High-fat Diet-induced Inflammation Research Articles

Hypothalamic Microglial Heterogeneity and Signature under High Fat Diet-Induced Inflammation.

Under high-fat feeding, the hypothalamus atypically undergoes pro-inflammatory signaling activation. Recent data from transcriptomic analysis of microglia from rodents and humans has allowed the identification of several microglial subpopulations throughout the brain. Numerous studies have clarified the roles of these cells in hypothalamic inflammation, but how each microglial subset plays its functions upon inflammatory stimuli remains unexplored. Fortunately, these data unveiling microglial heterogeneity have triggered the development of novel experimental models for studying the roles and characteristics of each microglial subtype. In this review, we explore microglial heterogeneity in the hypothalamus and their crosstalk with astrocytes under high fat diet–induced inflammation. We present novel currently available ex vivo and in vivo experimental models that can be useful when designing a new research project in this field of study. Last, we examine the transcriptomic data already published to identify how the hypothalamic microglial signature changes upon short-term and prolonged high-fat feeding.

Anti-neuroinflammatory effect of daidzein in human hypothalamic GnRH neurons in an in vitro membrane-based model.

Phytoestrogens can control high-fat diet-induced hypothalamic inflammation that is associated with severe consequences, including obesity, type 2 diabetes, cardiovascular and neurodegenerative diseases. However, the phytoestrogen anti-neuroinflammatory action is poorly understood. In this study, we explored the neuroprotection mediated by daidzein in hypothalamic neurons by using a membrane-based model of obesity-related neuroinflammation. To test the daidzein therapeutic potential a biohybrid membrane system, consisting of hfHypo GnRH-neurons in culture on PLGA membranes, was set up. It served as reliable in vitro tool capable to recapitulate the in vivo structure and function of GnRH hypothalamic tissue. Our findings highlighted the neuroprotective role of daidzein, being able to counteract the palmitate induced neuroinflammation. Daidzein protected hfHypo GnRH cells by downregulating cell death, proinflammatory processes, oxidative stress, and apoptosis. It also restored the proper cell morphology and functionality through a mechanism which probably involves the activation of ERβ and GPR30 receptors along with the expression of GnRH peptide and KISS1R.

TIR-Domain-Containing Adaptor-Inducing Interferon-β (TRIF) Is Involved in Glucose Metabolism in Adipose Tissue through the Insulin/AKT Signaling Pathway.

Obesity significantly increases the risk of developing type 2 diabetes mellitus and other metabolic diseases. Obesity is associated with chronic low-grade inflammation in white adipose tissues, which is thought to play an essential role in developing insulin resistance. Many lines of evidence indicate that toll-like receptors (TLRs) and their downstream signaling pathways are involved in development of chronic low-grade inflammation and insulin resistance, which are associated with obesity. Mice lacking molecules positively involved in the TLR signaling pathways are generally protected from high-fat diet-induced inflammation and insulin resistance. In this study, we have determined the effects of genetic deficiency of toll/interleukin-1 receptor-domain-containing adaptor-inducing interferon-β (TRIF) on food intake, bodyweight, glucose metabolism, adipose tissue macrophage polarization, and insulin signaling in normal chow diet-fed mice to investigate the role of the TRIF-dependent TLR signaling in adipose tissue metabolism and inflammation. TRIF deficiency (TRIF−/−) increased food intake and bodyweight. The significant increase in bodyweight in TRIF−/− mice was discernible as early as 24 weeks of age and sustained thereafter. TRIF−/− mice showed impaired glucose tolerance in glucose tolerance tests, but their insulin tolerance tests were similar to those in TRIF+/+ mice. Although no difference was found in the epididymal adipose mass between the two groups, the percentage of CD206+ M2 macrophages in epididymal adipose tissue decreased in TRIF−/− mice compared with those in TRIF+/+ mice. Furthermore, activation of epididymal adipose AKT in response to insulin stimulation was remarkably diminished in TRIF−/− mice compared with TRIF+/+ mice. Our results indicate that the TRIF-dependent TLR signaling contributes to maintaining insulin/AKT signaling and M2 macrophages in epididymal adipose tissue under a normal chow diet and provide new evidence that TLR4-targeted therapies for type 2 diabetes require caution.

An Endoplasmic Reticulum Stress-MicroRNA-26a Feedback Circuit in NAFLD.

Endoplasmic reticulum (ER) stress is an adaptive response to excessive ER demand and contributes to the development of numerous diseases, including nonalcoholic fatty liver disease (NAFLD), which is hallmarked by the accumulation of lipid within hepatocytes. However, the underlying mechanisms remain elusive. MicroRNAs (miRNAs) play an indispensable role in various stress responses, but their implications in ER stress have not yet been systemically investigated. In this study, we identify a negative feedback loop consisting of hepatic ER stress and miR-26a in NAFLD pathogenesis. Combining miRNA dot blot array and quantitative PCR, we find that miR-26a is specifically induced by ER stress in liver cells. This induction of miR-26a is critical for cells to cope with ER stress. In human hepatoma cells and murine primary hepatocytes, overexpression of miR-26a markedly alleviates chemical-induced ER stress, as well as palmitate-triggered ER stress and lipid accumulation. Conversely, deficiency of miR-26a exhibits opposite effects. Mechanistically, miR-26a directly targets the eukaryotic initiation factor 2α, a core ER stress effector controlling cellular translation. Intriguingly, miR-26a is reduced in the livers of patients with NAFLD. Hepatocyte-specific restoration of miR-26a in mice significantly mitigates high-fat diet-induced ER stress and hepatic steatosis. In contrast, deficiency of miR-26a in mice exacerbates high-fat diet-induced ER stress, lipid accumulation, inflammation and hepatic steatosis. Our findings suggest ER stress-induced miR-26a up-regulation as a regulator for hepatic ER stress resolution, and highlight the ER stress/miR-26a/eukaryotic initiation factor 2α cascade as a promising therapeutic strategy for NAFLD.

Gut microbial bile acid metabolite skews macrophage polarization and contributes to high-fat diet-induced colonic inflammation

ABSTRACT High-fat diet (HFD) leads to systemic low-grade inflammation, which has been involved in the pathogenesis of diverse metabolic and inflammatory diseases. Colon is thought to be the first organ suffering from inflammation under HFD conditions due to the pro-inflammatory macrophages infiltration, however, the mechanisms concerning the induction of pro-inflammatory phenotype of colonic macrophages remains unclear. In this study, we show that HFD increased the percentage of gram-positive bacteria, especially genus Clostridium, and resulted in the significant increment of fecal deoxycholic acid (DCA), a gut microbial metabolite produced by bacteria mainly restricted to genus Clostridium. Notably, reducing gram-positive bacteria with vancomycin diminished fecal DCA and profoundly alleviated pro-inflammatory macrophage infiltration in colon, whereas DCA-supplemented feedings to vancomycin-treated mice provoked obvious pro-inflammatory macrophage infiltration and colonic inflammation. Meanwhile, intra-peritoneal administration of DCA also elicited considerable recruitment of macrophages with pro-inflammatory phenotype. Mechanistically, DCA dose-dependently promoted M1 macrophage polarization and pro-inflammatory cytokines production at least partially through toll-like receptor 2 (TLR2) transactivated by M2 muscarinic acetylcholine receptor (M2-mAchR)/Src pathway. In addition, M2-mAchR mediated increase of TLR2 transcription was mainly achieved via targeting AP-1 transcription factor. Moreover, NF-κB/ERK/JNK signalings downstream of TLR2 are involved in the DCA-induced macrophage polarization. In conclusion, our findings revealed that high level DCA induced by HFD may serve as an initiator to activate macrophages and drive colonic inflammation, thus offer a mechanistic basis that modulation of gut microbiota or intervening specific bile acid receptor signaling could be potential therapeutic approaches for HFD-related inflammatory diseases.

TLR4/AP-1-Targeted Anti-Inflammatory Intervention Attenuates Insulin Sensitivity and Liver Steatosis.

