Indirubin, a small molecular deriving from connectivity map (CMAP) screening, ameliorates obesity-induced metabolic dysfunction by enhancing brown adipose thermogenesis and white adipose browning

Abstract

Background: Obesity occurs when the body's energy intake is constantly greater than its energy consumption and the pharmacological enhancing the activity of brown adipose tissue (BAT) and (or) browning of white adipose tissue (WAT) has been considered promising strategies to treat obesity.Methods: In this study, we took a multi-pronged approach to screen UCP1 activators, including in silico predictions, in vitro assays, as well as in vivo experiments. Results: Base on Connectivity MAP (CMAP) screening, we obtained multiple drugs that possess a remarkably correlating gene expression pattern to that of enhancing activity in BAT and (or) sWAT signature. Particularly, we focused on a previously unreported drug-indirubin, a compound obtained from the Indigo plant, which is now mainly used for the treatment of chronic myelogenous leukemia (CML). In the current study, our results shown that indirubin could enhance the BAT activity, as evidenced by up-regulated Ucp1 expression and enhanced mitochondrial respiratory function in vitro cellular model. Furthermore, indirubin treatment restrained high-fat diet (HFD)-induced body weight gain, improved glucose homeostasis and ameliorated hepatic steatosis which were associated with the increase of energy expenditure in the mice model. Moreover, we revealed that indirubin treatment increased BAT activity by promoting thermogenesis and mitochondrial biogenesis in BAT and induced browning of subcutaneous inguinal white adipose tissue (sWAT) of mice under HFD. Besides, our results indicated that indirubin induced UCP1 expression in brown adipocytes, at least in part, via activation of PKA and p38MAPK signaling pathways.(Continued on next page) Conclusions:Our results clearly show that as an effective BAT (as well as beige cells) activator, indirubin may have a protective effect on the prevention and treatment of obesity and its complications.

High fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats

“…1 a). This is most probably due to reduction in adipose tissue mass caused by Indirubin treatment, as reported previously in mice 24 . The percentage of fibrosis also showed significant decrease in skeletal muscle of diabetic rats treated with IHZ.…”

“…Group IV (IHZ) rats received IHZ only at the above mentioned dose. IHZ dose was chosen based on the literature and our previous study 15 , 24 .…”

High fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats

“…1a). This is possibly due to reduction in adipose tissue mass caused by Indirubin treatment as previously reported in mice [24]. The percentage of brosis also showed signi cant decrease in skeletal muscle of diabetic rats treated with IHZ.…”

T-stage-specific abdominal visceral fat, haematological nutrition indicators and inflammation as prognostic factors in patients with clear renal cell carcinoma

“…However, the mechanism underlying regulation of rVFA expression during tumour progression in cells remains unclear. Notably, some studies have suggested that up-regulation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) and uncoupled protein 1 (UCP1) expression in adipose tissues leads to a robust resistance to obesity and related diseases [ 39 , 40 ]. Functionally, the adipose tissue secretes various adipokines and cytokines, which can systemically regulate physiological functions through endocrine-like activity.…”