withaferin-a and Obesity

Obesity is not only viewed as a chronic aggressive disorder but is also associated with an increased risk for various diseases. Nonetheless, new anti-obesity drugs are an urgent need since few pharmacological choices are available on the market. Natural compounds have served as templates for drug discovery, whereas modified molecules from the leads identified based on in vitro models often reveal noncorresponding bioactivity between in vitro and in vivo studies. Therefore, to provide inspiration for the exploration of innovative anti-obesity agents, recent discoveries of natural anti-obesity compounds with in vivo evidence have been summarized according to their chemical structures, and the comparable efficacy of these compounds is categorized using animal models. In addition, several synthetic derivatives optimized from the phytochemicals are also provided to discuss medicinal chemistry achievements guided by natural sources.

Topics: Animals; Anti-Obesity Agents; Drug Discovery; Obesity; Phytochemicals

Stress is a state of homeostasis in the body being challenged, resulting in a systemic response. It has become more prevalent in recent years and affects mental and physical health.. Evaluate the effects of ashwagandha on stress, fatigue, and sex hormones in overweight or mildly obese men and women with self-reported stress and fatigue.. Two-arm, parallel-group, 12-week, randomized, double-blind, placebo-controlled trial on overweight or mildly obese men and women aged 40-75 years, supplementing with 200 mg of an ashwagandha root extract (Witholytin®) twice daily.. Supplementation with ashwagandha was associated with a significant reduction in stress levels based on the Perceived Stress Scale (primary outcome); however, the improvements were not significantly different to the placebo group (. The results of this study suggest that in overweight middle-to-older age adults experiencing high stress and fatigue, compared to the placebo, ashwagandha did not have a significantly greater impact on perceived stress levels. However, based on secondary outcome measures, it may have anti-fatigue effects. This may be via its impact on the autonomic nervous system. However, further research is required to expand on these current findings.

Topics: Adult; Double-Blind Method; Fatigue; Female; Humans; Male; Obesity; Overweight; Plant Extracts; Withania

The increasing prevalence of obesity has resulted in demands for the development of new effective strategies for obesity treatment. Withaferin A (WA) shows a great potential for prevention of obesity by sensitizing leptin signaling in the hypothalamus. However, the mechanism underlying the weight- and adiposity-reducing effects of WA remains to be elucidated. In this study, we report that WA treatment induced white adipose tissue (WAT) browning, elevated energy expenditure, decreased respiratory exchange ratio, and prevented high-fat diet-induced obesity. The sympathetic chemical denervation dampened the WAT browning and also impeded the reduction of adiposity in WA-treated mice. WA markedly upregulated the levels of Prdm16 and FATP1 (Slc27a1) in the inguinal WAT (iWAT), and this was blocked by sympathetic denervation. Prdm16 or FATP1 knockdown in iWAT abrogated the WAT browning-inducing effects of WA and restored the weight gain and adiposity in WA-treated mice. Together, these findings suggest that WA induces WAT browning through the sympathetic nerve-adipose axis, and the adipocytic Prdm16-FATP1 pathway mediates the promotive effects of WA on white adipose browning.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Cell Transdifferentiation; Diet, High-Fat; DNA-Binding Proteins; Fatty Acid Transport Proteins; Humans; Male; Mice; Mice, Inbred C57BL; Obesity; Signal Transduction; Sympathetic Nervous System; Transcription Factors; Withanolides

The enhancement of energy expenditure has attracted attention as a therapeutic target for the management of body weight. Withaferin A (WFA), a major constituent of Withania somnifera extract, has been reported to possess anti-obesity properties, however the underlying mechanism remains unknown.. To investigate whether WFA exerts anti-obesity effects via increased energy expenditure, and if so, to characterize the underlying pathway.. C57BL/6 J mice were fed a high-fat diet (HFD) for 10 weeks, and WFA was orally administered for 7 days. The oxygen consumption rate of mice was measured at 9 weeks using an OxyletPro™ system. Hematoxylin and eosin (H&E), immunohistochemistry, immunoblotting, and real-time PCR methods were used.. Treatment with WFA ameliorated HFD-induced obesity by increasing energy expenditure by improving of mitochondrial activity in brown adipose tissue (BAT) and promotion of subcutaneous white adipose tissue (scWAT) browning via increasing uncoupling protein 1 levels. WFA administration also significantly increased AMP-activated protein kinase (AMPK) phosphorylation in the BAT of obese mice. Additionally, WFA activated mitogen-activated protein kinase (MAPK) signaling, including p38/extracellular signal-regulated kinase MAPK, in both BAT and scWAT.. WFA enhances energy expenditure and ameliorates obesity via the induction of AMPK and activating p38/extracellular signal-regulated kinase MAPK, which triggers mitochondrial biogenesis and browning-related gene expression.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Energy Metabolism; Gene Expression; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondria; Obesity; Thermogenesis; Uncoupling Protein 1; Withania; Withanolides

