High-fat Diet-induced Inflammation Research Articles

Asprosin aggravates nonalcoholic fatty liver disease via inflammation and lipid metabolic disturbance mediated by reactive oxygen species.

Asprosin (ASP) is a newly-identified adipokine and plays important roles in energy metabolism homeostasis. However, there is no report on whether and how ASP is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Therefore, in the study, we investigated the protective effects of ASP-deficiency on the liver in the NAFLD model mice and the detrimental effects of ASP treatment on the human normal hepatocytes (LO2 cell line). More important, we explored the underlying mechanism from the perspective of lipid metabolism and inflammation. In the in vivo experiments, our data showed that the ASP-deficiency significantly alleviated the high-fat diet-induced inflammation and NAFLD, inhibited the hepatic fat deposition and downregulated the expressions of fat acid synthase (FASN), peroxisome proliferator-activated receptor γ (PPARγ) and forkhead box protein O1 (FOXO1); moreover, the ASP-deficiency attenuated the inflammatory state and inhibited the activation of the IKK/NF-κBp65 inflammation pathway. In the in vitro experiments, our results revealed that ASP treatment caused and even exacerbated the injury of LO2 cells induced by FFA; In contrast, the ASP treatment upregulated the expressions of PPARγ, FOXO1, FASN, ACC and acyl-CoA oxidase 1 (ACOX1) and elevated the reactive oxygen species (ROS) levels. Accordingly, these results demonstrate that ASP causes NAFLD through disrupting lipid metabolism and promoting the inflammation mediated by ROS.

Construction of a NIR hydrogen sulfide fluorescent probe for revealing the role of astrocytes in hypothalamic inflammation

Hydrogen sulfide (H2S) is a crucial endogenous gas signaling molecule in the central nervous system, playing a significant role in anti-inflammation, anti-oxidation, and neuroprotection. Our studies have shown that the level of H2S is closely related to hypothalamic inflammation-induced obesity. Compared to neurons, astrocytes, exhibit a preferential activation in response to high-fat diet-induced hypothalamic inflammation. Whether the reduction of hydrogen sulfide in astrocytes is the cause of neuronal damage leading to hypothalamic inflammation is worth exploring. The key to discussing the role of astrocytes is to accurately and quickly detect the levels of H2S in the complex microenvironment of the brain. In this work, we designed and synthesized a H2S near-infrared fluorescence probe (NIR-HS) based on dicyanideisophorone. NIR-HS selectively responds to H2S at 668 nm, with an effective linear range (0–20 μM), high sensitivity (35 nM). This probe has been successfully applied to detect hydrogen sulfide levels in astrocytes and to perform H2S fluorescence imaging on the slices of the ventromedial nucleus of the hypothalamus. Additionally, the effect of the H2S donor drug allicin on the levels of H2S in the hypothalamus and its therapeutic effect on hypothalamic inflammation were confirmed using NIR-HS and a series of signal pathway studies. Ultimately, we revealed the mechanism of that H2S inhibits hypothalamic neuronal inflammation by suppressing the expression of the pro-inflammatory factor IL-1β in astrocytes.

Microbial metabolite deoxycholic acid-mediated ferroptosis exacerbates high-fat diet-induced colonic inflammation

High-fat diet (HFD) has long been recognized as risk factors for the development and progression of ulcerative colitis (UC), but the exact mechanism remained elusive. Here, HFD increased intestinal deoxycholic acid (DCA) levels, and DCA further exacerbated colonic inflammation. Transcriptome analysis revealed that DCA triggered ferroptosis pathway in colitis mice. Mechanistically, DCA upregulated hypoxia-inducible factor-2α (HIF-2α) and divalent metal transporter-1 (DMT1) expression, causing the ferrous ions accumulation and ferroptosis in intestinal epithelial cells, which was reversed by ferroptosis inhibitor ferrostatin-1. DCA failed to promote colitis and ferroptosis in intestine-specific HIF-2α-null mice. Notably, byak-angelicin inhibited DCA-induced pro-inflammatory and pro-ferroptotic effects through blocking the up-regulation of HIF-2α by DCA. Moreover, fat intake was positively correlated with disease activity in UC patients consuming HFD, with ferroptosis being more pronounced. Collectively, our findings demonstrated that HFD exacerbated colonic inflammation by promoting DCA-mediated ferroptosis, providing new insights into diet-related bile acid dysregulation in UC.

Geniposide ameliorates atherosclerosis by restoring lipophagy via suppressing PARP1/PI3K/AKT signaling pathway

BackgroundAtherosclerosis (AS) is the leading cause of global death, which manifests as arterial lipid stack and plaque formation. Geniposide is an iridoid glycoside extract from Gardenia jasminoides J.Ellis that ameliorates AS by mediating autophagy. However, how Geniposide regulates autophagy and treats AS remains unclear. PurposeTo evaluate the efficacy and mechanism of Geniposide in treating AS.Study design and methods: Geniposide was administered to high-fat diet-fed ApoE−/− mice and oxidized low-density lipoprotein-incubated primary vascular smooth muscle cells (VSMCs). AS was evaluated with arterial lipid stack, plaque progression, and collagen loss in the artery. Foam cell formation was detected by lipid accumulation, inflammation, apoptosis, and the expression of foam cell markers. The mechanism of Geniposide in treating AS was assessed using network pharmacology. Lipophagy was measured by lysosomal activity, expression of lipophagy markers, and the co-localization of lipids and lipophagy markers. The effects of lipophagy were blocked using Chloroquine. The role of PARP1 was assessed by Olaparib (a PARP1 inhibitor) intervention and PARP1 overexpression. ResultsIn vivo, Geniposide reversed high-fat diet-induced hyperlipidemia, plaque progression, and inflammation. In vitro, Geniposide inhibited VSMC-derived foam cell formation by suppressing lipid stack, apoptosis, and the expressions of foam cell markers. Network pharmacological analysis and in vitro validation suggested that Geniposide treated AS by enhancing lipophagy via suppressing the PI3K/AKT signaling pathway. The benefits of Geniposide in alleviating AS were offset by Chloroquine in vivo and in vitro. Inhibiting PARP1 using Olaparib promoted lipophagy and alleviated AS progression, while PARP1 overexpression exacerbated foam cell formation and lipophagy blockage. The above effects of PARP1 were weakened by PI3K inhibitor LY294002. PARP1 also inhibited the combination of the ABCG1 and PLIN1. ConclusionGeniposide alleviated AS by restoring PARP1/PI3K/AKT signaling pathway-suppressed lipophagy. This study is the first to present the lipophagy-inducing effect of Geniposide and the binding of ABCG1 and PLIN1 inhibited by PARP1.

Aerobic exercise mitigates high-fat diet-induced cardiac dysfunction, pyroptosis, and inflammation by inhibiting STING-NLRP3 signaling pathway.

Obesity has been identified as an independent risk factor for cardiovascular disease. Recent reports have highlighted the significance of stimulator of interferon genes (STING)-NOD-like receptor protein 3 (NLRP3) signaling pathway mediated pyroptosis, and inflammation in cardiovascular disease. Previous studies have demonstrated that exercise training effectively prevents cardiac pyroptosis and inflammation in high-fat diet (HFD)-fed mice. However, it is currently unknown whether exercise reduces pyroptosis and inflammation in obese hearts by targeting the STING-NLRP3 signaling pathway. We investigated the impact of an 8-week aerobic exercise regimen on cardiac function, pyroptosis, inflammation, and the STING-NLRP3 signaling pathway in HFD-induced obese mice. Additionally, to explore the underlying mechanism of STING in exercise-mediated cardioprotection, we administered intraperitoneal injections of the STING agonist diABZI to the mice. Furthermore, to investigate the role of the STING-NLRP3 signaling pathway in HFD-induced cardiac dysfunction, we administered adeno-associated virus 9 (AAV9) encoding shRNA targeting STING (shRNA-STING) via tail vein injection to knockdown STING expression specifically in mouse hearts. After one week of AAV9 injection, we intraperitoneally injected nigericin as an NLRP3 agonist. We first found that aerobic exercise effectively suppressed HFD-mediated upregulation of STING and NLRP3 in the hearts. Moreover, we demonstrated that the protective effect of aerobic exercise in HFD-induced cardiac dysfunction, pyroptosis, and inflammation was impaired by stimulating the STING pathway using diABZI. Additionally, activation of the NLRP3 with nigericin abolished the ameliorative effect of STING deficiency in HFD-induced cardiac dysfunction, pyroptosis, and inflammation. Based on these findings, we concluded that 8-week aerobic exercise alleviates HFD-induced cardiac dysfunction, pyroptosis, and inflammation by targeting STING-NLRP3 signaling pathway. Inhibition of STING-NLRP3 signaling pathway may serve as a promising therapeutic strategy against obesity-induced cardiomyopathy.

