Inhibition of gastric inhibitory polypeptide signaling prevents obesity.
Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat. Here we describe a novel pathway of obesity promotion via GIP. Wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with insulin resistance. In contrast, mice lacking the GIP receptor (Gipr(-/-)) fed a high-fat diet were clearly protected from both the obesity and the insulin resistance. Moreover, double-homozygous mice (Gipr(-/-), Lep(ob)/Lep(ob)) generated by crossbreeding Gipr(-/-) and obese ob/ob (Lep(ob)/Lep(ob)) mice gained less weight and had lower adiposity than Lep(ob)/Lep(ob) mice. The Gipr(-/-) mice had a lower respiratory quotient and used fat as the preferred energy substrate, and were thus resistant to obesity. Therefore, GIP directly links overnutrition to obesity and it is a potential target for anti-obesity drugs.
Miyawaki
Kazumasa
K
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yamada
Yuichiro
Y
Ban
Nobuhiro
N
Ihara
Yu
Y
Tsukiyama
Katsushi
K
Zhou
Heying
H
Fujimoto
Shimpei
S
Oku
Akira
A
Tsuda
Kinsuke
K
Toyokuni
Shinya
S
Hiai
Hiroshi
H
Mizunoya
Wataru
W
Fushiki
Tohru
T
Holst
Jens Juul
JJ
Makino
Mitsuhiro
M
Tashita
Akira
A
Kobara
Yukari
Y
Tsubamoto
Yoshiharu
Y
Jinnouchi
Takayoshi
T
Jomori
Takahito
T
Seino
Yutaka
Y
D000273:Adipose Tissue / Q000033:anatomy & histology / Q000502:physiology*; D000818:Animals; D001835:Body Weight; D003433:Crosses, Genetic; D004041:Dietary Fats; D005749:Gastric Inhibitory Polypeptide / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000517:prevention & control*; D011964:Receptors, Gastrointestinal Hormone / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D004041:Dietary Fats; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor