Regulation of PPARgamma and obesity by agouti/melanocortin signaling in adipocytes.
To study the potential biological role of agouti/melanocortin signaling in human adipose tissue, we engineered transgenic mice to overexpress agouti in adipose tissue. The aP2-agouti transgenic mice become significantly heavier than littermates. The increased body weight is maintained at approximately 15% above nontransgenic mice through 20 weeks and is caused by increased fat mass. The obesity is increased by a high-fat diet. There is no change in food intake in the aP2-agouti mice suggesting changes in energy utilization. A possible mechanism is that the agouti/melanocortin signaling regulates levels of PPARgamma. PPARgamma functions as a major regulator of adipocyte differentiation and as a receptor for the antidiabetic thiazolidinediones. Agouti increases PPARgamma protein levels in differentiated 3T3-L1 adipocytes, and PPARgamma expression is elevated in the fat pads of the aP2-agouti transgenic mice. The modest weight gain observed in the transgenic mice suggests that hypothalamic pathways regulating food intake are intact and the observed adiposity is within ranges that can be achieved by a paracrine mechanism at the adipocyte level.
Mynatt
Randall L
RL
Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. mynattrl@pbrc.edu
Stephens
Jacquelins M
JM
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology / Q000502:physiology; D054366:Agouti Signaling Protein; D000818:Animals; D001835:Body Weight; D004041:Dietary Fats; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D000521:alpha-MSH / Q000378:metabolism*
D054366:Agouti Signaling Protein; D004041:Dietary Fats; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000521:alpha-MSH