Outer Membrane Vesicles Released from Garlic Exosome-like Nanoparticles (GaELNs) Train Gut Bacteria that Reverses Type 2 Diabetes via the Gut-Brain Axis.

Gut microbiota function has numerous effects on humans and the diet humans consume has emerged as a pivotal determinant of gut microbiota function. Here, a new concept that gut microbiota can be trained by diet-derived exosome-like nanoparticles (ELNs) to release healthy outer membrane vesicles (OMVs) is introduced. Specifically, OMVs released from garlic ELN (GaELNs) trained human gut Akkermansia muciniphila (A. muciniphila) can reverse high-fat diet-induced type 2 diabetes (T2DM) in mice. Oral administration of OMVs released from GaELNs trained A. muciniphila can traffick to the brain where they are taken up by microglial cells, resulting in inhibition of high-fat diet-induced brain inflammation. GaELNs treatment increases the levels of OMV Amuc-1100, P9, and phosphatidylcholines. Increasing the levels of Amuc-1100 and P9 leads to increasing the GLP-1 plasma level. Increasing the levels of phosphatidylcholines is required for inhibition of cGas and STING-mediated inflammation and GLP-1R crosstalk with the insulin pathway that leads to increasing expression of Insulin Receptor Substrate (IRS1 and IRS2) on OMV targeted cells. These findings reveal a molecular mechanism whereby OMVs from plant nanoparticle-trained gut bacteria regulate genes expressed in the brain, and have implications for the treatment of brain dysfunction caused by a metabolic syndrome.

Sativoside Mitigates High-Fat Diet-Induced Inflammation and Type-2 Diabetes in Adipose Tissue of Wistar Rats

This study aimed to investigate the impact of Stevioside, on the biochemical changes in high-fat diet-fed Wistar rats. Adult male Wistar rats were induced into a diabetic state through the administration of a high-fat diet and sucrose for 60 days, followed by oral administration of stevioside (20 mg/kg/day) for 45 days. Various parameters, including fasting blood glucose, oral glucose tolerance, insulin, insulin tolerance, liver function (ALT, AST, ALP), kidney function (urea and creatinine), and lipid profiles (TC, TG, FFA, HDL-c and LDL-c), serum adipokines levels such as adiponectin, leptin, resistin were assessed. Stevioside treatment notably improved glucose and insulin tolerances in diabetic rats and normalized their elevated levels of fasting blood glucose, serum insulin, and lipid profile. In the high-fat diet-induced type 2 diabetes rat model, Stevioside effectively restored the altered blood serum levels, demonstrating efficacy comparable to that of metformin. Therefore, Stevioside displays promise as a potential phytomedicine for managing type 2 diabetes mellitus. Keywords: High-fat diet, Insulin tolerance, Type-2 diabetes, Stevia rebaudiana.

