scholarly journals A Role of Stress Sensor Nrf2 in Stimulating Thermogenesis and Energy Expenditure

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1196
Author(s):  
Seo-Hyuk Chang ◽  
Jeong-Soo Lee ◽  
Ui Jeong Yun ◽  
Kye Won Park
Keyword(s):  
Energy Expenditure ◽  
Metabolic Diseases ◽  
Atp Synthesis ◽  
Related Factor ◽  
Nrf2 Activation ◽  
Dietary Phytochemicals ◽  
Potential Applications ◽  
Thermogenic Adipocytes ◽  
Endogenous Metabolites

During chronic cold stress, thermogenic adipocytes generate heat through uncoupling of mitochondrial respiration from ATP synthesis. Recent discovery of various dietary phytochemicals, endogenous metabolites, synthetic compounds, and their molecular targets for stimulating thermogenesis has provided promising strategies to treat or prevent obesity and its associated metabolic diseases. Nuclear factor E2 p45-related factor 2 (Nrf2) is a stress response protein that plays an important role in obesity and metabolisms. However, both Nrf2 activation and Nrf2 inhibition can suppress obesity and metabolic diseases. Here, we summarized and discussed conflicting findings of Nrf2 activities accounting for part of the variance in thermogenesis and energy metabolism. We also discussed the utility of Nrf2-activating mechanisms for their potential applications in stimulating energy expenditure to prevent obesity and improve metabolic deficits.

scholarly journals The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials

2021 ◽  
Author(s):  
Tom Clifford ◽  
Jarred P. Acton ◽  
Stuart P. Cocksedge ◽  
Kelly A. Bowden Davies ◽  
Stephen J. Bailey
Keyword(s):  
Systematic Review ◽  
Assessment Tool ◽  
Cochrane Collaboration ◽  
Risk Of Bias ◽  
Related Factor ◽  
Human Intervention ◽  
Nrf2 Activation ◽  
Dietary Phytochemicals ◽  
Intervention Trials

AbstractWe conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans. Well controlled human intervention trials are needed to corroborate the findings from in vitro and animal studies.

scholarly journals Knockout of inositol-requiring enzyme 1α in pro-opiomelanocortin neurons decreases fat mass via increasing energy expenditure

Open Biology ◽  
2016 ◽  
Vol 6 (8) ◽  
pp. 160131 ◽  
Author(s):  
Yuzhong Xiao ◽  
Tingting Xia ◽  
Junjie Yu ◽  
Yalan Deng ◽  
Hao Liu ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Liver Steatosis ◽  
Leptin Resistance ◽  
Hormone Production ◽  
Melanocyte Stimulating Hormone ◽  
Diet Induced Obesity ◽  
Brown Adipose

Although numerous functions of inositol-requiring enzyme 1α (IRE1α) have been identified, a role of IRE1α in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus is largely unknown. Here, we showed that mice lacking IRE1α specifically in POMC neurons (PIKO) are lean and resistant to high-fat diet-induced obesity and obesity-related insulin resistance, liver steatosis and leptin resistance. Furthermore, PIKO mice had higher energy expenditure, probably due to increased thermogenesis in brown adipose tissue. Additionally, α-melanocyte-stimulating hormone production was increased in the hypothalamus of PIKO mice. These results demonstrate that IRE1α in POMC neurons plays a critical role in the regulation of obesity and obesity-related metabolic disorders. Our results also suggest that IRE1α is not only an endoplasmic reticulum stress sensor, but also a new potential therapeutic target for obesity and obesity-related metabolic diseases.

scholarly journals The Role of Nrf2: Adipocyte Differentiation, Obesity, and Insulin Resistance

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Hyun-Ae Seo ◽  
In-Kyu Lee
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Energy Metabolism ◽  
Leucine Zipper ◽  
Adipocyte Differentiation ◽  
Metabolic Diseases ◽  
Related Factor ◽  
Basic Leucine Zipper ◽  
Cellular Defense

