Upregulation of adipocyte metabolism by agouti protein: possible
paracrine actions in obesity of the yellow mouse.
Jones, Brynn H., Jung H. Kim, Michael B. Zemel, Richard P. Woychik,
Edward J. Michaud, William O. Wilkison, and Na[diaeresis]ima
Mousta[diaeresis]id.
Department of Nutrition and Physiology Program, University of
Tennessee, 1215 W. Cumberland Avenue. Knoxville TN 37996-1900, Tel:
(615)974-6255, Fax: (615)974-3491, Oak Ridge National Laboratory,
P.O. Box 2009, Oak Ridge, TN 37831-8080, Glaxo Research Institute,
V211 5 Moore Dr., Research Triangle Park, NC 27709
APStracts 2:0220E, 1995.
Mutations leading to ectopic expression of the murine agouti gene (a)
result in progressive obesity. To further characterize this model we
analyzed adipose and hepatic mRNA levels for fatty acid synthase
(FAS) and stearoyl-CoA desaturase (SCD), two key enzymes in de novo
fatty acid synthesis and desaturation, respectively. FAS and SCD mRNA
in both tissues of obese (Avy) mice were dramatically increased
relative to lean (a/a) controls. Excessive expression of these genes
in this model could be due to direct effects of the agouti gene
product; to test this possibility we treated 3T3-L1 adipocytes in
vitro with recombinant agouti protein. Agouti treatment increased FAS
and SCD mRNA levels by 1.5- and 4-fold, respectively. In addition FAS
activity and triglyceride content were 3-fold higher in agouti
-treated 3T3-L1 cells relative to controls; these effects were
attenuated by simultaneous treatment with a calcium channel blocker
(nitrendipine). These data demonstrate that the agouti protein can
directly increase lipogenesis in adipocytes and suggest that these
effects are mediated through a [Ca2+]i-dependent mechanism.
Received 8 September 1995; accepted in final form 25 October
1995.
APS Manuscript Number E438-5.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 6 November 95