, J. Li, M. Levi, J. Biol. Chem. 280(37), 32317–32325 (2005)
P.I. Parekh, A.E. Petro, J.M. Tiller, M.N. Feinglos, R.S. Surwit, Metabolism 47(9), 1089–1096 (1998)
S. Lin, T.C. Thomas, L.H. Storlien, X.F. Huang, Int. J. Obes. Relat. Metab. Disord. 24(5), 639–646 (2000)
R.S. Surwit, C.M. Kuhn, C. Cochrane, J.A. McCubbin, M.N. Feinglos, Diabetes 37(9), 1163–1167 (1988)
A.S. Muhlfeld, M.W. Spencer, K.L. Hudkins, E. Kirk, R.C. LeBoeuf, C.E. Alpers, Kidney Int. 66(4), 1393–1402 (2004)
K.L. Townsend, M.M. Lorenzi, E.P. Widmaier, Endocrine 33(2), 176–188 (2008)
National Research Council, Guide for the Care and Use of Laboratory Animals (National Academy Press, Washington, D.C., 1996)
J. Yuan, J. Pharm. Sci. 82(7), 761–763 (1993)
A.J. Bailer, J. Pharmacokinet. Biopharm. 16(3), 303–309 (1988)
H. Karasawa, S. Nagata-Goto, K. Takaishi, Y. Kumagae, Metabolism 58(3), 296–303 (2009)
C.T. Montague, I.S. Farooqi, J.P. Whitehead, M.A. Soos, H. Rau, N.J. Wareham, C.P. Sewter, J.E. Digby, S.N. Mohammed, J.A. Hurst, C.H. Cheetham, A.R. Earley, A.H. Barnett, J.B. Prins, S. O’Rahilly, Nature 387(6636), 903–908 (1997)
S. Grinspoon, T. Gulick, H. Askari, M. Landt, K. Lee, E. Anderson, Z. Ma, L. Vignati, R. Bowsher, D. Herzog, A. Klibanski, J. Clin. Endocrinol. Metab. 81(11), 3861–3863 (1996)
Z.J. Liu, J. Bian, J. Liu, A. Endoh, Horm. Metab. Res. 39(7), 489–494 (2007)
W.A. Banks, A.B. Coon, S.M. Robinson, A. Moinuddin, J.M. Shultz, R. Nakaoke, J.E. Morley, Diabetes 53(5), 1253–1260 (2004)
W.A. Banks, C.R. DiPalma, C.L. Farrell, Peptides 20(11), 1341–1345 (1999)
S.M. Hileman, D.D. Pierroz, H. Masuzaki, C. Bjorbaek, K. El-Haschimi, W.A. Banks, J.S. Flier, Endocrinology 143(3), 775–783 (2002)
J. Wilsey, S. Zolotukhin, V. Prima, P.J. Scarpace, Am. J. Physiol. Regul. Integr. Comp. Physiol. 285(5), R1011–R1020 (2003)
G.R. Steinberg, A. Bonen, D.J. Dyck, Am. J. Physiol. Endocrinol. Metab. 282(3), E593–E600 (2002)
R.B. Ceddia, H.A. Koistinen, J.R. Zierath, G. Sweeney, FASEB J. 16(10), 1163–1176 (2002)
T.H. Schindler, J. Cardenas, J.O. Prior, A.D. Facta, M.C. Kreissl, X.L. Zhang, J. Sayre, M. Dahlbom, J. Licinio, H.R. Schelbert, J. Am. Coll. Cardiol. 47(6), 1188–1195 (2006)
H.C. Fehmann, C. Peiser, H.P. Bode, M. Stamm, P. Staats, C. Hedetoft, R.E. Lang, B. Goke, Peptides 18(8), 1267–1273 (1997)
Y. Tanizawa, S. Okuya, H. Ishihara, T. Asano, T. Yada, Y. Oka, Endocrinology 138(10), 4513–4516 (1997)
J. Seufert, Diabetes 53(Suppl 1), S152–S158 (2004)
S. Soderberg, B. Ahren, M. Eliasson, B. Dinesen, K. Brismar, T. Olsson, Eur. J. Endocrinol. 144(3), 283–290 (2001)
J.M. Holly, A.M. Cotterill, R.C. Jemmott, D. Shears, S. al-Othman, T. Chard, J.A. Wass, Clin. Endocrinol. (Oxf) 34(4), 275–280 (1991)
J. Seufert, T.J. Kieffer, C.A. Leech, G.G. Holz, W. Moritz, C. Ricordi, J.F. Habener, J. Clin. Endocrinol. Metab. 84(2), 670–676 (1999)
D. Chandrasagar, K. Amira, EMBRO Rep. 6(12), 1137–1142 (2005)
L. Qi, M. Saberi, E. Zmuda, Y. Wang, J. Altarejos, X. Zhang, R. Dentin, S. Hedrick, G. Bandyopadhyay, T. Hai, J. Olefsky, M. Montminy, Cell Metab. 9(3), 277–286 (2009)