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Dietary Supplements; Energy Metabolism; Lipid Metabolism; Male; Mice, Inbred C57BL; Mitochondria; Muscle, Skeletal; Obesity; Oxygen Consumption; Phytotherapy; Plant Extracts; Withania; Withanolides

Withaferin A (WA), a bioactive constituent derived from Withania somnifera plant, has been shown to exhibit many qualifying properties in attenuating several metabolic diseases. The current investigation sought to elucidate the protective mechanisms of WA (1.25 mg/kg/day) on pre-existing obese mice mediated by high-fat diet (HFD) for 12 weeks. Following dietary administration of WA, significant metabolic improvements in hepatic insulin sensitivity, adipocytokines with enhanced glucose tolerance were observed. The hepatic oxidative functions of obese mice treated with WA were improved via augmented antioxidant enzyme activities. The levels of serum pro-inflammatory cytokines and hepatic mRNA expressions of toll-like receptor (TLR4), nuclear factor κB (NF-κB), tumor necrosis factor-α (TNF-α), chemokine (C-C motif) ligand-receptor, and cyclooxygenase 2 (COX2) in HFD-induced obese mice were reduced. Mechanistically, WA increased hepatic mRNA expression of peroxisome proliferator-activated receptors (PPARs), cluster of differentiation 36 (CD36), fatty acid synthase (FAS), carnitine palmitoyltransferase 1 (CPT1), glucokinase (GCK), phosphofructokinase (PFK), and phosphoenolpyruvate carboxykinase (PCK1) that were associated with enhanced lipid and glucose metabolism. Taken together, these results indicate that WA exhibits protective effects against HFD-induced obesity through attenuation of hepatic inflammation, oxidative stress, and insulin resistance in mice.

Topics: Animals; Blood Glucose; Body Weight; Cytokines; Diet, High-Fat; Enzyme-Linked Immunosorbent Assay; Fatty Liver; Feeding Behavior; Inflammation; Inflammation Mediators; Insulin Resistance; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Oxidative Stress; RNA, Messenger; Withanolides

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.

Topics: 3T3 Cells; Adipogenesis; Animals; Anti-Obesity Agents; Cell Differentiation; Diet, High-Fat; Down-Regulation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Weight Loss; Withanolides

Celastrol is a natural pentacyclic triterpene used in traditional Chinese medicine with significant weight-lowering effects. Celastrol-administered mice at 100 μg/kg decrease food consumption and body weight via a leptin-dependent mechanism, yet its molecular targets in this pathway remain elusive. Here, we demonstrate in vivo that celastrol-induced weight loss is largely mediated by the inhibition of leptin negative regulators protein tyrosine phosphatase (PTP) 1B (PTP1B) and T-cell PTP (TCPTP) in the arcuate nucleus (ARC) of the hypothalamus. We show in vitro that celastrol binds reversibly and inhibits noncompetitively PTP1B and TCPTP. NMR data map the binding site to an allosteric site in the catalytic domain that is in proximity of the active site. By using a panel of PTPs implicated in hypothalamic leptin signaling, we show that celastrol additionally inhibited PTEN and SHP2 but had no activity toward other phosphatases of the PTP family. These results suggest that PTP1B and TCPTP in the ARC are essential for celastrol's weight lowering effects in adult obese mice.

Topics: Allosteric Site; Animals; Anti-Obesity Agents; Catalytic Domain; Diet, High-Fat; Hypothalamus; Magnetic Resonance Spectroscopy; Male; Mice, Transgenic; Obesity; Pentacyclic Triterpenes; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 2; Structure-Activity Relationship; Triterpenes; Weight Loss

The increasing global prevalence of obesity and its associated disorders points to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules that have mRNA expression profiles similar to that of celastrol, a naturally occurring compound that we previously identified as a leptin sensitizer. Through this process, we identified another naturally occurring compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin-A treatment of mice with diet-induced obesity (DIO) resulted in a 20-25% reduction of body weight, while also decreasing obesity-associated abnormalities, including hepatic steatosis. Withaferin-A treatment marginally affected the body weight of ob/ob and db/db mice, both of which are deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism that occur independently of its leptin-sensitizing effect. Our results show that the metabolic abnormalities of DIO can be mitigated by sensitizing animals to endogenous leptin, and they indicate that withaferin A is a potential leptin sensitizer with additional antidiabetic actions.

Topics: Animals; Blood Glucose; Blotting, Western; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Fatty Liver; Fluorescent Antibody Technique; Glucose Tolerance Test; Hypothalamus; Immunohistochemistry; Leptin; Liver; Mice; Mice, Obese; Obesity; Pentacyclic Triterpenes; Real-Time Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor; Triterpenes; Withanolides

Topics: Animals; Anti-Obesity Agents; Humans; Leptin; Mice; Obesity; STAT3 Transcription Factor; Withanolides