Flavopiridol inhibits adipogenesis and improves metabolic homeostasis by ameliorating adipose tissue inflammation in a diet-induced obesity model

• Published in: Biomedicine & pharmacotherapy 2024-10, Vol.179, p.117330, Article 117330
• Main Authors: Varshney, Salil, Kumar, Durgesh, Choudhary, Rakhi, Gupta, Abhishek, Beg, Muheeb, Shankar, Kripa, Rajan, Sujith, Srivastava, Ankita, Gupta, Sanchita, Khandelwal, Nilesh, Balaramnavar, Vishal M., Gaikwad, Anil N.
• Format: Article
• Language: English
• Subjects: 3T3-L1; Anti-adipogenic; Anti-inflammatory; Anti-obesity
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.117330

Repositioning of FDA approved/clinical phase drugs has recently opened a new opportunity for rapid approval of drugs, as it shortens the overall process of drug discovery and development. In previous studies, we predicted the possibility of better activity profiles of flavopiridol, the FDA approved orphan drug with better fit value 2.79 using a common feature pharmacophore model for anti-adipogenic compounds (CFMPA). The present study aimed to investigate the effect of flavopiridol on adipocyte differentiation and to determine the underlying mechanism. Flavopiridol inhibited adipocyte differentiation in different cell models like 3T3-L1, C3H10T1/2, and hMSCs at 150 nM. Flavopiridol was around 135 times more potent than its parent molecule rohitukine. The effect was mediated through down-regulation of key transcription factors of adipogenesis i.e. Peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and their downstream targets, including adipocyte protein −2 (aP2) and fatty acid synthase (FAS). Further, results revealed that flavopiridol arrested the cell cycle in G1/S phase during mitotic clonal expansion by suppressing cell cycle regulatory proteins i.e. Cyclins and CDKs. Flavopiridol inhibited insulin-stimulated signalling in the early phase of adipocyte differentiation by downregulation of AKT/mTOR pathway. In addition, flavopiridol improved mitochondrial function in terms of increased oxygen consumption rate (OCR) in mature adipocytes. In the mouse model of diet-induced obesity, flavopiridol attenuated obesity-associated adipose tissue inflammation and improved serum lipid profile, glucose tolerance as well as insulin sensitivity. In conclusion, the FDA approved drug flavopiridol could be placed as a potential drug candidate for the treatment of cancer and obesity comorbid patients. [Display omitted] •CDKs inhibitor-Flavopiridol is a FDA approved orphan drug for indication of acute myeloid leukaemia.•Flavopiridol inhibited adipocyte differentiation in different cell models of adipogenesis.•Flavopiridol attenuated obesity and adipose tissue inflammation in high-fat diet fed C57BL/6 mice.•Flavopiridol can be the drug of choice for treating patients with obesity and cancer co-morbidities.