Kaempferol protects gut-vascular barrier from high glucose-induced disorder via NF-κB pathway

Kaempferol is a natural edible flavonoid reported to treat high-fat diet-induced intestinal inflammation; however, the underlying molecular mechanisms remain unclear. This research aims to investigate the protective effect of kaempferol on the gut-vascular barrier (GVB) induced by high glucose and elucidate the underlying mechanism. Evans blue albumin efflux assay was used to test endothelial cell permeability. The results showed that kaempferol (50 μM) significantly reversed the high glucose-induced monolayer barrier permeability of rat intestinal microvascular endothelial cells (RIMVECs), while kaempferol significantly alleviated the high glucose-induced rarefication of the tight junction protein Claudin-5. Moreover, kaempferol also reduced high glucose-induced angiogenesis and cell migration via inhibiting the VEGFR2/p38 pathway. Kaempferol also protected against high glucose-induced overproduction of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 by inhibiting NF-κB p65 nuclear translocation. In addition, kaempferol had similar effects to the NF-κB inhibitor SN50 in reducing high glucose-induced ICAM-1 expression and endothelial barrier permeabilization. Our findings in part reveal the pathological mechanism of hyperglycemia-related gastrointestinal diseases and underlie the molecular mechanism of kaempferol in inhibiting bowel inflammation from a novel perspective.

Microglia Sirt6 modulates the transcriptional activity of NRF2 to ameliorate high-fat diet-induced obesity.

Microglia play a pivotal role in neuroinflammation, while obesity triggers hypothalamic microglia activation and inflammation. Sirt6 is an important regulator of energy metabolism in many peripheral tissues and hypothalamic anorexic neurons. However, the exact mechanism for microglia Sirt6 in controlling high-fat diet-induced obesity remain unknown. Microglia Sirt6 expression levels under various nutritional conditions were measured in the hypothalamus of mice. Also, microglia Sirt6-deficient mice were provided various diets to monitor metabolic changes and hypothalamic inflammatory response. Besides, RNA-seq and Co-IP of microglia with Sirt6 alterations were conducted to further investigate the detailed mechanism by which Sirt6 modulated microglia activity. We found that Sirt6 was downregulated in hypothalamic microglia in mice given a high-fat diet (HFD). Additionally, knockout of microglia Sirt6 exacerbated high-fat diet-induced hypothalamic microglial activation and inflammation. As a result, mice were more prone to obesity, exhibiting a decrease in energy expenditure, impaired glucose tolerance, insulin and leptin resistance, and increased food intake. In vitro, Sirt6 overexpression in BV2 cells displayed protective effects against oleic acid and palmitic acid treatment-derived inflammatory response. Mechanically, Sirt6 deacetylated and stabilised NRF2 to increase the expression of anti-oxidative genes and defend against reactive oxygen species overload. Pharmacological inhibition of NRF2 eliminated the beneficial modulating effects of Sirt6 on microglial activity. Collectively, our results revealed that microglial Sirt6 was a primary contributor of microglial activation in the central regulation of obesity. Thus, microglial Sirt6 may be an important therapeutic target for obesity.

Tripartite motif 38 alleviates the pathological process of NAFLD–NASH by promoting TAB2 degradation

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease worldwide, without any Food and Drug Administration-approved pharmacological intervention in clinic. Trim38, as an important member of the TRIM (tripartite motif-containing) family, was largely reported to be involved in the regulation of innate immune and inflammatory responses. However, the functional roles of TRIM38 in NAFLD remain largely unknown. Here, the expression of TRIM38 was first detected in liver samples of both NAFLD mice model and patients diagnosed with NAFLD. We found that TRIM38 expression was downregulated in NAFLD liver tissues compared with normal liver tissues. Genetic Trim38-KO in vivo showed that TRIM38 depletion deteriorated the high-fat diet and high fat and high cholesterol diet-induced hepatic steatosis and high fat and high cholesterol diet-induced liver inflammation and fibrosis. In particular, we found that the effects of hepatocellular lipid accumulation and inflammation induced by palmitic acid and oleic acid were aggravated by TRIM38 depletion but mitigated by TRIM38 overexpression in vitro. Mechanically, RNA-Seq analysis demonstrated that TRIM38 ameliorated nonalcoholic steatohepatitis progression by attenuating the activation of MAPK signaling pathway. We further found that TRIM38 interacted with transforming growth factor-β-activated kinase 1 binding protein 2 and promoted its protein degradation, thus inhibiting the transforming growth factor-β-activated kinase 1-MAPK signal cascades. In summary, our study revealed that TRIM38 could suppress hepatic steatosis, inflammatory, and fibrosis in NAFLD via promoting transforming growth factor-β-activated kinase 1 binding protein 2 degradation. TRIM38 could be a potential target for NAFLD treatment.

