High-fat Diet-induced Inflammation Research Articles

Mice lacking myotubularin-related protein 14 show accelerated high-fat diet-induced lipid accumulation and inflammation.

The phosphoinositide phosphatase, myotubularin-related protein 14 (MTMR14), has been reported to play an important role in the regulation of muscle performance, autophagy, and aging in mice. We previously showed that MTMR14-knockout (KO) mice gain weight earlier than their wild-type (WT) littermates even on a normal chow diet (NCD), suggesting that this gene might also be involved in regulating metabolism. In the present study, we evaluated the effect of MTMR14 deficiency on high-fat diet (HFD)-induced obesity, lipid accumulation, metabolic disorders, and inflammation in WT and MTMR14-KO mice fed with NCD or HFD. To this end, MTMR14-KO mice fed with HFD showed significantly increased body weight, blood glucose levels, serum triglyceride (TG) levels, and total cholesterol (TC) levels as compared to their age-matched WT control. Additionally, lipid accumulation also increased in the KO mice. Simultaneously, the expression of metabolism-associated genes (Glut4, adiponectin, and leptin) was different in the liver, muscle, and fatty tissue of MTMR14-KO mice fed with HFD. More importantly, the expression of several inflammation-associated genes (TNF-α, IL-6, IL-1β, and MCP-1) dramatically increased in the liver, muscle, and fatty tissue of MTMR14-KO mice relative to control. Taken together, these results suggest that MTMR14 deficiency accelerates HFD-induced metabolic dysfunction and inflammation. Furthermore, the results showed that exacerbated metabolic dysfunction and inflammation may be regulated via the PI3K/Akt and ERK signaling pathways.

High-Fat Diet-Induced Complement Activation Mediates Intestinal Inflammation and Neoplasia, Independent of Obesity.

This study characterizes the relations between diet and metabolic conditions on risk for a common cancer and identifies complement activation as a novel target for cancer prevention. Mol Cancer Res; 14(10); 953-65. ©2016 AACR.

Hypothalamic kappa opioid receptor mediates both diet-induced and melanin concentrating hormone-induced liver damage through inflammation and endoplasmic reticulum stress.

The opioid system is widely known to modulate the brain reward system and thus affect the behavior of humans and other animals, including feeding. We hypothesized that the hypothalamic opioid system might also control energy metabolism in peripheral tissues. Mice lacking the kappa opioid receptor (κOR) and adenoviral vectors overexpressing or silencing κOR were stereotaxically delivered in the lateral hypothalamic area (LHA) of rats. Vagal denervation was performed to assess its effect on liver metabolism. Endoplasmic reticulum (ER) stress was inhibited by pharmacological (tauroursodeoxycholic acid) and genetic (overexpression of the chaperone glucose‐regulated protein 78 kDa) approaches. The peripheral effects on lipid metabolism were assessed by histological techniques and western blot. We show that in the LHA κOR directly controls hepatic lipid metabolism through the parasympathetic nervous system, independent of changes in food intake and body weight. κOR colocalizes with melanin concentrating hormone receptor 1 (MCH‐R1) in the LHA, and genetic disruption of κOR reduced melanin concentrating hormone–induced liver steatosis. The functional relevance of these findings was given by the fact that silencing of κOR in the LHA attenuated both methionine choline–deficient, diet‐induced and choline‐deficient, high‐fat diet–induced ER stress, inflammation, steatohepatitis, and fibrosis, whereas overexpression of κOR in this area promoted liver steatosis. Overexpression of glucose‐regulated protein 78 kDa in the liver abolished hypothalamic κOR‐induced steatosis by reducing hepatic ER stress. Conclusions: This study reveals a novel hypothalamic–parasympathetic circuit modulating hepatic function through inflammation and ER stress independent of changes in food intake or body weight; these findings might have implications for the clinical use of opioid receptor antagonists. (Hepatology 2016;64:1086‐1104)

Characterization of the Cytochrome P450 epoxyeicosanoid pathway in non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is an emerging public health problem without effective therapies. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into bioactive epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory and protective effects. However, the functional relevance of the CYP epoxyeicosanoid metabolism pathway in the pathogenesis of NASH remains poorly understood. Our studies demonstrate that both mice with methionine-choline deficient (MCD) diet-induced NASH and humans with biopsy-confirmed NASH exhibited significantly higher free EET concentrations compared to healthy controls. Targeted disruption of Ephx2 (the gene encoding for soluble epoxide hydrolase) in mice further increased EET levels and significantly attenuated MCD diet-induced hepatic steatosis, inflammation and injury, as well as high fat diet-induced adipose tissue inflammation, systemic glucose intolerance and hepatic steatosis. Collectively, these findings suggest that dysregulation of the CYP epoxyeicosanoid pathway is a key pathological consequence of NASH in vivo, and promoting the anti-inflammatory and protective effects of EETs warrants further investigation as a novel therapeutic strategy for NASH.

