Abstract
Obesity is characterized by an excessive body mass, but is also closely associated with metabolic syndrome. And, so far, only limited pharmacological treatments are available for obesity management. Celastrol, a pentacyclic triterpenoid from a traditional Chinese medicine (Tripterygium wilfordii Hook.f.), has shown remarkable potency against obesity, inflammation and cancer, but its high toxicity, low natural abundance and tedious chemical synthesis hindered its translation into clinics. In the present work, a triterpenoid library was screened for compounds with both high natural abundance and structural similarity to celastrol; from this library, glycyrrhetinic acid (GA), a compound present in extremely high yields in Glycyrrhiza uralensis Fisch. ex DC., was selected as a possible scaffold for a celastrol mimic active against obesity. A simple chemical modification of GA resulted in GA-02, a derivative that suppressed 68% of food intake in diet-induced obesity mice and led to 26.4% weight loss in 2 weeks. GA-02 plays a role in obesity treatment by re-activating leptin signaling and reducing systemic and, more importantly, hypothalamic inflammation. GA-02 was readily bioavailable with unnoticeable in vitro and in vivo toxicities. The strategy of scaffold search and modification on the basis of bio-content and structural similarity has proved to be a green, economic, efficient and practical way of widening the medicinal applications of “imperfect” bioactive natural compounds.
Highlights
Widespread obesity has attracted vast attention all over the world
Inflammation in metabolic organs is a well-known consequence of obesity (Wellen and Hotamisligil, 2005; Olefsky and Glass, 2010; Lumeng and Saltiel, 2011), but inflammation in hypothalamus precedes the onset of obvious obesity, occuring much earlier than the inflammatory response in peripheral tissues (Thaler et al, 2012)
Intracerebroventricular tumor necrosis factor (TNF) was found to promote food intake and increased body weight in a rodent model (Romanatto et al, 2007); whereas treatment with anti-TNF agents reduced body weight gain under high-fat diet (HFD), TNF receptor-deficient mice were shown resistant to HFDinduced body weight gain (Arruda et al, 2011)
Summary
Widespread obesity has attracted vast attention all over the world. Based on statistics from the World Health Organization, there were over 1.9 billion people over-weighted and 650 million were obese in 2016 (World Health Organization, 2021). Intracerebroventricular tumor necrosis factor (TNF) was found to promote food intake and increased body weight in a rodent model (Romanatto et al, 2007); whereas treatment with anti-TNF agents reduced body weight gain under HFD, TNF receptor-deficient mice were shown resistant to HFDinduced body weight gain (Arruda et al, 2011). All these results suggest that suppressing hypothalamic inflammation might be a key towards new approaches for treating obesity
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