GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet.
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.
McClean
Paula L
PL
School of Biomedical Sciences, Univ. of Ulster, Coleraine, Northern Ireland, BT52 1SA, United Kingdom.
Irwin
Nigel
N
Cassidy
Roslyn S
RS
Holst
Jens J
JJ
Gault
Victor A
VA
Flatt
Peter R
PR
D054392:Adipokines / Q000097:blood; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology* / Q000627:therapeutic use; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D018149:Glucose Intolerance / Q000097:blood / Q000378:metabolism; D054795:Incretins / Q000097:blood; D007328:Insulin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000032:analysis / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors*
D054392:Adipokines; D019440:Anti-Obesity Agents; D001786:Blood Glucose; D004041:Dietary Fats; D054795:Incretins; D007328:Insulin; D008055:Lipids; D011964:Receptors, Gastrointestinal Hormone; C479120:glucose-dependent insulinotropic polypeptide, Pro(3)-; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C041086:gastric inhibitory polypeptide receptor; D003345:Corticosterone