title: Treatment of genetically obese mice with the iminosugar N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin reduces body weight by decreasing food intake and increasing fat oxidation.
abstract: Obesity and its associated conditions such as type 2 diabetes mellitus are major causes of morbidity and mortality. The iminosugar N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin (AMP-DNM) improves insulin sensitivity in rodent models of insulin resistance and type 2 diabetes mellitus. In the current study, we characterized the impact of AMP-DNM on substrate oxidation patterns, food intake, and body weight gain in obese mice. Eight ob/ob mice treated with 100 mg/(kg d) AMP-DNM mixed in the food and 8 control ob/ob mice were placed in metabolic cages during the first, third, and fifth week of the experiment for measurement of substrate oxidation rates, energy expenditure, activity, and food intake. Mice were killed after 6 weeks of treatment. Initiation of treatment with AMP-DNM resulted in a rapid increase in fat oxidation by 129% (P = .05), a decrease in carbohydrate oxidation by 35% (P = .01), and a reduction in food intake by approximately 26% (P < .01) compared with control mice. Treatment with AMP-DNM decreased hepatic triglyceride content by 66% (P < .01) and, in line with the elevated fat oxidation rates, increased hepatic carnitine palmitoyl transferase 1a expression. Treatment with AMP-DNM increased plasma levels of the appetite-regulating peptide YY compared with control mice. Treatment with AMP-DNM rapidly reduces food intake and increases fat oxidation, resulting in improvement of the obese phenotype. These features of AMP-DNM, together with its insulin-sensitizing capacity, make it an attractive candidate drug for the treatment of obesity and its associated metabolic derangements.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 9, Amsterdam, the Netherlands. m.langeveld@amc.uva.nl
authors.forename: Mirjam
authors.initials: M
authors.lastname: Langeveld
authors.forename: Sjoerd A A
authors.initials: SA
authors.lastname: van den Berg
authors.forename: Nora
authors.initials: N
authors.lastname: Bijl
authors.forename: Silvia
authors.initials: S
authors.lastname: Bijland
authors.forename: Cindy P
authors.initials: CP
authors.lastname: van Roomen
authors.forename: Judith H
authors.initials: JH
authors.lastname: Houben-Weerts
authors.forename: Roelof
authors.initials: R
authors.lastname: Ottenhoff
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.forename: Ko Willems
authors.initials: KW
authors.lastname: van Dijk
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Romijn
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Aerts
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Voshol
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D050260:Carbohydrate Metabolism / Q000187:drug effects; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D004435:Eating / Q000187:drug effects*; D054439:Ghrelin / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D050111:Imino Sugars / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D019894:Peptide YY / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
chemical_list: D054439:Ghrelin; D050111:Imino Sugars; C496281:N-(5-adamantane-1-yl-methoxy-pentyl)deoxynojirimycin; D014280:Triglycerides; D019894:Peptide YY; D017485:1-Deoxynojirimycin; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose; D000218:Adamantane