Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 94; no. 3; pp. 919 - 922
• Main Authors: Mynatt, R.L, Miltenberger, R.J, Klebig, M.L, Zemel, M.B, Wilkinson, J.E, Wilkison, W.O, Woychik, R.P
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 04.02.1997; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences of the USA
• Subjects: Adipocytes; adipose tissue; Adipose Tissue - physiology; Adipose tissues; agouti gene; Agouti Signaling Protein; animal proteins; Animals; ap2 promoter; Biological Sciences; blood glucose; Body weight; Diabetes Mellitus, Type 2 - genetics; Disease Models, Animal; Gene Expression; Genes; Genetics; Humans; hyperinsulinemia; Hyperinsulinism; Insulin; Insulin - pharmacology; Intercellular Signaling Peptides and Proteins; intravenous injection; liveweight gain; Male; messenger RNA; Mice; Mice, Transgenic; Obesity; Obesity - chemically induced; Obesity - genetics; promoter regions; Proteins; Proteins - genetics; Proteins - physiology; recombinant DNA; RNA, Messenger - analysis; Rodents; simulation; structural genes; Transgenes; Transgenic animals; Weight gain; Weight Gain - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.3.919

The agouti gene product is a secreted protein that acts in a paracrine manner to regulate coat color in mammals. Several dominant mutations at the agouti locus in mice cause the ectopic, ubiquitous expression of agouti, resulting in a condition similar to adult-onset obesity and non-insulin-dependent diabetes mellitus. The human agouti protein is 85% homologous to mouse agouti; however, unlike the mouse agouti gene, human agouti is normally expressed in adipose tissue. To address whether expression of agouti in human adipose tissue is physiologically relevant, transgenic mice were generated that express agouti in adipose tissue. Similar to most humans, these mice do not become obese or diabetic. However, we found that daily insulin injections significantly increased weight gain in the transgenic lines expressing agouti in adipose tissue, but not in nontransgenic mice. These results suggest that insulin triggers the onset of obesity and that agouti expression in adipose tissue potentiates this effect. Accordingly, the investigation of agouti's role in obesity and non-insulin-dependent diabetes mellitus in mice holds significant promise for understanding the pathophysiology of human obesity.