Beneficial effects of eicosapentaenoic acid on the metabolic profile of obese female mice entails upregulation of HEPEs and increased abundance of enteric Akkermansia muciniphila

Pal, Anandita; Sun, Shan; Armstrong, Michael; Manke, Jonathan; Reisdorph, N.; Adams, Victoria R.; Kennedy, Arion; Zu, Yujiao; Moustaid‐Moussa, Naima; Carroll, Ian M.; Shaikh, Saame Raza

doi:10.1016/j.bbalip.2021.159059

Cited by 13 publications

(7 citation statements)

References 52 publications

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“…In this study, we studied the fecal free fatty acids profiles and found that the content of a group of LCFAs was increased in response to Rb1 treatment. EPA which is a long-chain n-3 polyunsaturated fatty acid is reported to prevent hypertriglyceridemia and maintains insulin/glucose homeostasis ( Soni et al, 2019 ; Zhuang et al, 2020 ; Pal et al, 2021 ). LA and CLA (a type of linoleic acid isomer) have health benefits ( Shen and McIntosh, 2016 ; Hamilton and Klett, 2021 ) and are associated with a lower risk of T2DM ( Mousavi et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rb1 Improves Metabolic Disorder in High-Fat Diet-Induced Obese Mice Associated With Modulation of Gut Microbiota

et al. 2022

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Gut microbiota plays an important role in metabolic homeostasis. Previous studies demonstrated that ginsenoside Rb1 might improve obesity-induced metabolic disorders through regulating glucose and lipid metabolism in the liver and adipose tissues. Due to low bioavailability and enrichment in the intestinal tract of Rb1, we hypothesized that modulation of the gut microbiota might account for its pharmacological effects as well. Here, we show that oral administration of Rb1 significantly decreased serum LDL-c, TG, insulin, and insulin resistance index (HOMA-IR) in mice with a high-fat diet (HFD). Dynamic profiling of the gut microbiota showed that this metabolic improvement was accompanied by restoring of relative abundance of some key bacterial genera. In addition, the free fatty acids profiles in feces were significantly different between the HFD-fed mice with or without Rb1. The content of eight long-chain fatty acids (LCFAs) was significantly increased in mice with Rb1, which was positively correlated with the increase of Akkermansia and Parasuttereller, and negatively correlated with the decrease of Oscillibacter and Intestinimonas. Among these eight increased LCFAs, eicosapentaenoic acid (EPA), octadecenoic acids, and myristic acid were positively correlated with metabolic improvement. Furthermore, the colonic expression of the free fatty acid receptors 4 (Ffar4) gene was significantly upregulated after Rb1 treatment, in response to a notable increase of LCFA in feces. These findings suggested that Rb1 likely modulated the gut microbiota and intestinal free fatty acids profiles, which should be beneficial for the improvement of metabolic disorders in HFD-fed mice. This study provides a novel mechanism of Rb1 for the treatment of metabolic disorders induced by obesity, which may provide a therapeutic avenue for the development of new nutraceutical-based remedies for treating metabolic diseases, such as hyperlipidemia, insulin resistance, and type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Ginsenoside Rb1 Improves Metabolic Disorder in High-Fat Diet-Induced Obese Mice Associated With Modulation of Gut Microbiota

et al. 2022

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“…This is an important question for aging societies. In addition, studies regarding 8-HEPE have demonstrated that (1) apoE carrier causes greater increase in EPA-derived 8-HEPE [64] and (2) EPA ethyl esters inhibit HFD-induced fat mass accumulation through EPA-derived 8-HEPE in female mice [65]. These results suggest 8-HEPE plays important roles in human health, even if it is derived from EPA.…”

Section: Discussionmentioning

confidence: 93%

Euphausia pacifica (North Pacific Krill): Review of Chemical Features and Potential Benefits of 8-HEPE against Metabolic Syndrome, Dyslipidemia, NAFLD, and Atherosclerosis

