Abstract
The increased prevalence of obesity and associated insulin resistance calls for effective therapeutic treatment of metabolic diseases. The current PPARγ-targeting antidiabetic drugs have undesirable side effects. The present study investigated the anti-diabetic and anti-obesity effects of withaferin A (WFA) in diet-induced obese (DIO) C57BL/6J mice and also the anti-adipogenic effect of WFA in differentiating 3T3- F442A cells. DIO mice were treated with WFA (6 mg/kg) or rosiglitazone (10 mg/kg) for 8 weeks. At the end of the treatment period, metabolic profile, liver function and inflammatory parameters were obtained. Expression of selective genes controlling insulin signaling, inflammation, adipogenesis, energy expenditure and PPARγ phosphorylation-regulated genes in epididymal fats were analyzed. Furthermore, the anti-adipogenic effect of WFA was evaluated in 3T3- F442A cell line. WFA treatment prevented weight gain without affecting food or caloric intake in DIO mice. WFA-treated group also exhibited lower epididymal and mesenteric fat pad mass, an improvement in lipid profile and hepatic steatosis and a reduction in serum inflammatory cytokines. Insulin resistance was reduced as shown by an improvement in glucose and insulin tolerance and serum adiponectin. WFA treatment upregulated selective insulin signaling (insr, irs1, slc2a4 and pi3k) and PPARγ phosphorylation-regulated (car3, selenbp1, aplp2, txnip, and adipoq) genes, downregulated inflammatory (tnf-α and il-6) genes and altered energy expenditure controlling (tph2 and adrb3) genes. In 3T3- F442A cell line, withaferin A inhibited adipogenesis as indicated by a decrease in lipid accumulation in differentiating adipocytes and protein expression of PPARγ and C/EBPα. The effect of rosiglitazone on physiological and lipid profiles, insulin resistance, some genes expression and differentiating adipocytes were markedly different. Our data suggest that WFA is a promising therapeutic agent for both diabetes and obesity.
Highlights
Obesity and its associated metabolic disorders such as type 2 diabetes, dyslipidemia and cardiovascular diseases has become a global epidemic [1]
A previous study has demonstrated that withaferin A (WFA) improves insulin sensitivity and promotes weight loss by acting as a leptin sensitizer [13], while the present study investigated further the insulin sensitizing and anti-obesity effects of WFA
Our results clearly demonstrates that WFA induces beneficial changes in glucose metabolism and lipid profiles, attenuates inflammation and promotes weight loss in diet-induced obese (DIO) mice, all of which contribute to increased insulin sensitivity
Summary
Obesity and its associated metabolic disorders such as type 2 diabetes, dyslipidemia and cardiovascular diseases has become a global epidemic [1]. The exact molecular mechanisms linking obesity to insulin resistance is not completely understood and blood levels of free fatty acids (FFAs) appears to play a vital role in the development of obesity-associated insulin resistance [2]. Clinical studies have shown increased plasma FFA levels in most obese subjects and have associated it to insulin resistance [1, 3]. Thiazolidinedione drugs including rosiglitazone strongly activate PPARγ and are potent insulin-sensitizing agents. These drugs decrease expression of insulin resistance-inducing adipokines including TNF-α, IL-1 and resistin, and increase production of the insulin-sensitizing hormone, adiponectin [8, 9]. Identification of an insulin sensitizing agent with minimal side effects yet effective in modulating energy metabolism is critically needed
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