Fenofibrate improves high-fat diet-induced and palmitate-induced endoplasmic reticulum stress and inflammation in skeletal muscle

AimsFenofibrate (FF) is commonly used clinically as a lipid-lowering drug, but whether it participates in endoplasmic reticulum (ER) stress and decreases inflammation in skeletal muscle is still unknown. The aim of this study is to determine whether FF treatment reduces insulin resistance (IR) by alleviating ER stress and downstream inflammation in skeletal muscle tissues and cells. Main methodsFemale SD rats were randomly divided into groups receiving the standard chow diet (SCD), a high-fat diet (HFD), or HFD plus FF (HFD+FF). The rats in the latter two groups were subjected to a standard HFD for 20weeks, then the HFD+FF rats were administered FF (30mg/kg once daily via gavage) for another 8weeks. Whole-body IR, expression of peroxisome proliferator-activated receptor α (PPARα), ER stress-related genes, and inflammatory genes in the soleus muscle were assessed. The differentiated C2C12 myotubes were treated with palmitic acid or pretreated with fenofibric acid or 4-phenylbutyric acid (4-PBA), etomoxir, and the expression of ER stress, beta-oxidation-related genes, inflammatory genes, Toll-like receptor 4 (TLR4), and insulin-signaling-related molecules were determined. Key findingsEight weeks of FF treatment attenuated HFD-induced IR by decreased tribbles 3 (TRB3) expression, ER stress and inflammation in skeletal muscle. FA pretreatment markedly inverted the PA-induced expression of TLR4 and downstream inflammatory genes, activated ER stress, improved β-oxidation and insulin signaling in differentiated myotube cells. SignificanceFF treatment significantly improved HFD-induced IR in skeletal muscle and PA-induced IR in myotube cells, which may be related to reduced ER stress-induced inflammation.

High fat diet promotes prostatic basal-to-luminal differentiation and accelerates initiation of prostate epithelial hyperplasia originated from basal cells

Recent lineage tracing studies showed that the prostate basal and luminal cells in adult mice are two independent lineages under the physiological condition, but basal cells are capable of generating luminal progenies during bacterial infection-induced prostatitis. Because acute bacterial infection in human prostate tissues is relatively rare, the disease relevance of the bacterial infection-induced basal-to-luminal differentiation is uncertain. Herein we employ a high fat diet-induced sterile prostate inflammation model to determine whether basal-to-luminal differentiation can be induced by inflammation irrespective of the underlying etiologies. A K14-CreER model and a fluorescent report line are utilized to specifically label basal cells with the green fluorescent protein. We show that high fat diet promotes immune cell infiltration into the prostate tissues and basal-to-luminal differentiation. Increased cell proliferation accompanies basal-to-luminal differentiation, suggesting a concurrent regulation of basal cell proliferation and differentiation. This study demonstrates that basal-to-luminal differentiation can be induced by different types of prostate inflammation evolved with distinct etiologies. Finally, high fat diet also accelerates initiation and progression of prostatic intraepithelial neoplasia that are originated from basal cells with loss-of-function of the tumor suppressor Pten. Because prostate cancer originated from basal cells tends to be invasive, our study also provides an alternative explanation for the association between obesity and aggressive prostate cancer.

