Upregulation of adipocyte metabolism by agouti protein: possible paracrine actions in yellow mouse obesity

• Published in: The American journal of physiology Vol. 270; no. 1; pp. E192 - E196
• Main Authors: Jones, B.H, Kim, J.H, Zemel, M.B, Woychik, R.P, Michaud, E.J, Wilkison, W.O, Moustaid, N
• Format: Journal Article
• Language: English
• Published: United States 1996
• Subjects: a gene; a locus; adipocytes; Adipocytes - metabolism; adipose tissue; agouti protein; Agouti Signaling Protein; Animals; calcium; Cell Line; fatty acid biosynthesis; fatty acid desaturation; Fatty Acid Synthases - antagonists & inhibitors; Fatty Acid Synthases - genetics; Fatty Acid Synthases - metabolism; fatty-acid synthase; Female; Gene Expression; genes; genetic models; inorganic ions; Intercellular Signaling Peptides and Proteins; intracellular calcium dependent mechanism; lipogenesis; liver; Liver - metabolism; Male; messenger RNA; Mice; Mice, Inbred C57BL; Nitrendipine - pharmacology; obesity; Obesity - genetics; Obesity - metabolism; Obesity - pathology; pigmentation; proteins; Proteins - genetics; Proteins - metabolism; Proteins - pharmacology; Recombinant Proteins; Reference Values; RNA, Messenger - metabolism; stearoyl-CoA desaturase; Stearoyl-CoA Desaturase - genetics; triacylglycerols; Triglycerides - antagonists & inhibitors; Triglycerides - metabolism
• ISSN: 0002-9513; 2163-5773
• DOI: 10.1152/ajpendo.1996.270.1.E192

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 an intracellular calcium-dependent mechanism.