Insulin resistance has been shown to be the common pathogenesis of many metabolic diseases. Metainflammation is one of the important characteristics of insulin resistance. Macrophage polarization mediates the production and development of metainflammation. Toll-like receptor 4 (TLR4) mediates macrophage activity and is probably the intersection of immunity and metabolism, but the detailed mechanism is probably not fully understood. Activated protein 1 (AP1) signaling pathway is very important in macrophage activation-mediated inflammation. However, it is unclear whether AP1 signaling pathway mediates metabolic inflammation in the liver. We aimed to investigate the effects of macrophage TLR4-AP1 signaling pathway on hepatocyte metabolic inflammation, insulin sensitivity, and lipid deposition, as well as to explore the potential of TLR4-AP1 as new intervention targets of insulin resistance and liver steatosis. TLR4 and AP1 were silenced in the RAW264.7 cells by lentiviral siRNA transfection. In vivo transduction of lentivirus was administered in mice fed with high-fat diet. Insulin sensitivity and inflammation were evaluated in the treated cells or animals. Our results indicated that TLR4/AP-1 siRNA transfection alleviated high-fat diet-induced systemic and hepatic inflammation, obesity, and insulin resistance in mice. Additionally, TLR4/AP-1 siRNA transfection mitigated palmitic acid- (PA-) induced inflammation in RAW264.7 cells and metabolic abnormalities in cocultured AML hepatocytes. Herein, we propose that TLR4-AP1 signaling pathway activation plays a crucial role in high fat- or PA-induced metabolic inflammation and insulin resistance in hepatocytes. Intervention of the TLR4 expression regulates macrophage polarization and metabolic inflammation and further alleviates insulin resistance and lipid deposition in hepatocytes.

Histone Deacetylase 3 Couples Mitochondria to Drive IL-1β-Dependent Inflammation by Configuring Fatty Acid Oxidation

Immune cell function depends on specific metabolic programs dictated by mitochondria, including nutrient oxidation, macromolecule synthesis, and post-translational modifications. Mitochondrial adaptations have been linked to acute and chronic inflammation, but the metabolic cues and precise mechanisms remain unclear. Here we reveal that histone deacetylase 3 (HDAC3) is essential for shaping mitochondrial adaptations for IL-1β production in macrophages through non-histone deacetylation. Invivo, HDAC3 promoted lipopolysaccharide-induced acute inflammation and high-fat diet-induced chronic inflammation by enhancing NLRP3-dependent caspase-1 activation. HDAC3 configured the lipid profile in stimulated macrophages and restricted fatty acid oxidation (FAO) supported by exogenous fatty acids for mitochondria to acquire their adaptations and depolarization. Rather than affecting nuclear gene expression, HDAC3 translocated to mitochondria to deacetylate and inactivate an FAO enzyme, mitochondrial trifunctional enzyme subunit α. HDAC3 may serve as a controlling node that balances between acquiring mitochondrial adaptations and sustaining their fitness for IL-1β-dependent inflammation.

Palmitoleic acid reduces high fat diet-induced liver inflammation by promoting PPAR-γ-independent M2a polarization of myeloid cells

Palmitoleic acid (POA, 16:1n-7) is a lipokine that has potential nutraceutical use to treat non-alcoholic fatty liver disease. We tested the effects of POA supplementation (daily oral gavage, 300 mg/Kg, 15 days) on murine liver inflammation induced by a high fat diet (HFD, 59% fat, 12 weeks). In HFD-fed mice, POA supplementation reduced serum insulin and improved insulin tolerance compared with oleic acid (OA, 300 mg/Kg). The livers of POA-treated mice exhibited less steatosis and inflammation than those of OA-treated mice with lower inflammatory cytokine levels and reduced toll-like receptor 4 protein content. The anti-inflammatory effects of POA in the liver were accompanied by a reduction in liver macrophages (LM, CD11c+; F4/80+; CD86+), an effect that could be triggered by peroxisome proliferator activated receptor (PPAR)-γ, a lipogenic transcription factor upregulated in livers of POA-treated mice. We also used HFD-fed mice with selective deletion of PPAR-γ in myeloid cells (PPAR-γ KOLyzCre+) to test whether the beneficial anti-inflammatory effects of POA are dependent on macrophages PPAR-γ. POA-mediated improvement of insulin tolerance was tightly dependent on myeloid PPAR-γ, while POA anti-inflammatory actions including the reduction in liver inflammatory cytokines were preserved in mice bearing myeloid cells deficient in PPAR-γ. This overlapped with increased CD206+ (M2a) cells and downregulation of CD86+ and CD11c+ liver macrophages. Moreover, POA supplementation increased hepatic AMPK activity and decreased expression of the fatty acid binding scavenger receptor, CD36. We conclude that POA controls liver inflammation triggered by fat accumulation through induction of M2a macrophages independently of myeloid cell PPAR-γ.

