Bardoxolone Methyl Prevents Fat Deposition and Inflammation in Brown Adipose Tissue and Enhances Sympathetic Activity in Mice Fed a High-Fat Diet

Dinh, Chi H. L; Szabo, Alexander; Yu, Yinghua; Camer, Danielle; Zhang, Qingsheng; Wang, Hongqin; Huang, Xu‐Feng

doi:10.3390/nu7064705

Cited by 15 publications

(24 citation statements)

References 80 publications

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“…This class of compounds exhibits robust inhibition of ghrelin octanoylation by hGOAT, and effects reported in previous animal and clinical studies employing CDDO-family compounds support the potential for these compounds to impact ghrelin signaling. 37–44 Our study establishes these synthetic triterpenoids as effective small molecule inhibitors targeting ghrelin signaling, provides the first evidence implicating a cysteine thiol group in the catalytic mechanism of a MBOAT family acyltransferase, and offers a foundation for continued development of novel hGOAT inhibitors as therapeutics targeting diabetes and obesity.…”

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confidence: 76%

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

et al. 2017

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The peptide hormone ghrelin plays a key role in regulating hunger and energy balance within the body. Ghrelin signaling presents a promising and unexploited target for development of small-molecule therapeutics to treat obesity, diabetes, and other health conditions. Inhibition of ghrelin O-acyltransferase (GOAT), which catalyzes an essential octanoylation step in ghrelin maturation, offers a potential avenue for controlling ghrelin signaling. Through screening a small molecule library, we have identified a class of synthetic triterpenoids that efficiently inhibit ghrelin acylation by the human isoform of GOAT (hGOAT). These compounds function as covalent reversible inhibitors of hGOAT, providing the first evidence for involvement of a nucleophilic cysteine residue in substrate acylation by a MBOAT family acyltransferase. Surprisingly, the mouse form of GOAT does not exhibit susceptibility to cysteine modifying electrophiles revealing an important distinction in the activity and behavior between these closely related GOAT isoforms. This study establishes these compounds as potent small molecule inhibitors of ghrelin acylation and provides a foundation for the development of novel hGOAT inhibitors as therapeutics targeting diabetes and obesity.

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confidence: 76%

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

et al. 2017

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“…In addition, we showed none of these immune cells change with aging, yet during obesity, B cells increase and macrophages and eosinophils decrease in BAT. Other groups have also shown the presence of macrophages [29][30][31], eosinophils [31,32], T cells [31], regulatory T cells [33], natural killer T (NKT) cells [31], and gamma delta T (γδ T) by guest, on www.jlr.org Downloaded from cells in BAT [31]. In the most thorough study of BAT macrophages, Wolf et al…”

Section: Role Of Adipose Tissue In Systemic Energy Homeostasismentioning

confidence: 99%

Contributions of innate type 2 inflammation to adipose function

Bolus

Hasty

2019

Journal of Lipid Research

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A critical contributor to health consequences of the obesity epidemic is dysregulated adipose tissue (AT) homeostasis. While white, brown, and beige AT function are all altered in obesity-related disease, white AT is marked by progressive inflammation & adipocyte dysfunction and has been the focus of extensive "immunometabolism" research in the past decade. The exact triggering events initiating and sustaining AT inflammation are still under study, but it has been shown that reducing inflammation improves insulin action in AT. Scientific efforts continue seeking interventions to mitigate obesity-associated AT inflammation, and many groups are now determining how lean healthy AT homeostasis is maintained in order to leverage these mechanisms as therapeutic targets. Such studies have revealed an elaborate network of immune cells, cytokines, and other cellular mediators coordinate AT function. Recent studies elucidated the involvement of the innate immune system in AT homeostasis (e.g. beiging and insulin sensitivity), including M2-like macrophages, eosinophils, innate lymphoid type 2 cells, and several others. In this review, we summarize the existing literature on innate type 2 inflammation in AT; additionally we draw attention to areas of debate where seemingly conflicting data promises to yield more surprising and elegant biology as studies continue to dissect AT physiology. prospective analyses of nearly a million adults, showed that obesity can decrease a person's life span up to 10 years [7]. Thus, a better understanding of adipose tissue (AT), the organ that expands the most in size during obesity, should provide solutions to this health concern.When discussing AT, white adipose tissue (WAT) is most commonly considered; however, other types of AT, brown adipose tissue (BAT) and beige AT also exist.Adipocytes in WAT and BAT are generated from unique progenitors. WAT stores excess energy in the form of triglycerides. BAT can store small amounts of triglycerides; however, its primary role is to burn fatty acids to generate heat. Beige fat has brown-like properties but is transiently present in WAT depots (especially subcutaneous) upon beta-adrenergic stimulation. Regulation of all three of these fat depots is critically important for lipid and energy homeostasis.WAT consists of spatially distinct beds: visceral, omental, subcutaneous, perivascular, epicardial, and many others. These depots serve to cushion organs they BAT is localized primarily in subscapular regions in rodents, and was only discovered in adult humans in the past decade [10,11]. BAT has a characteristic brown appearance grossly, and is easily distinguished from WAT. This distinctive color is due to the presence of concentrated mitochondria within each brown adipocyte, accompanied by high iron concentrations required for activation of the electron transport chain during beta-oxidation. High expression of uncoupling protein 1 (UCP-1) causes this beta-oxidation to result in generation of heat rather than ATP (thermogenesis), thus assistin...

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“…Moreover, the reduction in noradrenergic and adrenergic activity is linked to reduced thermogenesis, increased body weight, and development of obesity [ 31 – 33 ]. We have found that HFD mice had reduced level of energy expenditure proteins including β 3 adrenergic receptor ( β 3 -AR), UCP2, and tyrosine hydroxylase (TH, a noradrenergic marker) in adipose tissues and the brainstem [ 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

Bardoxolone Methyl Prevents Mesenteric Fat Deposition and Inflammation in High‐Fat Diet Mice

Dinh

Szabo

et al. 2015

The Scientific World Journal

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Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of bardoxolone methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and uncoupling protein 2 (UCP2) proteins. Overall, BARD induces preventive effect in HFD mice through regulation of mesenteric adipose tissue.

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Bardoxolone Methyl Prevents Fat Deposition and Inflammation in Brown Adipose Tissue and Enhances Sympathetic Activity in Mice Fed a High-Fat Diet

Cited by 15 publications

References 80 publications

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

Contributions of innate type 2 inflammation to adipose function

Bardoxolone Methyl Prevents Mesenteric Fat Deposition and Inflammation in High‐Fat Diet Mice

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