Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

Nigel Irwin, IA Montgomery, Peter Flatt

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9 Citations (Scopus)

Abstract

AIMS/HYPOTHESIS: Cholecystokinin (CCK) and leptin are important hormones with effects on energy balance. The present study assessed the biological effects of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, smaller isoforms of CCK and leptin, respectively.METHODS: The actions and overall therapeutic use of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, alone and in combination, were evaluated in normal and high-fat-fed mice.RESULTS: (pGlu-Gln)-CCK-8 had prominent (p <0.01 to p <0.001), acute feeding-suppressive effects, which were significantly augmented (p <0.05 to p <0.01) by [D-Leu-4]-OB3. In agreement, the acute dose-dependent glucose-lowering and insulinotropic actions of (pGlu-Gln)-CCK-8 were significantly enhanced by concurrent administration of [D-Leu-4]-OB3. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in high-fat-fed mice for 18 days decreased body weight (p <0.05 to p <0.001), energy intake (p <0.01), circulating triacylglycerol (p <0.01), non-fasting glucose (p <0.05 to p <0.001) and triacylglycerol deposition in liver and adipose tissue (p <0.001). All treatment regimens improved glucose tolerance (p <0.05 to p <0.001) and insulin sensitivity (p <0.001). Combined treatment with (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3 resulted in significantly lowered plasma insulin levels, normalisation of circulating LDL-cholesterol and decreased triacylglycerol deposition in muscle. These effects were superior to either treatment regimen alone. There were no changes in overall locomotor activity or respiratory exchange ratio, but treatment with (pGlu-Gln)-CCK-8 significantly reduced (p <0.001) energy expenditure.CONCLUSIONS/INTERPRETATION: These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in the treatment of obesity and diabetes.
LanguageEnglish
Pages1425-1435
JournalDiabetologia
Volume56
Issue number6
DOIs
Publication statusPublished - 13 Mar 2013

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leptin (116-130)
Leptin
Fats
Energy Intake
Triglycerides
Cholecystokinin
Glucose
Therapeutics
cholecystokinin 8
Therapeutic Uses
Locomotion
LDL Cholesterol
Energy Metabolism
Insulin Resistance
Adipose Tissue

Cite this

@article{3802e36c77a841a6bd4e491fce3c0d41,
title = "Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice",
abstract = "AIMS/HYPOTHESIS: Cholecystokinin (CCK) and leptin are important hormones with effects on energy balance. The present study assessed the biological effects of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, smaller isoforms of CCK and leptin, respectively.METHODS: The actions and overall therapeutic use of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, alone and in combination, were evaluated in normal and high-fat-fed mice.RESULTS: (pGlu-Gln)-CCK-8 had prominent (p <0.01 to p <0.001), acute feeding-suppressive effects, which were significantly augmented (p <0.05 to p <0.01) by [D-Leu-4]-OB3. In agreement, the acute dose-dependent glucose-lowering and insulinotropic actions of (pGlu-Gln)-CCK-8 were significantly enhanced by concurrent administration of [D-Leu-4]-OB3. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in high-fat-fed mice for 18 days decreased body weight (p <0.05 to p <0.001), energy intake (p <0.01), circulating triacylglycerol (p <0.01), non-fasting glucose (p <0.05 to p <0.001) and triacylglycerol deposition in liver and adipose tissue (p <0.001). All treatment regimens improved glucose tolerance (p <0.05 to p <0.001) and insulin sensitivity (p <0.001). Combined treatment with (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3 resulted in significantly lowered plasma insulin levels, normalisation of circulating LDL-cholesterol and decreased triacylglycerol deposition in muscle. These effects were superior to either treatment regimen alone. There were no changes in overall locomotor activity or respiratory exchange ratio, but treatment with (pGlu-Gln)-CCK-8 significantly reduced (p <0.001) energy expenditure.CONCLUSIONS/INTERPRETATION: These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in the treatment of obesity and diabetes.",
author = "Nigel Irwin and IA Montgomery and Peter Flatt",
year = "2013",
month = "3",
day = "13",
doi = "10.1007/s00125-013-2878-0",
language = "English",
volume = "56",
pages = "1425--1435",
journal = "Diabetologia",
issn = "0012-186X",
number = "6",

