Activation of the retinoid X receptor suppresses appetite in the rat.
The retinoid X receptor (RXR), a ubiquitously expressed intracellular receptor, regulates pathways controlling glucose, triglycerides, cholesterol, and bile acid metabolism. In addition to its role in those metabolic pathways, we reported that RXR activation with a pan agonist [e.g. LG100268 (LG268)] decreases both body weight gain (BWG) and food consumption (FC) in obese, insulin-resistant rodents. In parallel with those changes in energy balance, we show here that activation of RXR pathways results in adipose tissue remodeling, particularly within sc fat where the rate of apoptosis is increased 5-fold. This change may underlie the selective decrease in fat mass observed in Zucker fatty rats treated with LG268 for 6 wk. Because FC is strongly correlated with BWG in treated animals, we hypothesized that regulation of FC might be the primary mechanism underlying reduced BWG during RXR agonist administration. Importantly, decreased FC is due to decreased meal size, suggestive of induced satiety rather than malaise and/or aversion to food. Furthermore, administration of LG268 directly into the brain via intracerebroventricular injection also reduces FC, BWG, and insulin, whereas the elevation in triglycerides observed after oral administration is absent. The latter observation suggests that RXR actions on energy balance and lipid homeostasis are separable. Therefore, ligand-mediated activation of either an RXR homodimer or an unidentified heterodimeric complex regulates pathways controlling energy balance at least in part via a central nervous system-mediated mechanism.
Ogilvie
Kathleen M
KM
Department of Pharmacology, Ligand Pharmacruticals Inc., San Diego, CA 92121, USA. kogilvie@pfizer.com
Saladin
Régis
R
Nagy
Tim R
TR
Urcan
Mary S
MS
Heyman
Richard A
RA
Leibowitz
Mark D
MD
D000273:Adipose Tissue / Q000166:cytology / Q000503:physiopathology; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis; D001069:Appetite Regulation / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D004435:Eating; D004734:Energy Metabolism; D005260:Female; D005502:Food; D006706:Homeostasis; D007276:Injections, Intraventricular; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology; D009930:Organic Chemicals; D051381:Rats; D011924:Rats, Zucker; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000502:physiology*; D047488:Retinoid X Receptors; D012527:Satiation; D014157:Transcription Factors / Q000819:agonists / Q000502:physiology*; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain
D000924:Anticholesteremic Agents; D007328:Insulin; C423914:LG 268; D008055:Lipids; D009930:Organic Chemicals; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014280:Triglycerides