AgRP & Syndecan-3

Obesity is a major health concern as reports suggest that more than 50% of U.S. citizens can be characterized as obese. Because complications resulting from obesity include diabetes, high blood pressure, heart disease, and certain cancers, considerable effort has been spent elucidating the mechanisms underlying weight homeostasis and energy expenditure.1

Agouti-Related Protein (AgRP) was originally identified by its homology to Agouti, a protein that regulates coat color and, when ectopically expressed in mouse brain, causes obesity.2,3 AgRP is expressed by a subset of neurons in the hypothalamic arcuate nucleus and stimulates an appetite increase that results from its actions as an antagonist of alpha melanocyte-stimulating hormone (alpha-MSH) on the melanocortin (MC) receptor MC-4.3-5 Recently, Syndecan-3, a cell surface heparan sulfate proteoglycan, has been shown to act as a co-receptor that facilitates interactions between AgRP and MC-4. Syndecans can be shed from the cell surface by matrix metalloproteinases (MMPs), potentially resulting in decreased association with AgRP.6 Pharmacological inhibition of MMP cleavage results in increased food intake in fasted rats, and the MMP inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP-3), and cell surface Syndecan-3 are both upregulated upon fasting.6,7 In addition, treatment with a pharmacological melanocortin agonist (MTII) results in a greater suppression of appetite in Syndecan-3 knockout mice compared to controls.6 These results suggest that changes in the cell surface expression of Syndecan-3 may modulate AgRP/MC-4 interactions and subsequently their roles in feeding behavior.6


  1. Crowley, V.E. et al. (2002) Nat. Rev. Drug Discov. 1:276.
  2. Lu, D. et al. (1994) Nature 371:799.
  3. Ollmann, M.M. et al. (1997) Science 278:135.
  4. Shutter, J.R. et al. (1997) Genes Dev. 11:593.
  5. Fong, T.M. et al. (1997) Biochem. Biophys. Res. Commun. 237:629.
  6. Reizes, O. et al. (2003) Ann. N.Y. Acad. Sci. 994:66.
  7. Reizes, O. et al. (2001) Cell 106:105.