Metabolic diseases, such as type 2 diabetes and obesity, are increasing globally, and much work has been performed to elucidate the regulatory mechanisms of these diseases. Nuclear factor E2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor that serves as a primary cellular defense against the cytotoxic effects of oxidative stress. Recent studies have proposed a close relationship between oxidative stress and energy metabolism-associated disease. The Nrf2 pathway, as a master regulator of cellular defense against oxidative stress, has emerged as a critical target of energy metabolism; however, its effects are controversial. This review examines the current state of research on the role of Nrf2 on energy metabolism, specifically with respect to its participation in adipocyte differentiation, obesity, and insulin resistance, and discusses the possibility of using Nrf2 as a therapeutic target in the clinic.

scholarly journals Oxyresveratrol Increases Energy Expenditure through Foxo3a-Mediated Ucp1 Induction in High-Fat-Diet-Induced Obese Mice

2018 ◽  
Vol 20 (1) ◽  
pp. 26 ◽  
Author(s):  
Jin Choi ◽  
No-Joon Song ◽  
A Lee ◽  
Dong Lee ◽  
Min-Ju Seo ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
High Fat Diet ◽  
Adipocyte Differentiation ◽  
Metabolic Diseases ◽  
Biological Activities ◽  
Obese Mice ◽  
High Fat ◽  
White Adipocyte

The phytochemical oxyresveratrol has been shown to exert diverse biological activities including prevention of obesity. However, the exact reason underlying the anti-obese effects of oxyresveratrol is not fully understood. Here, we investigated the effects and mechanism of oxyresveratrol in adipocytes and high-fat diet (HFD)-fed obese mice. Oxyresveratrol suppressed lipid accumulation and expression of adipocyte markers during the adipocyte differentiation of 3T3-L1 and C3H10T1/2 cells. Administration of oxyresveratrol in HFD-fed obese mice prevented body-weight gains, lowered adipose tissue weights, improved lipid profiles, and increased glucose tolerance. The anti-obese effects were linked to increases in energy expenditure and higher rectal temperatures without affecting food intake, fecal lipid content, and physical activity. The increased energy expenditure by oxyresveratrol was concordant with the induction of thermogenic genes including Ucp1, and the reduction of white adipocyte selective genes in adipose tissue. Furthermore, Foxo3a was identified as an oxyresveratrol-induced gene and it mimicked the effects of oxyresveratrol for induction of thermogenic genes and suppression of white adipocyte selective genes, suggesting the role of Foxo3a in oxyresveratrol-mediated anti-obese effects. Taken together, these data show that oxyresveratrol increases energy expenditure through the induction of thermogenic genes in adipose tissue and further implicates oxyresveratrol as an ingredient and Foxo3a as a molecular target for the development of functional foods in obesity and metabolic diseases.

scholarly journals Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

2016 ◽  
Vol 397 (5) ◽  
pp. 383-400 ◽  
Author(s):  
Noemí Esteras ◽  
Albena T. Dinkova-Kostova ◽  
Andrey Y. Abramov
Keyword(s):  
Transcription Factor ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Related Factor ◽  
Mitochondrial Bioenergetics ◽  
Cytoprotective Activity ◽  
Nrf2 Activation ◽  
Potential Therapeutic Role ◽  
And Function

Abstract The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor well-known for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich’s ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

Potential role for Nrf2 activation in the therapeutic effect of MG132 on diabetic nephropathy in OVE26 diabetic mice

2013 ◽  
Vol 304 (1) ◽  
pp. E87-E99 ◽  
Author(s):  
Wenpeng Cui ◽  
Bing Li ◽  
Yang Bai ◽  
Xiao Miao ◽  
Qiang Chen ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Therapeutic Effect ◽  
Mechanistic Study ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Diabetic Mice ◽  
Proteasomal Activity ◽  
Nrf2 Activation ◽  
Renal Tubular