S. Deng, M. Vatamaniuk, X. Huang, N. Doliba, M.M. Lian, A. Frank, E. Velidedeoglu, N.M. Desai, B. Koeberlein, B. Wolf, C.F. Barker, A. Naji, F.M. Matschinsky, J.F. Markmann, Diabetes 53(3), 624–632 (2004)
K.H. Yoon, S.H. Ko, J.H. Cho, J.M. Lee, Y.B. Ahn, K.H. Song, S.J. Yoo, M.I. Kang, B.Y. Cha, K.W. Lee, H.Y. Son, S.K. Kang, H.S. Kim, I.K. Lee, S. Bonner-Weir, J. Clin. Endocrinol. Metab. 88(5), 2300–2308 (2003)
M. Murray, Curr. Drug Metab. 7(1), 67–81 (2006)
M. Nangaku, Y. Izuhara, N. Usuda, R. Inagi, T. Shibata, S. Sugiyama, K. Kurokawa, C. van Ypersele de Strihou, T. Miyata, Nephrol. Dial. Transplant. 20(12), 2661–2669 (2005)
N. Kambham, G.S. Markowitz, A.M. Valeri, J. Lin, V.D. D’Agati, Kidney Int. 59(4), 1498–1509 (2001)
C. Garcia-Monzon, E. Martin-Perez, O.L. Iacono, M. Fernandez-Bermejo, P.L. Majano, A. Apolinario, E. Larranaga, R. Moreno-Otero, J. Hepatol. 33(5), 716–724 (2000)
R.H. Unger, Y.T. Zhou, Diabetes 50(Suppl 1), S118–S121 (2001)
P. Angulo, Ann. Hepatol. 1(1), 12–19 (2002)
E.Y. Dimova, T. Kietzmann, Thromb. Haemost. 100(6), 992–1006 (2008)
Y. Aso, S. Matsumoto, Y. Fujiwara, K. Tayama, T. Inukai, Y. Takemura, Metabolism 51(4), 471–476 (2002)
K. Landin, L. Stigendal, E. Eriksson, M. Krotkiewski, B. Risberg, L. Tengborn, U. Smith, Metabolism 39(10), 1044–1048 (1990)
M.C. Alessi, D. Bastelica, A. Mavri, P. Morange, B. Berthet, M. Grino, I. Juhan-Vague, Arterioscler. Thromb. Vasc. Biol. 23(7), 1262–1268 (2003)
R. Zhao, X. Ma, G.X. Shen, Mol. Cell. Biochem. 317(1–2), 197–204 (2008)
G.D. Norata, C. Banfi, A. Pirillo, E. Tremoli, A. Hamsten, A.L. Catapano, P. Eriksson, Br. J. Haematol. 127(1), 97–104 (2004)
I.A. Leclercq, J. Field, A. Enriquez, G.C. Farrell, G.R. Robertson, Biochem. Biophys. Res. Commun. 268(2), 337–344 (2000)
M.D. Weltman, G.C. Farrell, P. Hall, M. Ingelman-Sundberg, C. Liddle, Hepatology 27(1), 128–133 (1998)
I.M. Danko, N.A. Chaschin, Exp. Oncol. 27(4), 248–256 (2005)
A.A. Caro, A.I. Cederbaum, Annu. Rev. Pharmacol. Toxicol. 44, 27–42 (2004)
C.S. Lieber, Physiol. Rev. 77(2), 517–544 (1997)
K.C. Kregel, H.J. Zhang, Am. J. Physiol. Regul. Integr. Comp. Physiol. 292(1), R18–R36 (2007)
D.C. Han, M. Isono, S. Chen, A. Casaretto, S.W. Hong, G. Wolf, F.N. Ziyadeh, Kidney Int. 59(4), 1315–1323 (2001)
G. Remuzzi, A. Schieppati, P. Ruggenenti, N. Engl. J. Med. 346(15), 1145–1151 (2002)
S. Zheng, E.C. Carlson, L. Yang, P.M. Kralik, Y. Huang, P.N. Epstein, J. Am. Soc. Nephrol. 19(11), 2077–2085 (2008)
Acknowledgements
We extend our thanks to Drs. Retha Newbold and Susan Elmore for their commentary and careful review of this manuscript. We also sincerely appreciate Dr. Grace Kissling for her assistance with the statistical analyses. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hoffler, U., Hobbie, K., Wilson, R. et al. Diet-induced obesity is associated with hyperleptinemia, hyperinsulinemia, hepatic steatosis, and glomerulopathy in C57Bl/6J mice. Endocr 36, 311–325 (2009). https://doi.org/10.1007/s12020-009-9224-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-009-9224-9