Abstract
Celastrol is a leptin-sensitizing agent with profound anti-obesity effects in diet-induced obese (DIO) mice. However, the genes and pathways that mediate celastrol-induced leptin sensitization have not been fully understood. By comparing the hypothalamic transcriptomes of celastrol and vehicle-treated DIO mice, we identified lipocalin-2 (Lcn2) as the gene most strongly upregulated by celastrol. LCN2 was previously suggested as an anorexigenic and anti-obesity agent. Celastrol increased LCN2 protein levels in hypothalamus, liver, fat, muscle, and bone marrow, as well as in the plasma. However, genetic deficiency of LCN2 altered neither the development of diet-induced obesity, nor the ability of celastrol to promote weight loss and improve obesity-associated dyshomeostasis. We conclude that LCN2 is dispensable for both high fat diet-induced obesity and its therapeutic reduction by celastrol.
Highlights
Leptin, an adipocyte-derived hormone that suppresses appetite and reduces body weight in leptin deficiency, initially raised hopes for an effective treatment for obesity[4,5,6,7,8,9,10]
Diet-induced obese (DIO) mice were treated with either vehicle or celastrol for four days (100 μg/kg, i.p. injection, once daily); hypothalami were extracted and the mRNA was used for microarray hybridization as previously described[20]
The most effective anti-obesity agent reported to date[15], reduces endoplasmic reticulum (ER) stress, which is a central mechanism involved in the development of leptin resistance and the regulation of feeding and body weight during excess calorie consumption[17,25,26]
Summary
An adipocyte-derived hormone that suppresses appetite and reduces body weight in leptin deficiency, initially raised hopes for an effective treatment for obesity[4,5,6,7,8,9,10]. Oral administration of celastrol reduces the body weight of diet-induced obese (DIO) mice more than 45%, the strongest anti-obesity effect that has been reported to date, and further ameliorates insulin resistance/type-2 diabetes, nonalcoholic steatohepatitis (NASH), hypercholesterolemia, and liver damage in DIO mice[15]. Understanding the mechanism of action of celastrol will provide insights into the underlying biology of leptin signaling and resistance, but will create new avenues for the development of effective therapies for obesity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