Seaweed Supplementation Attenuates Long‐term High Fat Diet‐induced Chronic Inflammation and Insulin Resistance Regardless of Obesity in C57BL/6N Mice

Antidiabetic and anti‐inflammatory effects of brown seaweeds have been reported in various experimental models, however information is scarce on their effects combined with a long‐term high fat diet. In this present study, we investigated that effects and mechanisms of seaweed supplementation (Undaria pinnatifida (UP), Laminaria japonica (LJ), Sargassum fulvellum (SF), Hizikia fusiforme (HF)) along with high‐fat (HF) diet in C57BL/6N male mice for 16 weeks. Body weight, food intake, and fasting blood glucose concentrations were measured. Insulin tolerance test was performed at week 14. Animals were sacrificed at week 16 and tissues were dissected, weighted, and snap frozen for analysis. Bone‐marrow (BM) cells were isolated from femoral and tibial BM of a representative mouse from each group. As a result, 5% seaweed supplementation did not prevent HF‐induced obesity. Although there was a trend to have less weight gain in HF+LJ and HF+HF groups compared to HF group at week 8, this trend disappeared as HF continued. In spite of being obese, mice in HF+LJ group had significantly improved insulin resistance, lowered cholesterol in plasma and liver, and increased TG in feces compared to mice in HF group that were consistent with histological observations. In addition, BM‐derived macrophages(BMDM) from mice fed HF with seaweeds showed to have less inflammatory cytokines compared to BMDM from mice fed HF only. Increased phosphorylation of insulin signaling proteins was observed in liver of the seaweed supplemented HF groups compared to the HF group. In addition, levels of TG and cholesterol excretion were altered by seaweed supplementation. Conclusively, seaweed supplementation attenuated insulin resistance and chronic inflammation induced by a long‐term HF feeding partially due to altered insulin signaling and lipogenesis in liver and muscle as well as reduced inflammation in adipose tissue regardless of obesity in C57BL/6N mice.Support or Funding InformationThis work was supported by NRF‐2013R1A1A10575730.

Inhibition of inflammation and oxidative stress by an imidazopyridine derivative X22 prevents heart injury from obesity.

Inflammation and oxidative stress plays an important role in the development of obesity‐related complications and cardiovascular disease. Benzimidazole and imidazopyridine compounds are a class of compounds with a variety of activities, including anti‐inflammatory, antioxidant and anti‐cancer. X22 is an imidazopyridine derivative we synthesized and evaluated previously for anti‐inflammatory activity in lipopolysaccharide‐stimulated macrophages. However, its ability to alleviate obesity‐induced heart injury via its anti‐inflammatory actions was unclear. This study was designed to evaluate the cardioprotective effects of X22 using cell culture studies and a high‐fat diet rat model. We observed that palmitic acid treatment in cardiac‐derived H9c2 cells induced a significant increase in reactive oxygen species, inflammation, apoptosis, fibrosis and hypertrophy. All of these changes were inhibited by treatment with X22. Furthermore, oral administration of X22 suppressed high‐fat diet‐induced oxidative stress, inflammation, apoptosis, hypertrophy and fibrosis in rat heart tissues and decreased serum lipid concentration. We also found that the anti‐inflammatory and anti‐oxidative actions of X22 were associated with Nrf2 activation and nuclear factor‐kappaB (NF‐κB) inhibition, respectively, both in vitro and in vivo. The results of this study indicate that X22 may be a promising cardioprotective agent and that Nrf2 and NF‐κB may be important therapeutic targets for obesity‐related complications.

Bardoxolone Methyl Prevents High-Fat Diet-Induced Colon Inflammation in Mice.

Obesity induces chronic, low-grade inflammation, which increases the risk of colon cancer. We investigated the preventive effects of Bardoxolone methyl (BARD) on high-fat diet (HFD)-induced inflammation in a mouse colon. Male C57BL/6J mice (n=7) were fed a HFD (HFD group), HFD plus BARD (10 mg/kg) in drinking water (HFD/BARD group), or normal laboratory chow diet (LFD group) for 21 weeks. In HFD mice, BARD reduced colon thickness and decreased colon weight per length. This was associated with an increase in colon crypt depth and the number of goblet cells per crypt. BARD reduced the expression of F4/80 and CD11c but increased CD206 and IL-10, indicating an anti-inflammatory effect. BARD prevented an increase of the intracellular pro-inflammatory biomarkers (NF-қB, p NF-қB, IL-6, TNF-α) and cell proliferation markers (Cox2 and Ki67). BARD prevented fat deposition in the colon wall and prevented microbial population changes. Overall, we report the preventive effects of BARD on colon inflammation in HFD-fed mice through its regulation of macrophages, NF-қB, cytokines, Cox2 and Ki67, fat deposition and microflora.

Critical role of the C5a-activated neutrophils in high-fat diet-induced vascular inflammation.