Ginkgolide B ameliorates high-fat diet-induced hepatic steatosis and inflammation in mice

Ginkgolide B ameliorates high-fat diet-induced hepatic steatosis and inflammation in mice

Perilla Oil Alleviates High-Fat Diet-Induced Inflammation in the Colon of Mice by Suppressing Nuclear Factor-Kappa B Activation.

This study aimed to evaluate the effect of perilla oil (PO) on high-fat diet (HD)-induced colonic inflammation. Male C57BL/6J mice (5 weeks old) were divided into four groups: normal diet, HD, HD supplemented with fish oil (FO), and HD supplemented with PO, and were fed experimental diets for 16 weeks. PO significantly ameliorated (P < .05) the HD-induced colon inflammation as indicated by the increased colon length and low macroscopic score. PO increased the number of Bifidobacteria and reduced the number of Enterobacteriaceae, which in turn resulted in the lowering of endotoxin levels. Proinflammatory cytokines in serum and colon such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α were also decreased by PO treatment. In addition, PO suppressed the expression of cyclooxygenase 2 and inducible nitric oxide, and inhibited the activation of nuclear factor-κB in the colon while increasing the expression of the tight junction protein, Zonula occludens-1. The gene expression of GPR120, a membrane receptor activated by omega-3 fatty acids, was increased in the oil-treated groups. Altogether, PO improved HD-induced colon inflammatory conditions, and the effects were similar to those of FO, confirming that PO is a potential omega-3 fatty acid source for dietary supplements.

The Effects of Quercetin on High Fat Diet-Induced Inflammation and Oxidative Stress in Brown Adipose Tissue

Abstract Objectives Under obesity state, adipose tissue derived inflammatory mediators circulate all over the body and induce low-grade chronic inflammation, which is the main cause for the development of metabolic diseases. Moreover, inflammation-induced reactive oxygen species (ROS) cause oxidative stress, a process in damaging cellular structure and functions. Recently, microRNAs (miRNAs) were found to potentially regulate inflammation and its associated diseases. Brown adipose tissue (BAT) protects against obesity through thermogenic activity to increase energy expenditure. However, high levels of inflammation, ROS generation and aberrant level of miRNAs result in the dysfunction of BAT. Previously, quercetin showed anti-obesity effect through BAT activation. Thus, the purpose of this study was sought to investigate the effect of quercetin on high fat diet (HFD)-induced inflammation and oxidative stress in BAT. Methods C57BL/6 male mice were fed with a HFD or HFD supplemented with 1% quercetin (HFDQ) for 16 weeks. Total RNA was isolated from BAT to measure the expression of target mRNAs such as tumor necrosis factor alpha (TNFa), interleukin (IL) 1b, IL6, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX) 2, NADPH oxidase (NOX) 2, nuclear factor E2-related factor (NRF) 2, superoxide dismutase (SOD) 2, SOD3, and catalase that are involved in regulation of inflammation and oxidative stress, and microRNA (miRNA)-155, a master regulator of inflammation, using a quantitative PCR. Results BAT of HFDQ-fed mice exhibited decreased expression of COX2, TNFa, IL1b, IL6, and iNOS compared to that of HFD-induced obese mice. NOX2 gene encoding an enzyme that generates ROS was also decreased in BAT of HFDQ-fed mice. The genes such as SOD2, SOD3, NRF2, and catalase that are involved in regulation of antioxidant enzymes were significantly increased. As the cognate gene of TNFa, miRNA-155 levels were downregulated. Conclusions Quercetin ameliorates HFD-induced inflammation and oxidative stress in BAT by regulating miRNA-155. Intake of quercetin may improve obese conditions by regulating BAT function through anti-inflammatory and antioxidant effects. Funding Sources This work was supported by USDA.

