Withaferin A exerts an anti-obesity effect by increasing energy expenditure through thermogenic gene expression in high-fat diet-fed obese mice

Lee, Da-Hye; Park, So‐Hyun; Lee, Eun-Young; Seo, Hyo‐Deok; Ahn, Jiyun; Jang, Youngjin; Ha, Tae‐Youl; Im, Seung Soon; Jung, Chang Hwa

doi:10.1016/j.phymed.2020.153457

Cited by 19 publications

(9 citation statements)

References 32 publications

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“… 70 – 72 Thermogenic gene expression stimulated by substances including IL-27, irisin, cinnamaldehyde, and withaferin A, is perturbed by p38 MAPK or ERK inhibitors. 70 , 73 – 75 Overexpression of mitogen-activated protein kinase kinase 6 (MEK6), an upstream repressive factor of p38/ERK, decreases the expression of uncoupling protein 1 (UCP1) and hormone-sensitive lipase (HSL) in adipocytes. 76 Other stimuli, such as cold exposure, promote browning by inducing p38 MAPK signaling and secretion of fibroblast growth factor (FGF)21.…”

Section: Signaling Pathways In the Pathogenesis Of Obesitymentioning

confidence: 99%

Signaling pathways in obesity: mechanisms and therapeutic interventions

Wen

Zhang

et al. 2022

Sig Transduct Target Ther

141

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Obesity is a complex, chronic disease and global public health challenge. Characterized by excessive fat accumulation in the body, obesity sharply increases the risk of several diseases, such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease, and is linked to lower life expectancy. Although lifestyle intervention (diet and exercise) has remarkable effects on weight management, achieving long-term success at weight loss is extremely challenging, and the prevalence of obesity continues to rise worldwide. Over the past decades, the pathophysiology of obesity has been extensively investigated, and an increasing number of signal transduction pathways have been implicated in obesity, making it possible to fight obesity in a more effective and precise way. In this review, we summarize recent advances in the pathogenesis of obesity from both experimental and clinical studies, focusing on signaling pathways and their roles in the regulation of food intake, glucose homeostasis, adipogenesis, thermogenesis, and chronic inflammation. We also discuss the current anti-obesity drugs, as well as weight loss compounds in clinical trials, that target these signals. The evolving knowledge of signaling transduction may shed light on the future direction of obesity research, as we move into a new era of precision medicine.

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Section: Signaling Pathways In the Pathogenesis Of Obesitymentioning

confidence: 99%

Signaling pathways in obesity: mechanisms and therapeutic interventions

Wen

Zhang

et al. 2022

Sig Transduct Target Ther

141

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show abstract

“…This was the reason that the clozapine group's average body weight exceeded that of the control group; it also explains the relatively high masses of organs including the kidneys and liver, as well as the relatively high RWAT and EWAT masses in the clozapine group. Moreover, we found evidence that the body fat gain in the clozapine group was possibly caused by a decrease in energy expenditure due to uncoupling protein 1 (UCP1) being expressed within brown adipose tissue (as illustrated in Figure S2); energy expenditure is enhanced by UCP1 because this protein regulates the metabolic rate [48]. Comparing the two groups also revealed that the serum serotonin level was higher in the clozapine group; in a previous study, the glucose burning of brown fat was discovered to be inhibited when an excessive amount of peripheral serotonin was present in the blood, with this inhibition resulting in the development of diabetes and obesity [49] (as illustrated in Figure S3).…”

Section: Discussionmentioning

confidence: 98%

Clozapine Worsens Glucose Intolerance, Nonalcoholic Fatty Liver Disease, Kidney Damage, and Retinal Injury and Increases Renal Reactive Oxygen Species Production and Chromium Loss in Obese Mice

Chang

Liu

Yang

et al. 2021

IJMS

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Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine’s adverse metabolic effects—such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy—was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased iNOS and NF-κB expression; a net negative chromium balance occurred because more chromium was excreted through urine, and this influenced chromium mobilization, which did not help overcome the hyperglycemia. Our clozapine group had considerably higher fatty liver scores, which was supported by the findings of lowered adiponectin protein levels and increased FASN protein, PNPLA3 protein, FABP4 mRNA, and SREBP1 mRNA levels. We conclude that clozapine can worsen nonalcoholic fatty liver disease, diabetes, and kidney and retinal injury. Therefore, long-term administration of clozapine warrants higher attention.

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“…Quercetin (Lee et al, 2017), EGCG (Mi et al, 2018), and curcumin (Lone et al, 2016) enhance brown adipocyte formation and thermogenic function in mouse interscapular BAT (iBAT), increase mitochondrial biogenesis, increase expression of UCP1 and other brown adipocyte‐specific markers via the activation of AMPK pathway. Likewise, Withaferin A also increases the expression of brown adipocyte marker proteins, such as PGC‐1α, PDRM, and UCP1 in 3 T3‐L1 cells and mice (Lee et al, 2020; Lee et al, 2021). Resveratrol (Pan et al, 2019), zeaxanthin (Liu et al, 2017), lycopene (Wang et al, 2019), and sulforaphane (Zhang et al, 2016) enhance browning, thermogenesis and mitochondrial biogenesis via the activation of Sirt1 pathway.…”

Section: Phytochemicals With Antiadipogenic or Antiobesity Effectsmentioning

confidence: 99%

Adipogenesis and therapeutic potentials of antiobesogenic phytochemicals: Insights from preclinical studies

Murugan

Balan

Wong

2021

Phytotherapy Research

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Obesity is one of the most serious public health problems in both developed and developing countries in recent years. While lifestyle and diet modifications are the most important management strategies of obesity, these may be insufficient to ensure long‐term weight reduction in certain individuals and alternative strategies including pharmacotherapy need to be considered. However, drugs option remains limited due to low efficacy and adverse effects associated with their use. Hence, identification of safe and effective alternative therapeutic agents remains warranted to combat obesity. In recent years, bioactive phytochemicals are considered as valuable sources for the discovery of new pharmacological agents for the treatment of obesity. Adipocyte hypertrophy and hyperplasia increases with obesity and undergo molecular and cellular alterations that can affect systemic metabolism giving rise to metabolic syndrome and comorbidities such as type 2 diabetes and cardiovascular diseases. Many phytochemicals have been reported to target adipocytes by inhibiting adipogenesis, inducing lipolysis, suppressing the differentiation of preadipocytes to mature adipocytes, reducing energy intake, and boosting energy expenditure mainly in vitro and in animal studies. Nevertheless, further high‐quality studies are needed to firmly establish the clinical efficacy of these phytochemicals. This review outlines common pathways involved in adipogenesis and phytochemicals targeting effector molecules of these pathways, the challenges faced and the way forward for the development of phytochemicals as antiobesity agents.

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Withaferin A exerts an anti-obesity effect by increasing energy expenditure through thermogenic gene expression in high-fat diet-fed obese mice

Cited by 19 publications

References 32 publications

Signaling pathways in obesity: mechanisms and therapeutic interventions

Signaling pathways in obesity: mechanisms and therapeutic interventions

Clozapine Worsens Glucose Intolerance, Nonalcoholic Fatty Liver Disease, Kidney Damage, and Retinal Injury and Increases Renal Reactive Oxygen Species Production and Chromium Loss in Obese Mice

Adipogenesis and therapeutic potentials of antiobesogenic phytochemicals: Insights from preclinical studies

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