2021

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Marine n-3 fatty acids are well known to have health benefits. Recently, krill oil, which contains phospholipids, has been in the spotlight as an n-3 PUFA-containing oil. Euphausia pacifica (E. pacifica), also called North Pacific krill, is a small, red crustacean similar to shrimp that flourishes in the North Pacific Ocean. E. pacifica oil contains 8-hydroxyeicosapentaenoic acid (8-HEPE) at a level more than 10 times higher than Euphausia superba oil. 8-HEPE can activate the transcription of peroxisome proliferator-activated receptor alpha (PPARα), PPARγ, and PPARδ to levels 10, 5, and 3 times greater than eicosapentaenoic acid, respectively. 8-HEPE has beneficial effects against metabolic syndrome (reduction in body weight gain, visceral fat area, amount of gonadal white adipose tissue, and gonadal adipocyte cell size), dyslipidemia (reduction in serum triacylglycerol and low-density lipoprotein cholesterol and induction of serum high-density lipoprotein cholesterol), atherosclerosis, and nonalcoholic fatty liver disease (reduction in triglyceride accumulation and hepatic steatosis in the liver) in mice. Further studies should focus on the beneficial effects of North Pacific krill oil products and 8-HEPE on human health.

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“…In addition, we did not examine sex differences as there is an increasing appreciation that SPM bioavailability is different between males and females (9,69,70). In addition, the effects of RvE1's parent compound EPA on glucose homeostasis also appear to be sex-specific (71). Furthermore, we did not conduct studies at the cellular level, which will provide insight on how the RvE1-ChemR23 axis controls the transcriptional landscape, particularly at the exon level of distinct cell types that express high levels of ChemR23.…”

Section: Discussionmentioning

confidence: 99%

Resolvin E1-ChemR23 Axis Regulates the Hepatic Metabolic and Inflammatory Transcriptional Landscape in Obesity at the Whole Genome and Exon Level

2021

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Resolvin E1 (RvE1) is an immunoresolvent that is synthesized from eicosapentaenoic acid and can bind the receptor ERV1/ChemR23. We previously showed activation of the RvE1-ChemR23 axis improves hyperglycemia and hyperinsulinemia of obese mice; however, it remains unclear how RvE1 controls glucose homeostasis. Here we investigated hepatic metabolic and inflammatory transcriptional targets of the RvE1-ChemR23 axis using lean and obese wild type (WT) and ChemR23 knockout (KO) mice. We conducted an in-depth transcriptional study by preforming whole gene-level and exon-level analyses, which provide insight into alternative splicing variants and miRNA regulation. Compared to controls, WT and KO obese mice in the absence of RvE1 displayed similar gene-level profiles, which entailed dysregulated pathways related to glucose homeostasis. Notably, obese WT mice relative to lean controls showed a robust decrease in pathways related to the biosynthesis of unsaturated fatty acids. At the exon-level, obese ChemR23 KOs compared to obese WT mice displayed changes in pathways related to hepatic lipid transport, cholesterol metabolism, and immunological functions such as complement cascades and platelet activation. Importantly, upon RvE1 administration to WT obese mice, we discovered upregulated genes in pathways relating to insulin sensitivity and downregulated genes related to regulators of TGF-β signaling. This transcriptional profile was generally not recapitulated with obese ChemR23 KO mice administered RvE1. Collectively, gene and exon-level analyses suggest RvE1 controls the hepatic transcriptional profile related to glucose homeostasis, insulin sensitivity, and inflammation in a manner that is largely dependent on ChemR23. These studies will drive future mechanistic experiments on the RvE1-ChemR23 axis.

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Beneficial effects of eicosapentaenoic acid on the metabolic profile of obese female mice entails upregulation of HEPEs and increased abundance of enteric Akkermansia muciniphila

Cited by 13 publications

References 52 publications

Ginsenoside Rb1 Improves Metabolic Disorder in High-Fat Diet-Induced Obese Mice Associated With Modulation of Gut Microbiota

Ginsenoside Rb1 Improves Metabolic Disorder in High-Fat Diet-Induced Obese Mice Associated With Modulation of Gut Microbiota

Euphausia pacifica (North Pacific Krill): Review of Chemical Features and Potential Benefits of 8-HEPE against Metabolic Syndrome, Dyslipidemia, NAFLD, and Atherosclerosis

Resolvin E1-ChemR23 Axis Regulates the Hepatic Metabolic and Inflammatory Transcriptional Landscape in Obesity at the Whole Genome and Exon Level

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