Effect of Clostridium butyricum on High-Fat Diet-Induced Intestinal Inflammation and Production of Short-Chain Fatty Acids.

A high-fat diet (HFD) can cause intestinal inflammation and alter the gut microbiota; probiotics, however, are known to have anti-inflammatory effects. This study aimed to investigate the response of rat colon to HFD and the effect of Clostridium butyricum on HFD-induced intestinal inflammation and production of short-chain fatty acids (SCFAs) according to sex. Male and female 6-week-old Fischer-344 rats were fed a chow diet or HFD for 8weeks, and Biovita or three different concentrations of C. butyricum were orally gavaged. The levels of tight junction proteins (TJPs), inflammatory markers in the ascending colonic mucosa, and bile acids (BAs) and SCFAs in stool were measured. HFD significantly increased the histological inflammation scores and fat proportions. Fecal BA levels were higher in the HFD group than in the control group, with a more prominent increase in deoxycholic acid/cholic acid after probiotics administration in females; however, no statistically significant differences were observed. TJPs showed an opposite response to HFD depending on sex, and tended to increase and decrease after HFD in males and females, respectively. The HFD-reduced TJPs were recovered by probiotics, with some statistical significance in females. HFD-decreased butyric acid in stools appeared to be recovered by probiotics in males, but not in females. The expression of inflammatory markers (TNF-α) was increased by HFD in males and decreased with medium-concentration probiotic supplementation. The opposite was observed in females. MPO was increased by HFD in both sexes and decreased by probiotic supplementation. The probiotic C. butyricum improved indicators of HFD-induced colonic inflammation such as levels of inflammatory markers and increased the production of SCFAs and the expression of TJPs. These effects tended to be more pronounced in male rats, showing sex difference.

Conventional cigarette and electronic nicotine delivery systems exacerbate high-fat diet-induced inflammation and oxidative stress

Conventional cigarette and electronic nicotine delivery systems exacerbate high-fat diet-induced inflammation and oxidative stress

Excessive sucrose exacerbates high fat diet-induced hepatic inflammation and fibrosis promoting osteoarthritis in mice model

Osteoarthritis (OA) is marked by chronic low-grade systemic inflammation and cartilage destruction. High fat diet causes obesity and increases the risk of knee OA-development. However, the impact of high dietary sugar intake on OA pathogenesis has not been elucidated yet. Therefore, we investigated the effects of a high-fat and high-sucrose (HF+HS) diet in experimental OA mouse models. Eight-week-old male C57BL/6J mice were fed a standard chow (n=6), high-fat (HF) (n=5), or HF+HS (n=7) diets for 12 weeks; thereafter, the mice underwent surgical destabilization of the medial meniscus (DMM) and received the same experimental diets for an additional 8 weeks. The pathogenesis of knee OA, obesogenic parameters, and inflammation levels in the liver and adipose tissue were investigated. HF+HS diet induced severe cartilage erosion with osteophyte development and subchondral bone plate thickening, indicating that HF+HS diet exacerbated OA. Despite marginal differences in metabolic parameters, hepatic free cholesterol accumulation increased in mice with DMM-induced OA fed on HF+HS diet than in those fed HF diet. Notably, the levels of inflammatory cytokines and fibrosis markers were greater in the livers of mice with DMM-induced OA, fed on HF+HS diet than those in the control group. However, adipose tissue remodeling was not affected by the HF+HS diet. These findings indicate that excess sucrose intake along with a HF diet triggers hepatic inflammation and fibrosis, thereby, contributing to OA pathogenesis.

Flammulina velutipes Mycorrhizae Attenuate High Fat Diet-Induced Lipid Disorder, Oxidative Stress and Inflammation in the Liver and Perirenal Adipose Tissue of Mice.