Oxidative stress is a major cause of diabetic nephropathy. Upregulation of the key antioxidative transcription factor, nuclear factor-erythroid 2-related factor 2 (Nrf2), was found to prevent the development of diabetic nephropathy. The present study was designed to explore the therapeutic effect of Nrf2 induced by proteasomal inhibitor MG132 at a low dose (10 μg/kg) on diabetic nephropathy. Transgenic type 1 diabetic (OVE26) mice displayed renal dysfunction with albuminuria by 3 mo of age, at which time MG132 treatment was started. After 3-mo treatment with MG132, renal function, morphology, and biochemical changes were examined with real-time PCR, Western blotting, and immunohistochemical examination. Compared with age-matched, nontreated diabetic mice, MG132-treated diabetic mice showed significant improvements in terms of renal structural and functional alterations. These therapeutic effects were associated with increased Nrf2 expression and transcriptional upregulation of Nrf2-regulated antioxidants. Mechanistic study using human renal tubular HK11 cells confirmed the role of Nrf2, as silencing the Nrf2 gene with its specific siRNA abolished MG132 prevention of high-glucose-induced profibrotic response. Furthermore, diabetes was found to significantly increase proteasomal activity in the kidney, an effect that was significantly attenuated by 3 mo of treatment with MG132. These results suggest that MG132 upregulates Nrf2 function via inhibition of diabetes-increased proteasomal activity, which can provide the basis for the therapeutic effect of MG132 on the kidney against diabetes-induced oxidative damage, inflammation, fibrosis, and eventual dysfunction.

scholarly journals Thermogenic Fat: Development, Physiological Function, and Therapeutic Potential

2021 ◽  
Vol 22 (11) ◽  
pp. 5906
Author(s):  
Bruna B. Brandão ◽  
Ankita Poojari ◽  
Atefeh Rabiee
Keyword(s):  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Comprehensive Overview ◽  
Glucose Levels ◽  
Increase Energy Expenditure ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
Thermogenic Adipocytes

The concerning worldwide increase of obesity and chronic metabolic diseases, such as T2D, dyslipidemia, and cardiovascular disease, motivates further investigations into preventive and alternative therapeutic approaches. Over the past decade, there has been growing evidence that the formation and activation of thermogenic adipocytes (brown and beige) may serve as therapy to treat obesity and its associated diseases owing to its capacity to increase energy expenditure and to modulate circulating lipids and glucose levels. Thus, understanding the molecular mechanism of brown and beige adipocytes formation and activation will facilitate the development of strategies to combat metabolic disorders. Here, we provide a comprehensive overview of pathways and players involved in the development of brown and beige fat, as well as the role of thermogenic adipocytes in energy homeostasis and metabolism. Furthermore, we discuss the alterations in brown and beige adipose tissue function during obesity and explore the therapeutic potential of thermogenic activation to treat metabolic syndrome.

scholarly journals The role of Nrf2 in skeletal muscle contractile and mitochondrial function

2016 ◽  
Vol 121 (3) ◽  
pp. 730-740 ◽  
Author(s):  
Matthew J. Crilly ◽  
Liam D. Tryon ◽  
Avigail T. Erlich ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Mitochondrial Function ◽  
Fold Increase ◽  
Muscle Performance ◽  
Related Factor ◽  
Cellular Protection ◽  
Nrf2 Activation ◽  
Normal Increase

