GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet
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GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet. / McClean, Paula L; Irwin, Nigel; Cassidy, Roslyn S; Holst, Jens Juul; Gault, Victor A; Flatt, Peter R.
In: American Journal of Physiology: Endocrinology and Metabolism, Vol. 293, No. 6, 12.2007, p. E1746-55.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet
AU - McClean, Paula L
AU - Irwin, Nigel
AU - Cassidy, Roslyn S
AU - Holst, Jens Juul
AU - Gault, Victor A
AU - Flatt, Peter R
PY - 2007/12
Y1 - 2007/12
N2 - The gut hormone gastric inhibitory polypeptide (GIP) plays a key role in glucose homeostasis and lipid metabolism. This study investigated the effects of administration of a stable and specific GIP receptor antagonist, (Pro(3))GIP, in mice previously fed a high-fat diet for 160 days to induce obesity and related diabetes. Daily intraperitoneal injection of (Pro(3))GIP over 50 days significantly decreased body weight compared with saline-treated controls, with a modest increase in locomotor activity but no change of high-fat diet intake. Plasma glucose, glycated hemoglobin, and pancreatic insulin were restored to levels of chow-fed mice, and circulating triglyceride and cholesterol were significantly decreased. (Pro(3))GIP treatment also significantly decreased circulating glucagon and corticosterone, but concentrations of GLP-1, GIP, resistin, and adiponectin were unchanged. Adipose tissue mass, adipocyte hypertrophy, and deposition of triglyceride in liver and muscle were significantly decreased. These changes were accompanied by significant improvement of insulin sensitivity, meal tolerance, and normalization of glucose tolerance in (Pro(3))GIP-treated high-fat-fed mice. (Pro(3))GIP concentrations peaked rapidly and remained elevated 24 h after injection. These data indicate that GIP receptor antagonism using (Pro(3))GIP provides an effective means of countering obesity and related diabetes induced by consumption of a high-fat, energy-rich diet.
AB - The gut hormone gastric inhibitory polypeptide (GIP) plays a key role in glucose homeostasis and lipid metabolism. This study investigated the effects of administration of a stable and specific GIP receptor antagonist, (Pro(3))GIP, in mice previously fed a high-fat diet for 160 days to induce obesity and related diabetes. Daily intraperitoneal injection of (Pro(3))GIP over 50 days significantly decreased body weight compared with saline-treated controls, with a modest increase in locomotor activity but no change of high-fat diet intake. Plasma glucose, glycated hemoglobin, and pancreatic insulin were restored to levels of chow-fed mice, and circulating triglyceride and cholesterol were significantly decreased. (Pro(3))GIP treatment also significantly decreased circulating glucagon and corticosterone, but concentrations of GLP-1, GIP, resistin, and adiponectin were unchanged. Adipose tissue mass, adipocyte hypertrophy, and deposition of triglyceride in liver and muscle were significantly decreased. These changes were accompanied by significant improvement of insulin sensitivity, meal tolerance, and normalization of glucose tolerance in (Pro(3))GIP-treated high-fat-fed mice. (Pro(3))GIP concentrations peaked rapidly and remained elevated 24 h after injection. These data indicate that GIP receptor antagonism using (Pro(3))GIP provides an effective means of countering obesity and related diabetes induced by consumption of a high-fat, energy-rich diet.
KW - Adipokines
KW - Adipose Tissue
KW - Animals
KW - Anti-Obesity Agents
KW - Blood Glucose
KW - Body Weight
KW - Corticosterone
KW - Dietary Fats
KW - Eating
KW - Gastric Inhibitory Polypeptide
KW - Glucagon
KW - Glucagon-Like Peptide 1
KW - Glucose Intolerance
KW - Incretins
KW - Insulin
KW - Insulin Resistance
KW - Lipids
KW - Liver
KW - Male
KW - Mice
KW - Motor Activity
KW - Muscle, Skeletal
KW - Obesity
KW - Pancreas
KW - Receptors, Gastrointestinal Hormone
U2 - 10.1152/ajpendo.00460.2007
DO - 10.1152/ajpendo.00460.2007
M3 - Journal article
C2 - 17848629
VL - 293
SP - E1746-55
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
SN - 0193-1849
IS - 6
ER -
ID: 132049457