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


METHODS
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.


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
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.
Hui
D Y
DY
Department of Pathology and Laboratory Medicine, Genome Research Institute, University of Cincinnati College of Medicine, 2120 E. Galbraith Road, Cincinnati, OH 45237-0507, USA. david.hui@uc.edu
Cope
M J
MJ
Labonté
E D
ED
Chang
H-T
HT
Shao
J
J
Goka
E
E
Abousalham
A
A
Charmot
D
D
Buysse
J
J
D000818:Animals; D019440:Anti-Obesity Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001646:Bile / Q000187:drug effects / Q000201:enzymology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D018938:Caco-2 Cells; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004041:Dietary Fats / Q000008:administration & dosage; D004435:Eating / Q000187:drug effects; D018149:Glucose Intolerance / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D054500:Group IB Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology*; D008246:Lysophospholipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D019518:Postprandial Period; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
D019440:Anti-Obesity Agents; D001713:Biphenyl Compounds; D004040:Dietary Carbohydrates; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007211:Indoles; D008246:Lysophospholipids; D011994:Recombinant Proteins; C546301:methyl indoxam; D054500:Group IB Phospholipases A2