Effects of Berries on High-Fat Diet-Induced Inflammation

Abstract Objectives Studies suggest that inflammation mediates the link between obesity and its comorbidities including type 2 diabetes and cardiovascular disease. Hence, there is a demand for effective alternative or complementary approaches to treat obesity-associated inflammation. The objective of this study was to determine whether consumption of blackberries (BL) and raspberries (RB) alone or in combination reduce obesity-induced inflammation. Methods In Vitro Study: RAW 264.7 macrophages were pretreated with either BL, RB, or BL + RB, each at a final concentration of 200 µg/mL for 2 h. LPS (1 ng/mL) was then added to the media for 16 h. mRNA expression of inflammatory cytokines was measured. In Vivo Study: Five-week-old mice were acclimated to a low-fat low-sucrose (LFLS) diet for one week after which mice were randomized 10 per group to one of five groups: 1) LFLS, 2) high-fat high-sucrose (HFHS), 3) HFHS + 10% BL, 4) HFHS + 10% RB, or 5) HFHS + 5% BL + 5% RB. Expression of inflammatory markers was measured in the liver as well as epididymal and inguinal white adipose tissue. Results In Vitro Study: Each berry alone and in combination suppressed the LPS-induced increase in inflammatory markers, with the combination (BL + RB) having the greatest effect. The combination suppressed LPS-induced expression of Ccl2, Tnfa, F4/80, and Il6 by 3.7−, 5.3−, 5.3−, and 4.4-fold, respectively. In Vivo Study: Gene expression analysis indicated that berry consumption had no significant effect on proinflammatory (Ccl2, Il1b, Tnfa, Il6, Itgam) or anti-inflammatory (Adipoq, Arg1, Mgl1) markers in adipose tissue depots or liver. However, relatively low gene expression of inflammatory markers in the tissues indicates that the mice fed the HFHS diet failed to develop a robust inflammatory state. Conclusions BL and RB have direct anti-inflammatory effects on immune cells. Initial analysis indicates that consumption of BL and RB has no significant effects on markers of inflammation in a diet-induced mouse model of obesity. However, it is possible that the relatively low levels of inflammation in these mice masked the anti-inflammatory potential of BL and RB. Ongoing analysis will provide additional insights into the effects of BL and RB on inflammation in these tissues. Funding Sources Lewis Foundation Award.

Red Kidney Beans Ameliorate the High Fat Diet-Induced Hepatic Fat Accumulation and Inflammation

Abstract Objectives High fat diet (HFD)-induced obesity links with prevalence of metabolic dysfunction, including low-grade chronic inflammation, insulin resistance, and hepatic steatosis. Dry edible beans (DEBs) play a significant role in human nutrition as a rich source of proteins, carbohydrates, fibers, and various micronutrients. The aim of this study is to evaluate the ability of red kidney beans (RKBs) to attenuate the deleterious effects of HFD in the liver. Methods Syrian hamsters were randomly assigned with one of five experimental diet groups; low fat diet (control), high fat diet, high fat diet with 5% whole beans (HFD + B), high fat diet with 4.5% dehulled beans (HFD + DHB) and high fat diet with 0.5% hull of beans (HFD + HB) and fed for 4 weeks. Results Supplementation of RKB resulted in lower body weight, liver weight, and glucose levels (P &amp;lt; 0.001) in HFD + B and HFD + DHB group compared to HFD group. Adding RKBs downregulated gene expressions related to inflammation (e.g., interleukin 6 (IL-6)) and lipogenesis (e.g., hepatic fatty acid synthase (FASN)) in the liver. Furthermore, RKBs supplemented groups showed reduced hepatic fat accumulation in comparison with the HFD group. Conclusions Supplementation of RKBs and their hulls attenuates hepatic stresses by decreasing the lipogenesis and inflammation, which contribute to enhancing insulin sensitivity. Funding Sources USDA Multi-Hatch, Program: W-3150.

Hot Water Extract of Mulberry Leaf Ameliorates Hepatic Fat Accumulation and Inflammation in Rats Fed a High-Fat Diet

Abstract Objectives This study was conducted to investigate the effect of mulberry leaf extract on hepatic fat accumulation and inflammation in rats fed a high-fat diet. Methods Male Sprague–Dawley rats were randomly divided into three groups. Each group fed normal diet (NOR), high-fat diet (HF), or HF supplemented with 0.8% (w/w) hot water extract of mulberry leaf (HF + ME) for 14 weeks. Results The mulberry extract (ME) supplementation reduced body weight and white adipose tissues (epididymal, retroperitoneal, and mesenteric) weights. Serum levels of triglyceride (TG), total cholesterol (TC), free fatty acids (FFAs), and low-density lipoprotein cholesterol (LDL-C) were lower, while high-density lipoprotein cholesterol (HDL-C) level was higher in the HF + ME group compared to the HF group. The ME reduced the hepatic total lipid, TG, and TC levels compared to the HF group. The mRNA levels of genes related to fatty acid synthesis, such as CD36, sterol regulatory element binding protein 1c (SREBP-1c), and fatty acid synthase (FAS) were down-regulated by the ME supplementation. In addition, the ME lowered the mRNA levels of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), compared to the HF group. The serum TNF-α level of the HF + ME group was significantly lower than that of the HF group. Conclusions These results suggested that the ME attenuated high-fat diet-induced hepatic fat accumulation and inflammation via regulating gene expression related to hepatic lipid metabolism and pro-inflammatory mediators. Therefore, it is postulated that the ME might be useful as a functional food ingredient to prevent obesity-induced hepatic fat accumulation and inflammation. Funding Sources None.

(-)-Epicatechin Mitigates High Fat Diet-induced Inflammation in the Hippocampus and Altered Recognition Memory in Mice

Abstract Objectives This project investigated the capacity of dietary (-)-epicatechin (EC) to mitigate hippocampal inflammation and impaired memory in high fat diet (HFD)-fed mice. Methods Healthy 6 weeks old male C57BL/6J mice (10 mice/group) were fed for 13 weeks either: a control diet (10% total calories from fat), a high fat diet (60% total calories from lard fat), or the control and high fat diets supplemented with 20 mg EC/kg body weight. Between weeks 10 and 12 of the dietary intervention, object recognition memory was evaluated by the novel object recognition task and short-term spatial memory by the object location memory task, and the Morris Water Maze. After 13 weeks on the dietary treatments, mice were euthanized, and brain tissues and blood were collected. Hippocampus was isolated, flash-frozen in liquid nitrogen, and stored at −80°C. Metabolic endotoxemia was assessed by measuring plasma lipopolysaccharide (LPS) levels. Gene expressions related to inflammation (Toll-like receptor 4 (TLR4) and tumor necrosis factor-α (TNF-α)), activation of microglia (ionized calcium-binding adapter molecule 1 (Iba-1)), and oxidative stress (NADPH oxidase 4 (NOX4)) were analyzed in the hippocampus with RT-qPCR. Results After 13 weeks on the dietary treatments, HFD-fed mice developed obesity, endotoxemia, and showed increased parameters of hippocampal inflammation, i.e., high mRNA levels of TLR4, Iba-1, and NOX4. While not affecting body weight gain, EC supplementation prevented all other HFD-induced changes. Impaired recognition memory was observed in HFD-fed mice, which was prevented by EC supplementation. Neither HFD consumption nor EC supplementation affected mouse spatial memory. Conclusions EC supplementation prevented short-term recognition memory in HFD-induced obese mice, which could be in part due to the capacity of EC to mitigate metabolic endotoxemia and associated hippocampal inflammation and oxidative stress. Funding Sources HA Jastro Shields Award.

A human-origin probiotic cocktail ameliorates aging-related leaky gut and inflammation via modulating the microbiota/taurine/tight junction axis.

Inflammation is a major risk factor of morbidity and mortality in older adults. Although its precise etiology is unknown, low-grade inflammation in older adults is commonly associated with increased intestinal epithelial permeability (leaky gut) and abnormal (dysbiotic) gut microbiota. The increasing older population and lack of treatments to reduce aging-related microbiota dysbiosis, leaky gut, and inflammation culminates in a rise in aging-related comorbidities, constituting a significant public health concern. Here, we demonstrate that a human-origin probiotic cocktail containing 5 Lactobacillus and 5 Enterococcus strains isolated from healthy infant gut prevented high-fat diet-induced (HFD-induced) microbiota dysbiosis, leaky gut, inflammation, metabolic dysfunctions, and physical function decline in older mice. Probiotic-modulated gut microbiota primarily reduced leaky gut by increasing tight junctions, which in turn reduced inflammation. Mechanistically, probiotics modulated microbiota in a way to increase bile salt hydrolase activity, which in turn increased taurine abundance in the gut that stimulated tight junctions and suppressed gut leakiness. Furthermore, in Caenorhabditis elegans, taurine increased life span, reduced adiposity and leaky gut, and enhanced physical function. The results suggest that such probiotic therapies could prevent or treat aging-related leaky gut and inflammation in the elderly.

Inhibition of Serine Protease Activity Protects Against High Fat Diet-Induced Inflammation and Insulin Resistance

Recent evidence suggests that enhanced protease-mediated inflammation may promote insulin resistance and result in diabetes. This study tested the hypothesis that serine protease plays a pivotal role in type 2 diabetes, and inhibition of serine protease activity prevents hyperglycemia in diabetic animals by modulating insulin signaling pathway. We conducted a single-center, cross-sectional study with 30 healthy controls and 57 patients with type 2 diabetes to compare plasma protease activities and inflammation marker between groups. Correlations of plasma total and serine protease activities with variables were calculated. In an in-vivo study, LDLR−/− mice were divided into normal chow diet, high-fat diet (HFD), and HFD with selective serine protease inhibition groups to examine the differences of obesity, blood glucose level, insulin resistance and serine protease activity among groups. Compared with controls, diabetic patients had significantly increased plasma total protease, serine protease activities, and also elevated inflammatory cytokines. Plasma serine protease activity was positively correlated with body mass index, hemoglobin A1c, homeostasis model assessment-insulin resistance index (HOMA-IR), tumor necrosis factor-α, and negatively with adiponectin concentration. In the animal study, administration of HFD progressively increased body weight, fasting glucose level, HOMA-IR, and upregulated serine protease activity. Furthermore, in-vivo serine protease inhibition significantly suppressed systemic inflammation, reduced fasting glucose level, and improved insulin resistance, and these effects probably mediated by modulating insulin receptor and cytokine expression in visceral adipose tissue. Our findings support the serine protease may play an important role in type 2 diabetes and suggest a rationale for a therapeutic strategy targeting serine protease for clinical prevention of type 2 diabetes.

Inulin with different degrees of polymerization protects against diet-induced endotoxemia and inflammation in association with gut microbiota regulation in mice

Societal lifestyle changes, especially increased consumption of a high-fat diet lacking dietary fibers, lead to gut microbiota dysbiosis and enhance the incidence of adiposity and chronic inflammatory disease. We aimed to investigate the metabolic effects of inulin with different degrees of polymerization on high-fat diet-fed C57BL/6 J mice and to evaluate whether different health outcomes are related to regulation of the gut microbiota. Short-chain and long-chain inulins exert beneficial effects through alleviating endotoxemia and inflammation. Antiinflammation was associated with a proportional increase in short-chain fatty acid-producing bacteria and an increase in the concentration of short-chain fatty acids. Inulin might decrease endotoxemia by increasing the proportion of Bifidobacterium and Lactobacillus, and their inhibition of endotoxin secretion may also contribute to antiinflammation. Interestingly, the beneficial health effects of long-chain inulin were more pronounced than those of short-chain inulin. Long-chain inulin was more dependent than short-chain inulin on species capable of processing complex polysaccharides, such as Bacteroides. A good understanding of inulin-gut microbiota-host interactions helps to provide a dietary strategy that could target and prevent high-fat diet-induced endotoxemia and inflammation through a prebiotic effect.