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that confers cellular protection by upregulating antioxidant enzymes in response to oxidative stress. However, Nrf2 function within skeletal muscle remains to be further elucidated. We examined the role of Nrf2 in determining muscle phenotype using young (3 mo) and older (12 mo) Nrf2 wild-type (WT) and knockout (KO) mice. Basally, the absence of Nrf2 did not impact mitochondrial content. In intermyofibrillar mitochondria, lack of Nrf2 resulted in a 40% reduction in state 4 respiration, which coincided with a 68% increase in reactive oxygen species (ROS) emission. Nrf2 abrogation impaired in situ muscle performance, characterized by a 48% greater rate of fatigue and a 35% decrease in force within the first 5 min of stimulation. Acute treadmill exercise resulted in a 1.5-fold increase in Nrf2 activation via enhanced DNA binding in WT animals. In response to training, cytochrome- c oxidase activity increased by 20% in the WT animals; however, this response was attenuated in KO mice. Nrf2 protein was reduced 30% by training. Despite this, exercise training normalized respiration, ROS production, and muscle performance in KO mice. Our results suggest that Nrf2 transcriptional activity is increased by exercise and that Nrf2 is required for the maintenance of basal mitochondrial function as well as for the normal increase in specific mitochondrial proteins in response to training. Nonetheless, the decrements in mitochondrial function in Nrf2 KO muscle can be rescued by exercise training, suggesting that this restorative function operates via a pathway independent of Nrf2.

scholarly journals Nrf2 activation does not affect adenoma development in a mouse model of colorectal cancer

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Elena V. Knatko ◽  
Cecilia Castro ◽  
Maureen Higgins ◽  
Ying Zhang ◽  
Tadashi Honda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colorectal Adenomas ◽  
Negative Regulator ◽  
Related Factor ◽  
Early Stages ◽  
Nrf2 Activation ◽  
One Carbon Metabolism ◽  
Nrf2 Protein ◽  
Transcription Factor Nuclear Factor

AbstractTranscription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator, Kelch-like ECH associated protein 1 (Keap1), are at the interface between redox and intermediary metabolism. Nrf2 activation is protective in models of human disease and has benefits in clinical trials. Consequently, the Keap1/Nrf2 protein complex is a drug target. However, in cancer Nrf2 plays a dual role, raising concerns that Nrf2 activators may promote growth of early neoplasms. To address this concern, we examined the role of Nrf2 in development of colorectal adenomas by employing genetic, pharmacological, and metabolomic approaches. We found that colorectal adenomas that form in Gstp−/−: ApcMin/+ mice are characterized by altered one-carbon metabolism and that genetic activation, but not disruption of Nrf2, enhances these metabolic alterations. However, this enhancement is modest compared to the magnitude of metabolic differences between tumor and peri-tumoral tissues, suggesting that the metabolic changes conferred by Nrf2 activation may have little contribution to the early stages of carcinogenesis. Indeed, neither genetic (by Keap1 knockdown) nor pharmacological Nrf2 activation, nor its disruption, affected colorectal adenoma formation in this model. We conclude that pharmacological Nrf2 activation is unlikely to impact the early stages of development of colorectal cancer.

scholarly journals Potential Role of NRF2 Agonist in Managing AHR-Mediated Chloracne by Dioxin

2018 ◽  
Author(s):  
Masutaka Furue ◽  
Yoko Fuyuno ◽  
Chikage Mitoma ◽  
Hiroshi Uchi ◽  
Gaku Tsuji
Keyword(s):  
Potential Role ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Cytochrome P450 1A1 ◽  
Skin Symptom ◽  
Aryl Hydrocarbon ◽  
Nrf2 Activation ◽  
Dual Functions

Chloracne is the major skin symptom caused by dioxin intoxication. Dioxin activates the aryl hydrocarbon receptor (AHR)–cytochrome p450 1A1 (CYP1A1) system, generates oxidative stress, and induces hyperkeratinization of keratinocytes and sebocytes leading to chloracne. Nuclear factor-erythroid 2-related factor-2 (NRF2) is a master switch inducing expression of various antioxidative enzymes such as heme oxygenase-1. Cinnamaldehyde is an antioxidant phytochemical that inhibits AHR–CYP1A1 signaling and activates the NRF2–antioxidative axis. The cinnamaldehyde-containing Kampo herbal medicine Keishibukuryogan is capable of improving chloracne in Yusho patients who are highly contaminated with dioxin. Agents with dual functions in promoting AHR–CYP1A1 inhibition and NRF2 activation may be useful in managing dioxin-related health hazards.

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