Link between GIP and osteopontin in adipose tissue and insulin resistance.
Low-grade inflammation in obesity is associated with accumulation of the macrophage-derived cytokine osteopontin (OPN) in adipose tissue and induction of local as well as systemic insulin resistance. Since glucose-dependent insulinotropic polypeptide (GIP) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate OPN expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13 ± 0.04 vs. 0.04 ± 0.01, P < 0.05) and correlated inversely with measures of insulin sensitivity (r = -0.24, P = 0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with a lower amount of the exon 9-containing isoform required for transmembrane activity. Carriers of the A allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of the GIPR rs10423928 A allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions.
Department of Clinical Sciences, Diabetes, and Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden.
Emma
E
Ahlqvist
Peter
P
Osmark
Tiina
T
Kuulasmaa
Kasper
K
Pilgaard
Bilal
B
Omar
Charlotte
C
Brøns
Olga
O
Kotova
Anna V
AV
Zetterqvist
Alena
A
Stancáková
Anna
A
Jonsson
Ola
O
Hansson
Johanna
J
Kuusisto
Timothy J
TJ
Kieffer
Tiinamaija
T
Tuomi
Bo
B
Isomaa
Sten
S
Madsbad
Maria F
MF
Gomez
Pernille
P
Poulsen
Markku
M
Laakso
Eva
E
Degerman
Jussi
J
Pihlajamäki
Nils
N
Wierup
Allan
A
Vaag
Leif
L
Groop
Valeriya
V
Lyssenko
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D053495:Osteopontin / Q000235:genetics; D051381:Rats; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D011964:Receptors, Gastrointestinal Hormone; D053495:Osteopontin; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor