Syndecan-3 modulates food intake by interacting with the melanocortin/AgRP pathway.
Syndecan-3, expressed in the developing nervous system and adult brain, alters feeding behavior through its interaction with the CNS melanocortin system, which provides critical tonic inhibition of both food intake and body adipose stores. A variety of both in vitro and transgenic data supports the hypothesis that syndecan-3 modulates melanocortin activity via syndecan-3 facilitation of agouti-related protein (AgRP), a competitive antagonist of alpha-melanocyte-stimulating hormone (alpha-MSH) at the melanocortin-3 and -4 receptors. Consistent with this hypothesis, mice lacking syndecan-3, which therefore would be predicted to have less effective AgRP, are more sensitive to inhibition of food intake by the melanocortin agonist MTII. Additionally, we took advantage of the fact that syndecan-3 facilitation of AgRP is limited to when it is bound to the cell membrane. Pharmacologic inhibition of the enzyme that cleaves syndecan-3 from the cell membrane leads to increased food intake in fasted rats, which have elevated levels of AgRP. Furthermore, the shedding process appears to be regulated under physiologic conditions, because a putative inhibitor of the shedding process, tissue inhibitor of metalloprotease-3 (TIMP-3), is increased by food deprivation. These observations contribute to the hypothesis that syndecan-3 regulation of melanocortin signaling contributes to the normal control of energy balance. Collectively, the data suggest that the modulation of melanocortin regulation of energy balance by syndecan-3 is modulated by the action of a TIMP-3-sensitive metalloprotease.
Reizes
Ofer
O
Procter Gamble Pharmaceuticals, Inc, Health Care Research Center, Mason, Ohio 45040, USA. reizes.o@pg.com
Benoit
Stephen C
SC
Strader
April D
AD
Clegg
Deborah J
DJ
Akunuru
Shailaja
S
Seeley
Randy J
RJ
D054369:Agouti-Related Protein; D000818:Animals; D004435:Eating; D005508:Food Deprivation; D036341:Intercellular Signaling Peptides and Proteins; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009074:Melanocyte-Stimulating Hormones / Q000819:agonists / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin / Q000235:genetics / Q000378:metabolism; D044101:Receptors, Melanocortin; D053670:Syndecan-3; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000378:metabolism
C515197:AGRP protein, rat; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D061965:Matrix Metalloproteinase Inhibitors; C470053:Mc3r protein, mouse; D008562:Membrane Glycoproteins; D011506:Proteins; D011509:Proteoglycans; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C508302:Sdc3 protein, mouse; C508303:Sdc3 protein, rat; D053670:Syndecan-3; D019717:Tissue Inhibitor of Metalloproteinase-3; C081720:alpha-MSH (4-10)amide, Ac-Nle(4)-cyclo(Asp(5)-Phe(7)-Lys(10))-; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones; D020782:Matrix Metalloproteinases