Flammulina velutipes (FV) is edible mushroom that has nutritional and medicinal values. FV mycorrhizae, the by-products of FV, are an abundant source and receive less attention. The objective of this study was to investigate the composition of FV mycorrhizae, and its effects on high fat diet (HFD)-induced lipid disorder, oxidative stress, and inflammatory cytokines, both in the liver and perirenal adipose tissue (PAT) of mice. The results showed that FV mycorrhizae contain abundant trace elements, polysaccharide, amino acids and derivatives, and organic compounds. It was found that 4% FV mycorrhizae (HFDFV) supplementation decreased HFD-induced liver weight and triglyceride (TG) in the plasma, liver and PAT, altered plasma and hepatic fatty acids profiles, promoted gene expression involved in lipid hydrolysis, fatty acid transportation and β-oxidation in the liver and reduced lipid synthesis in the liver and PAT. HFDFV attenuated HFD-induced oxidative stress and pro-inflammatory cytokine by increasing GSH/GSSG, and decreasing levels of MDA and IL6 both in the liver and PAT, while it differentially regulated gene expression of IL1β, IL6, and CCL2 in liver and PAT. The results indicated that FV mycorrhizae are effective to attenuate HFD-induced lipid disorder, oxidative stress and inflammation in the liver and PAT, indicating their promising constituents for functional foods and herbal medicine.

Phaseolus vulgaris extract ameliorates high-fat diet-induced colonic barrier dysfunction and inflammation in mice by regulating peroxisome proliferator-activated receptor expression and butyrate levels

Obesity is a health concern worldwide, and its onset is multifactorial. In addition to metabolic syndrome, a high-fat diet induces many deleterious downstream effects, such as chronic systemic inflammation, a loss of gut barrier integrity, and gut microbial dysbiosis, with a reduction of many butyrate-producing bacteria. These conditions can be ameliorated by increasing legumes in the daily diet. White and kidney beans (Phaseolus vulgaris L.) and their non-nutritive bioactive component phaseolamin were demonstrated to mitigate several pathological features related to a metabolic syndrome-like condition. The aim of the present study was to investigate the molecular pathways involved in the protective effects on the intestinal and liver environment of a chronic oral treatment with P. vulgaris extract (PHAS) on a murine model of the high-fat diet. Results show that PHAS treatment has an anti-inflammatory effect on the liver, colon, and cecum. This protective effect was mediated by peroxisome proliferator-activated receptor (PPAR)-α and γ. Moreover, we also observed that repeated PHAS treatment was able to restore tight junctions’ expression and protective factors of colon and cecum integrity disrupted in HFD mice. This improvement was correlated with a significant increase of butyrate levels in serum and fecal samples compared to the HFD group. These data underline that prolonged treatment with PHAS significantly reduces some pathological features related to the metabolic syndrome-like condition, such as inflammation and intestinal barrier disruption; therefore, PHAS could be a valid tool to be associated with the therapeutic strategy.

Myristic Acid Supplementation Aggravates High Fat Diet-Induced Adipose Inflammation and Systemic Insulin Resistance in Mice.

Saturated fatty acids (SFAs) are considered to be detrimental to human health. One of the SFAs, myristic acid (MA), is known to exert a hypercholesterolemic effect in mice as well as humans. However, its effects on altering adipose tissue (AT) inflammation and systemic insulin resistance (IR) in obesity are still unclear. Here, we sought to determine the effects of a high fat (HF) diet supplemented with MA on obesity-associated metabolic disorders in mice. Wild-type C57BL/6 mice were fed a HF diet in the presence or absence of 3% MA for 12 weeks. Plasma lipids, plasma adipokines, AT inflammation, systemic IR, glucose homeostasis, and hepatic steatosis were assessed. The body weight and visceral adipose tissue (VAT) mass were significantly higher in mice receiving the HF+MA diet compared to HF diet-fed controls. Plasma total cholesterol levels were marginally increased in HF+MA-fed mice compared to controls. Fasting blood glucose was comparable between HF and HF+MA-fed mice. Interestingly, the plasma insulin and HOMA-IR index, a measure of insulin resistance, were significantly higher in HF+MA-fed mice compared to HF controls. Macrophage and inflammatory markers were significantly elevated in the AT and AT-derived stromal vascular cells upon MA feeding. Moreover, the level of circulating resistin, an adipokine promoting insulin resistance, was significantly higher in HF+MA-fed mice compared with HF controls. The insulin tolerance test revealed that the IR was higher in mice receiving the MA supplementation compared to HF controls. Moreover, the glucose tolerance test showed impairment in systemic glucose homeostasis in MA-fed mice. Analyses of liver samples showed a trend towards an increase in liver TG upon MA feeding. However, markers of oxidative stress and inflammation were reduced in the liver of mice fed an MA diet compared to controls. Taken together, our data suggest that chronic administration of MA in diet exacerbates obesity-associated insulin resistance and this effect is mediated in part, via increased AT inflammation and increased secretion of resistin.

