A retinoid X receptor antagonist, HX531, improves leptin resistance without increasing plasma leptin level in KK-Ay mice under normal dietary conditions.
4-(5 H -2,3-(2,5-Dimethyl-2,5-hexano)-5-methyl-8-nitrodibenzo[b,e][1,4]diazepin-11-yl)benzoic acid (HX531) is a novel retinoid X receptor antagonist. This study provides evidence that HX531 improves leptin resistance without increasing plasma leptin levels in KK-A y mice, an animal model with high plasma leptin levels and leptin resistance. Under normal dietary conditions, 3 weeks of treatment with HX531 (0.03% and 0.06% food admixture) in KK-A y mice decreased plasma leptin levels in a dose- and time-dependent manner, in addition to decreasing body weight and mesenteric fatty tissue weight. To evaluate the effect of HX531 on leptin resistance, leptin was injected intraperitoneally in the KK-A y mice for 4 days after 1 week of treatment with HX531 (0.06% food admixture). This pretreatment with HX531 resulted in exogenously administered leptin causing a significant decrease in food intake. These results suggested that HX531 decreased plasma leptin levels accompanied by a decrease in fatty tissue content in the KK-A y mice and a simultaneous improvement in leptin resistance. This is the first report that HX531 improves leptin resistance without increasing plasma leptin level in KK-A y mice, under normal dietary conditions.
Yotsumoto
Takashi
T
Biological research Laboratories, Nissan Chemical Industries Ltd., Saitama 349-0294, Japan. yotsumotot@nissanchem.co.jp
Naitoh
Takeshi
T
Kanaki
Tatsuro
T
Tsuruzoe
Nobutomo
N
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004032:Diet; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005508:Food Deprivation; D020738:Leptin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008643:Mesentery; D051379:Mice; D008815:Mice, Inbred Strains; D012007:Rectum / Q000503:physiopathology; D047488:Retinoid X Receptors / Q000037:antagonists & inhibitors*
D001565:Benzoates; D001713:Biphenyl Compounds; D020738:Leptin; D047488:Retinoid X Receptors; C438269:diazepinylbenzoic acid; D020155:3-Hydroxybutyric Acid