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TY - JOUR

T1 - Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

AU - Irwin, Nigel

AU - Montgomery, IA

AU - Flatt, Peter

PY - 2013/3/13

Y1 - 2013/3/13

N2 - AIMS/HYPOTHESIS: Cholecystokinin (CCK) and leptin are important hormones with effects on energy balance. The present study assessed the biological effects of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, smaller isoforms of CCK and leptin, respectively.METHODS: The actions and overall therapeutic use of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, alone and in combination, were evaluated in normal and high-fat-fed mice.RESULTS: (pGlu-Gln)-CCK-8 had prominent (p <0.01 to p <0.001), acute feeding-suppressive effects, which were significantly augmented (p <0.05 to p <0.01) by [D-Leu-4]-OB3. In agreement, the acute dose-dependent glucose-lowering and insulinotropic actions of (pGlu-Gln)-CCK-8 were significantly enhanced by concurrent administration of [D-Leu-4]-OB3. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in high-fat-fed mice for 18 days decreased body weight (p <0.05 to p <0.001), energy intake (p <0.01), circulating triacylglycerol (p <0.01), non-fasting glucose (p <0.05 to p <0.001) and triacylglycerol deposition in liver and adipose tissue (p <0.001). All treatment regimens improved glucose tolerance (p <0.05 to p <0.001) and insulin sensitivity (p <0.001). Combined treatment with (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3 resulted in significantly lowered plasma insulin levels, normalisation of circulating LDL-cholesterol and decreased triacylglycerol deposition in muscle. These effects were superior to either treatment regimen alone. There were no changes in overall locomotor activity or respiratory exchange ratio, but treatment with (pGlu-Gln)-CCK-8 significantly reduced (p <0.001) energy expenditure.CONCLUSIONS/INTERPRETATION: These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in the treatment of obesity and diabetes.

AB - AIMS/HYPOTHESIS: Cholecystokinin (CCK) and leptin are important hormones with effects on energy balance. The present study assessed the biological effects of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, smaller isoforms of CCK and leptin, respectively.METHODS: The actions and overall therapeutic use of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, alone and in combination, were evaluated in normal and high-fat-fed mice.RESULTS: (pGlu-Gln)-CCK-8 had prominent (p <0.01 to p <0.001), acute feeding-suppressive effects, which were significantly augmented (p <0.05 to p <0.01) by [D-Leu-4]-OB3. In agreement, the acute dose-dependent glucose-lowering and insulinotropic actions of (pGlu-Gln)-CCK-8 were significantly enhanced by concurrent administration of [D-Leu-4]-OB3. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in high-fat-fed mice for 18 days decreased body weight (p <0.05 to p <0.001), energy intake (p <0.01), circulating triacylglycerol (p <0.01), non-fasting glucose (p <0.05 to p <0.001) and triacylglycerol deposition in liver and adipose tissue (p <0.001). All treatment regimens improved glucose tolerance (p <0.05 to p <0.001) and insulin sensitivity (p <0.001). Combined treatment with (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3 resulted in significantly lowered plasma insulin levels, normalisation of circulating LDL-cholesterol and decreased triacylglycerol deposition in muscle. These effects were superior to either treatment regimen alone. There were no changes in overall locomotor activity or respiratory exchange ratio, but treatment with (pGlu-Gln)-CCK-8 significantly reduced (p <0.001) energy expenditure.CONCLUSIONS/INTERPRETATION: These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in the treatment of obesity and diabetes.

U2 - 10.1007/s00125-013-2878-0

DO - 10.1007/s00125-013-2878-0

M3 - Article

VL - 56

SP - 1425

EP - 1435

JO - Diabetologia

T2 - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 6

ER -