Concentrated fish oil ameliorates non-alcoholic fatty liver disease by regulating fibroblast growth factor 21–adiponectin axis

ObjectivesThe fibroblast growth factor 21 (FGF21)–adiponectin axis participates in energy hemostasis and obesity-related syndrome. The present study aimed to investigate whether concentrated fish oil (FO) intervention could alleviate non-alcoholic fatty liver disease (NAFLD) via the regulation of the FGF21–adiponectin axis. MethodsIn a randomized controlled trial, 61 patients with NAFLD, age 55.9 ± 15.6 y, were randomly divided into two groups: FO (3 g/d; n = 30) and corn oil (CO; 3 g/d; n = 31), which served as the control group. ResultsAfter a 3-mo intervention, there were significant net reductions in serum alanine transaminase (–5.4 ± 14.5 U/L vs. –0.25 ± 4.70 U/L; P = 0.001) and triacylglycerol (–0.70 ± 1.10 mmol/L vs. 0.11 ± 1.04 mmol/L; P = 0.018) levels in the FO group compared with the CO group. Furthermore, the mean changes of FGF21 levels (–16.3 ± 20.1 pg/mL vs. 7.2 ± 32.9 pg/mL; P = 0.002) were significantly decreased, but adiponectin levels (1.14 ± 1.53 μg/mL vs. –0.42 ± 2.04 pg/mL; P = 0.011) were significantly increased in the FO group compared with the CO group. In the animal study, the mice fed the high-fat diet demonstrated characteristics of NAFLD. The administration of FO significantly improved high-fat diet-induced hepatic steatosis, insulin resistance, and inflammation compared with the high-fat control group. In addition, FO improved the sensitivity of FGF21, and stimulated the expression levels of adiponectin in the liver. ConclusionsThe present study suggested that FO could potentially ameliorate NAFLD through mediating the FGF21–adiponectin axis.

Aged green tea reduces high-fat diet-induced fat accumulation and inflammation via activating the AMP-activated protein kinase signaling pathway.

BackgroundObesity is a global public health concern and increases the risk of metabolic syndrome and other diseases. The anti-obesity effects of various plant-derived bioactive compounds, such as tea extracts, are well-established. The mechanisms underlying the anti-obesity activity of Jinxuan green tea (JXGT) from different storage years are still unclear.ObjectiveThe aim of this study was to evaluate the effects of JXGTs from three different years on the high fat diet (HFD)-fed mouse model.DesignThe mice were divided into six groups, the control group received normal diet and the obese model group received HFD. We analyzed the effects of JXGTs from 2005, 2008, and 2016 on HFD-fed obese mice over a period of 7 weeks.ResultsThe JXGTs reduced the body weight of the obese mice, and also alleviated fat accumulation and hepatic steatosis. Mechanistically, JXGTs increased the phosphorylation of AMP-activated protein kinase (p-AMPK)/AMP-activated protein kinase (AMPK) ratio, up-regulated carnitine acyl transferase 1A (CPT-1A), and down-regulated fatty acid synthase (FAS), Glycogen synthase kinase-3beta (GSK-3β), Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1α), Interleukin 6 (IL-6), and Tumour necrosis factor alpha (TNFα). Thus, JXGTs can alleviate HFD-induced obesity by inhibiting lipid biosynthesis and inflammation, thereby promoting fatty acid oxidation via the AMPK pathway.DiscussionThe anti-obesity effect of three aged JXGTs were similar. However, JXGT2016 exhibited a more potent activation of AMPK, and JXGT2005 and JXGT2008 exhibited a more potent inhibiting glycogen synthase and inflammation effect. Furthermore, the polyphenol (–)-epicatechin (EC) showed the strongest positive correlation with the anti-obesity effect of JXGT.ConclusionsThese findings demonstrate that JXGT treatment has a potential protection on HFD-induced obesity mice via activating the AMPK/CPT-1A and down-regulating FAS/GSK-3β/PGC-1α and IL-6/TNFα. Our study results also revealed that different storage time would not affect the anti-obesity and anti-inflammation effect of JXGT.Graphical abstract

