A retinoid X receptor antagonist, HX531, improves leptin resistance without increasing plasma leptin level in KK-Ay mice under normal dietary conditions.

Abstract	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.
Authors	Takashi Yotsumoto, Takeshi Naitoh, Tatsuro Kanaki, Nobutomo Tsuruzoe
Journal	Metabolism: clinical and experimental (Metabolism) Vol. 54 Issue 5 Pg. 573-8 (May 2005) ISSN: 0026-0495 [Print] United States
PMID	15877285 (Publication Type: Journal Article)
Chemical References	Benzoates Biphenyl Compounds Leptin Retinoid X Receptors diazepinylbenzoic acid 3-Hydroxybutyric Acid
Topics	3-Hydroxybutyric Acid (blood) Adipose Tissue (pathology) Animals Benzoates (pharmacology) Biphenyl Compounds (pharmacology) Body Temperature (drug effects) Body Weight (drug effects) Diabetes Mellitus, Type 2 (metabolism, pathology, physiopathology) Diet Disease Models, Animal Drug Resistance (drug effects) Eating (drug effects) Food Deprivation Leptin (blood, metabolism, pharmacology) Male Mesentery Mice Mice, Inbred Strains Rectum (physiopathology) Retinoid X Receptors (antagonists & inhibitors)

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