This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Albarado, D. C. Articles by Butler, A. A. Search for Related Content PubMed PubMed Citation Articles by Albarado, D. C. Articles by Butler, A. A.

Impaired Coordination of Nutrient Intake and Substrate Oxidation in Melanocortin-4 Receptor Knockout Mice

Pennington Biomedical Research Center/Louisiana State University (D.C.A., J.M., R.L.M., J.Y., A.A.B.), Baton Rouge, Louisiana 70808; Department of Biological Sciences (J.M.S.), Louisiana State University, Baton Rouge, Louisiana 70803; and Amgen Inc. (A.W.B., W.G.R.), Thousand Oaks, California 91320

Address all correspondence and requests for reprints to: Andrew A. Butler, Ph.D., Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808. E-mail: butleraa{at}pbrc.edu.

Mutations in the melanocortin-4 receptor (MC4R) are associated with obesity. The obesity syndrome observed in humans with MC4R haploinsufficiency is similar to that observed in MC4R knockout mice, including increased longitudinal growth, hyperphagia, and fasting hyperinsulinemia. For comparison with other commonly investigated models of obesity and insulin resistance, we have backcrossed Mc4r-/- mice into the C57BL/6J (B6) background. Female obese Mc4r-/- mice exhibit reduced energy expenditure and an attenuated increase in fatty acid (FA) oxidation after exposure to high-fat diets compared with obese Lep^ob/Lep^ob mice. The reduced energy expenditure and FA oxidation correlates with changes in hepatic gene expression. The expression of genes involved in FA oxidation increased in obese Lep^ob/Lep^ob mice compared with wild-type and obese Mc4r-/- mice. In contrast, a key lipogenic enzyme, FA synthase (FAS), is increased in obese Mc4r-/- mice compared with obese Lep^ob/Lep^ob mice. Hyperinsulinemia, increased FAS mRNA expression and hepatic steatosis appear to be secondary to obesity in B6 Mc4r-/- mice. However, Mc4r-/- mice in a mixed genetic background develop severe hepatic steatosis at an early age. This might suggest an important role of the MC4R in regulating liver FA metabolism that is masked on the B6 background. Interestingly, the 10- to 20-fold increase in liver triglyceride in the outbred strain of Mc4r-/- mice is not always associated with fasting hyperinsulinemia or increased FAS mRNA expression. This observation suggests that changes in liver secondary to triglyceride accumulation lead to hyperinsulinemia and increased hepatic FAS expression in Mc4r-/- mice.

This article has been cited by other articles:

				H. Yang, Y.-H. Youm, B. Vandanmagsar, J. Rood, K. G. Kumar, A. A. Butler, and V. D. Dixit Obesity accelerates thymic aging Blood, October 29, 2009; 114(18): 3803 - 3812. [Abstract] [Full Text] [PDF]

				A. W. Norris, M. F. Hirshman, J. Yao, N. Jessen, N. Musi, L. Chen, W. I. Sivitz, L. J. Goodyear, and C. R. Kahn Endogenous Peroxisome Proliferator-Activated Receptor-{gamma} Augments Fatty Acid Uptake in Oxidative Muscle Endocrinology, November 1, 2008; 149(11): 5374 - 5383. [Abstract] [Full Text] [PDF]

				J. L. Trevaskis, E. A. Meyer, J. E. Galgani, and A. A. Butler Counterintuitive Effects of Double-Heterozygous Null Melanocortin-4 Receptor and Leptin Genes on Diet-Induced Obesity and Insulin Resistance in C57BL/6J Mice Endocrinology, January 1, 2008; 149(1): 174 - 184. [Abstract] [Full Text] [PDF]

				K. L. J. Ellacott, J. G. Murphy, D. L. Marks, and R. D. Cone Obesity-Induced Inflammation in White Adipose Tissue Is Attenuated by Loss of Melanocortin-3 Receptor Signaling Endocrinology, December 1, 2007; 148(12): 6186 - 6194. [Abstract] [Full Text] [PDF]

				M. Lee, A. Kim, S. C. Chua Jr., S. Obici, and S. L. Wardlaw Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E121 - E131. [Abstract] [Full Text] [PDF]

				Z. Gao, Z. Wang, X. Zhang, A. A. Butler, A. Zuberi, B. Gawronska-Kozak, M. Lefevre, D. York, E. Ravussin, H.-R. Berthoud, et al. Inactivation of PKC{theta} leads to increased susceptibility to obesity and dietary insulin resistance in mice Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E84 - E91. [Abstract] [Full Text] [PDF]

				K. L.J Ellacott and R. D Cone The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models Phil Trans R Soc B, July 29, 2006; 361(1471): 1265 - 1274. [Abstract] [Full Text] [PDF]

				G. M. Sutton, J. L. Trevaskis, M. W. Hulver, R. P. McMillan, N. J. Markward, M. J. Babin, E. A. Meyer, and A. A. Butler Diet-Genotype Interactions in the Development of the Obese, Insulin-Resistant Phenotype of C57BL/6J Mice Lacking Melanocortin-3 or -4 Receptors Endocrinology, May 1, 2006; 147(5): 2183 - 2196. [Abstract] [Full Text] [PDF]

				J. L. Trevaskis and A. A. Butler Double Leptin and Melanocortin-4 Receptor Gene Mutations Have an Additive Effect on Fat Mass and Are Associated with Reduced Effects of Leptin on Weight Loss and Food Intake Endocrinology, October 1, 2005; 146(10): 4257 - 4265. [Abstract] [Full Text] [PDF]

				Y. Zhang, G. E Kilroy, T. M. Henagan, V. Prpic-Uhing, W. G. Richards, A. W. Bannon, R. L. Mynatt, and T. W. Gettys Targeted deletion of melanocortin receptor subtypes 3 and 4, but not CART, alters nutrient partitioning and compromises behavioral and metabolic responses to leptin FASEB J, September 1, 2005; 19(11): 1482 - 1491. [Abstract] [Full Text] [PDF]