The agouti gene product stimulates pancreatic [beta]-cell Ca2+ signaling and insulin release.
Ubiquitous expression of the mouse agouti gene results in obesity and hyperinsulinemia. Human agouti is expressed in adipose tissue, and we found recombinant agouti protein to stimulate lipogenesis in adipocytes in a Ca(2+)-dependent fashion. However, adipocyte-specific agouti transgenic mice only became obese in the presence of hyperinsulinemia. Because intracellular Ca(2+) concentration ([Ca(2+)](i)) is a primary signal for insulin release, and we have shown agouti protein to increase [Ca(2+)](i) in several cell types, we examined the effects of agouti on [Ca(2+)](i) and insulin release. We demonstrated the expression of agouti in human pancreas and generated recombinant agouti to study its effects on Ca(2+) signaling and insulin release. Agouti (100 nM) stimulated Ca(2+) influx, [Ca(2+)](i) increase, and a marked stimulation of insulin release in two beta-cell lines (RIN-5F and HIT-T15; P < 0. 05). Agouti exerted comparable effects in isolated human pancreatic islets and beta-cells, with a 5-fold increase in Ca(2+) influx (P < 0.001) and a 2.2-fold increase in insulin release (P < 0.01). These data suggest a potential role for agouti in the development of hyperinsulinemia in humans.
Xue
B Z
BZ
Department of Nutrition, University of Tennessee, Knoxville, Tennessee 37996, USA.
Wilkison
W O
WO
Mynatt
R L
RL
Moustaid
N
N
Goldman
M
M
Zemel
M B
MB
D054366:Agouti Signaling Protein; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D016257:Fura-2 / Q000031:analogs & derivatives*; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics / Q000503:physiopathology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D036341:Intercellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008345:Manganese / Q000494:pharmacology; D019899:Paracrine Communication / Q000187:drug effects; D011189:Potassium Chloride / Q000378:metabolism / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
C515182:ASIP protein, human; D054366:Agouti Signaling Protein; C515184:Asip protein, rat; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; C515183:a protein, mouse; C049925:fura-2-am; D008345:Manganese; D011189:Potassium Chloride; D005947:Glucose; D002118:Calcium; D016257:Fura-2