SOD3 Is Secreted by Adipocytes and Mitigates High-Fat Diet-Induced Obesity, Inflammation, and Insulin Resistance.

Aims: To study the expression and regulatory role of SOD3 in adipocytes and adipose tissue. Results: SOD3 expression was determined in various tissues of adult C57BL/6J mice, human adipose tissue and epididymal adipose tissue, subcutaneous adipose tissue and brown adipose tissue of high-fat diet (HFD)-induced obese mice. SOD3 expression and release were evaluated in adipocytes differentiated from primary human preadipocytes and murine bone marrow-derived mesenchymal stem cells (BM-MSCs). The regulatory role for SOD3 was determined by SOD3 lentivirus knockdown in human adipocytes and global sod3 knockout (KO) mice. SOD3 was expressed at high levels in white adipose tissue, and adipocytes were the main cells expressing SOD3 in adipose tissue. SOD3 expression was significantly elevated in adipose tissue of HFD-fed mice. Moreover, SOD3 expression and release were markedly increased in differentiated human adipocytes and adipocytes differentiated from mouse BM-MSCs compared with undifferentiated cells. In addition, SOD3 silencing in human adipocytes increased expression of genes involved in lipid metabolic pathways such as PPARγ and SREBP1c and promoted the accumulation of triglycerides. Finally, global sod3 KO mice were more obese and insulin resistant with enlarged adipose tissue and increased triglyceride accumulation. Innovation: Our data showed that SOD3 is secreted from adipocytes and regulates lipid metabolism in adipose tissue. This important discovery may open up new avenues of research for the cytoprotective role of SOD3 in obesity and its associated metabolic disorders. Conclusion: SOD3 is a protective factor secreted by adipocytes in response to HFD-induced obesity and regulates adipose tissue lipid metabolism.

Effect of vegetable oils with different fatty acid composition on high-fat diet-induced obesity and colon inflammation.

BACKGROUND/OBJECTIVESDifferent fatty acids exert different health benefits. This study investigated the potential protective effects of perilla, olive, and safflower oils on high-fat diet-induced obesity and colon inflammation.MATERIALS/METHODSFive-week old, C57BL/6J mice were assigned to 5 groups: low-fat diet (LFD), high-fat diet (HFD) and high-fat diet supplemented with-perilla oil (HPO), olive oil (HOO), and safflower oil (HSO). After 16 weeks of the experimental period, the mice were sacrificed, and blood and tissues were collected. The serum was analyzed for obesity- and inflammation-related biomarkers. Gene expression of the biomarkers in the liver, adipose tissue, and colon tissue was analyzed. Micro-computed tomography (CT) analysis was performed one week before sacrifice.RESULTSTreatment with all the three oils significantly improved obesity-induced increases in body weight, liver weight, and epididymal fat weight as well as serum triglyceride and leptin levels. Treatment with perilla oil (PO) and safflower oil (SO) increased adiponectin levels. The micro-CT analysis revealed that PO and SO reduced abdominal fat volume considerably. The mRNA expression of lipogenic genes was reduced in all the three oil-supplemented groups and PO upregulated lipid oxidation in the liver. Supplementation of oils improved macroscopic score, increased colon length, and decreased serum endotoxin and proinflammatory cytokine levels in the colon. The abundance of Bifidobacteria was increased and that of Enterobacteriaceae was reduced in the PO-supplemented group. All three oils reduced proinflammatory cytokine levels, as indicated by the mRNA expression. In addition, PO increased the expression of tight junction proteins.CONCLUSIONSTaken together, our data indicate that the three oils exert similar anti-obesity effects. Interestingly, compared with olive oil and SO, PO provides better protection against high-fat diet-induced colon inflammation, suggesting that PO consumption helps manage inflammation-related diseases and provides omega-3 fatty acids needed by the body.