Erratum to “Cyanidin-3-O-galactoside from Aronia melanocarpa attenuates high-fat diet-induced obesity and inflammation via AMPK, STAT3, and NF-κB p65 signaling pathways in Sprague-Dawley rats” [J. Funct. Foods 85 (2021) 104616

Erratum to “Cyanidin-3-O-galactoside from Aronia melanocarpa attenuates high-fat diet-induced obesity and inflammation via AMPK, STAT3, and NF-κB p65 signaling pathways in Sprague-Dawley rats” [J. Funct. Foods 85 (2021) 104616

REEP6 knockout leads to defective β-adrenergic signaling in adipocytes and promotes obesity-related metabolic dysfunction.

IntroductionThe mobilization and catabolism of lipid energy is a central function of adipocytes that is under the control of the β-adrenergic signaling pathway, and defects in β-adrenergic signaling in adipocytes have been linked to obesity and obesity-related metabolic diseases. Receptor expression-enhancing proteins (REEPs) are endoplasmic reticulum (ER) proteins that play critical roles in subcellular targeting of receptor signaling complexes. Examination of gene expression profiles indicates that, among REEPs expressed in adipocytes, REEP6 expression is uniquely upregulated by sympathetic nervous system activation, suggesting involvement in regulating adrenergic signal transduction. ObjectiveThe aim of this study was to assess the contribution of REEP6 to the thermogenic activation of adipocytes and characterize the metabolic consequences of REEP6 deficiency in vivo. MethodsExpression levels of Reep6 in adipose tissue were examined by using public transcriptomic data and validated by Western blot and qPCR analyses. Adipocyte-specific regulatory roles of REEP6 were investigated in vitro in C3H10T1/2 adipocytes and in primary adipocytes obtained from REEP6 KO mice. Effects of in vivo REEP6 deficiency on energy expenditure were measured by indirect calorimetry. Mitochondrial content in adipose tissue was accessed by immunoblot, mitochondrial DNA analysis, and confocal and electron microscopy. Effects of REEP6 KO on obesity-induced metabolic dysfunction were tested in a high-fat diet-induced obesity mouse model by glucose tolerance test, Western blot, and histological analyses. ResultsREEP6 expression is highly enriched in murine adipocytes and is sharply upregulated upon adipocyte differentiation and by cold exposure. Inactivation of REEP6 in mice increased adiposity, and reduced energy expenditure and cold tolerance. REEP6 KO severely reduced protein kinase A-mediated signaling in BAT and greatly reduced mitochondrial mass. The effect of REEP6 inactivation on diminished β-adrenergic signaling was reproduced in cultured adipocytes, indicating that this effect is cell-autonomous. REEP6 KO also suppressed expression of adenylate cyclase 3 (Adcy3) in brown adipose tissue and knockdown of REEP6 in adipocytes reduced targeting of ADCY3 to the plasma membrane. Lastly, REEP6 KO exacerbated high-fat diet-induced insulin resistance and inflammation in adipose tissue. ConclusionsThis study indicates that REEP6 plays an important role in β-adrenergic signal transduction in adipocytes involving the expression and trafficking of Adcy3. Genetic inactivation of REEP6 reduces energy expenditure, increases adiposity, and the susceptibility to obesity-related metabolic dysfunction.