title: Attenuated secretion of glucose-dependent insulinotropic polypeptide (GIP) does not alleviate hyperphagic obesity and insulin resistance inob/obmice.
abstract: Glucose-dependent insulinotropic polypeptide (GIP) is released during meals and promotes nutrient uptake and storage. GIP receptor knockout mice are protected from diet induced weight gain and thus GIP antagonists have been proposed as a treatment for obesity. In this study, we assessed the role of GIP in hyperphagia induced obesity and metabolic abnormalities in leptin deficient (Lepob/ob) mice.
  
  
  
  We crossbred GIP-GFP knock-in homozygous mice (GIPgfp/gfp) that have complete GIP knockout, and mice heterozygous for theobmutation (Lepob/+) mice to generate Lepob/+/GIP+/+, Lepob/ob/GIP+/+, and Lepob/ob/GIPgfp/gfpmice. Male animals were weighed weekly and both oral glucose and insulin tolerance testing were performed to assess glucose homeostasis and circulating profiles of GIP and insulin. Body composition was evaluated by computerized tomography (CT) scan and analyses of indirect calorimetry and locomotor activity were performed.
  
  
  
  Postprandial GIP levels were markedly elevated in Lepob/ob/GIP+/+mice compared to Lepob/+/GIP+/+controls and were undetectable in Lepob/ob/GIPgfp/gfpmice. Insulin levels were equivalently elevated in both Lepob/ob/GIP+/+and Lepob/ob/GIPgfp/gfpmice compared to controls at 8 weeks of age but the hyperinsulinemia was marginally reduced in Lepob/ob/GIPgfp/gfpby 21 weeks, in association with amelioration of glucose intolerance. Both Lepob/ob/GIP+/+and Lepob/ob/GIPgfp/gfpmice remained equivalently insulin resistant. Body weight gain and subcutaneous and visceral fat volume of both Lepob/ob/GIP+/+and Lepob/ob/GIPgfp/gfpmice were significantly higher than that of Lepob/+/GIP+/+mice, while no significant differences were seen between Lepob/ob/GIP+/+and Lepob/ob/GIPgfp/gfpmice. Locomotor activity and energy expenditure were decreased in both Lepob/ob/GIP+/+and Lepob/ob/GIPgfp/gfpmice compared to control Lepob/+/GIP+/+mice, while no significant differences were seen between Lepob/ob/GIP+/+and Lepob/ob/GIPgfp/gfpmice. There was no significant difference in fat oxidation among the three groups. Fat content in liver was significantly lower in Lepob/ob/GIPgfp/gfpcompared to Lepob/ob/GIP+/+mice, while that of control Lepob/+/GIP+/+mice was the lowest.
  
  
  
  Our results indicate that GIP knockout does not prevent excess weight gain and metabolic derangement in hyperphagic leptin deficient mice.
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Shimazu-Kuwahara
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Harada
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yamane
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Joo
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Sankoda
authors.affiliation: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. Electronic address: inagaki@kuhp.kyoto-u.ac.jp.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics* / Q000494:pharmacology* / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance; D006946:Hyperinsulinism; D006963:Hyperphagia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D020738:Leptin / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D005947:Glucose
keywords: CT, computerized tomography; GFP, green fluorescent protein; GIP; GIPR, GIP receptor; Hyperphagia; ITT, insulin tolerance test; Insulin resistance; OGTT, oral glucose tolerance test; Obesity; ob/ob