The phospholipase A(2) inhibitor methyl indoxam suppresses diet-induced obesity and glucose intolerance in mice.

Abstract

BACKGROUND AND PURPOSE:

Previous results have shown that mice lacking in the group 1B phospholipase A(2) (Pla2g1b) are resistant to obesity and diabetes induced by feeding a diabetogenic high-fat/high-carbohydrate diet. This study examined the potential of using the Pla2g1b inhibitor methyl indoxam as therapy to suppress diet-induced obesity and diabetes.

EXPERIMENTAL APPROACH:

Male C57BL/6 mice were fed the diabetogenic diet with or without methyl indoxam supplementation. Body weight gain, fasting plasma glucose levels, glucose tolerance and postprandial lysophospholipid absorption were compared.

KEY RESULTS:

Wild-type C57BL/6 mice fed the diabetogenic diet without Pla2g1b inhibitor showed 31 and 69% body weight gain after 4 and 10 weeks respectively. These animals also showed elevated plasma glucose levels and were glucose intolerant. In contrast, C57BL/6 mice fed the diabetogenic diet with 90 mg.kg(-1) of methyl indoxam gained only 5% body weight after 10 weeks. These animals were also euglycaemic and displayed normal glucose excursion rates in glucose tolerance test. Methyl indoxam suppression of diet-induced body weight gain and glucose intolerance was correlated with the inhibition of Pla2g1b-mediated postprandial lysophospholipid absorption.

CONCLUSIONS AND IMPLICATIONS:

These results show that oral supplementation of a diabetogenic diet with the Pla2g1b inhibitor methyl indoxam effectively suppresses diet-induced obesity and diabetes in mice. This suggests that Pla2g1b inhibition may be a potentially effective oral therapeutic option for treatment of obesity and diabetes.

• Authors: D Y Hui, M J Cope, E D Labonté, H-T Chang, J Shao, E Goka, A Abousalham, D Charmot, J Buysse
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 157 Issue 7 Pg. 1263-9 (Aug 2009) ISSN: 1476-5381 [Electronic] England
• PMID: 19563529 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Obesity Agents
• Biphenyl Compounds
• Dietary Carbohydrates
• Dietary Fats
• Hypoglycemic Agents
• Indoles
• Lysophospholipids
• Recombinant Proteins
• methyl indoxam
• Group IB Phospholipases A2

Topics

• Animals
• Anti-Obesity Agents (pharmacokinetics, therapeutic use)
• Bile (drug effects, enzymology)
• Biphenyl Compounds (pharmacology)
• Caco-2 Cells
• Dietary Carbohydrates (administration & dosage)
• Dietary Fats (administration & dosage)
• Eating (drug effects)
• Glucose Intolerance (blood, drug therapy, etiology)
• Group IB Phospholipases A2 (antagonists & inhibitors, genetics, metabolism)
• Humans
• Hydrolysis
• Hypoglycemic Agents (pharmacokinetics, therapeutic use)
• Indoles (pharmacology)
• Lysophospholipids (blood)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Obesity (blood, drug therapy, etiology)
• Postprandial Period
• Recombinant Proteins (antagonists & inhibitors, metabolism)
• Weight Gain (drug effects)