Exceed and chronic high-fat diet (HFD) contributes to the diagnosis and development of atherosclerosis, obesity, and metabolic syndrome. However, the key molecular component(s) triggered by HFD responsible for initiating vascular inflammation remain unknown. We observed that feeding HFD for 4 weeks is sufficient to induce leukocyte recruitment in the femoral artery of wild-type mice. Neutrophil- and monocyte-depletion analyses confirmed the preferential recruitment of neutrophils in these mice. Protein analysis of sera from HFD-fed mice revealed a marked elevation of complement component C5a levels. Exogenous C5a alone induced leukocyte recruitment, which was abolished by a C5a-receptor antagonist. We also examined the role of neutrophil-derived MCP-1 in accumulation of leukocytes in the artery. These results demonstrated a previously unrecognized role for C5a and neutrophils in the early onset of HFD-induced vascular inflammation. Further study may help in elucidating a novel regulatory pathway to control diet-induced inflammation such as that in case of atherosclerosis.

Interleukin-15-mediated inflammation promotes non-alcoholic fatty liver disease

Interleukin-15 (IL-15) is essential for the homeostasis of lymphoid cells particularly memory CD8+ T cells and NK cells. These cells are abundant in the liver, and are implicated in obesity-associated pathogenic processes. Here we characterized obesity-associated metabolic and cellular changes in the liver of mice lacking IL-15 or IL-15Rα. High fat diet-induced accumulation of lipids was diminished in the livers of mice deficient for IL-15 or IL-15Rα. Expression of enzymes involved in the transport of lipids in the liver showed modest differences. More strikingly, the liver tissues of IL15-KO and IL15Rα-KO mice showed decreased expression of chemokines CCl2, CCL5 and CXCL10 and reduced infiltration of mononuclear cells. In vitro, IL-15 stimulation induced chemokine gene expression in wildtype hepatocytes, but not in IL15Rα-deficient hepatocytes. Our results show that IL-15 is implicated in the high fat diet-induced lipid accumulation and inflammation in the liver, leading to fatty liver disease.

Activation of proteinase 3 contributes to Non-alcoholic Fatty Liver Disease (NAFLD) and insulin resistance.

Activation of inflammatory pathways is known to accompany development of obesity-induced non-alcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes. In addition to caspase-1, the neutrophil serine proteases proteinase 3, neutrophil elastase and cathepsin G are able to process the inactive pro-inflammatory mediators IL-1β and IL-18 to their bioactive forms, thereby regulating inflammatory responses. In the present study, we investigated whether proteinase 3 is involved in obesity-induced development of insulin resistance and NAFLD. We investigated the development of NAFLD and insulin resistance in mice deficient for neutrophil elastase/proteinase 3 and neutrophil elastase/cathepsin G and in wild-type mice treated with the neutrophil serine proteinase inhibitor human alpha-1 antitrypsin. Expression profiling of metabolically relevant tissues obtained from insulin resistant mice showed that expression of proteinase 3 was specifically upregulated in the liver, whereas neutrophil elastase, cathepsin G and caspase-1 were not. Neutrophil elastase/proteinase 3 deficient mice showed strongly reduced levels of lipids in the liver after fed a high fat diet. Moreover, these mice were resistant to high fat diet-induced weight gain, inflammation and insulin resistance. Injection of proteinase 3 exacerbated insulin resistance in caspase-1(-/-) mice, indicating that proteinase 3 acts independently of caspase-1. Treatment with alpha-1 antitrypsin during the last 10 days of a 16 week high fat diet reduced hepatic lipid content and decreased fasting glucose levels. We conclude that proteinase 3 is involved in NAFLD and insulin resistance and that inhibition of proteinase 3 may have therapeutic potential.

High fat diet-induced inflammation and oxidative stress are attenuated by N-acetylneuraminic acid in rats.

BackgroundSerum sialic acid levels are positively correlated with coronary artery disease and inflammation. Although sialic acid is a non-specific marker, it is considered sensitive likely due to its influence in sialylation of glycoprotein structures all over the body.ObjectivesWe hypothesized that dietary supplementation with N-acetylneuraminic acid (Neu5Ac), a type of sialic acid, will have profound effects on high fat diet- (HFD-) induced inflammation and oxidative stress in view of the widespread incorporation of sialic acid into glycoprotein structures in the body.MethodsHFD-fed rats with or without simvastatin or Neu5Ac (50 and 400 mg/kg/day) were followed up for 12 weeks. Lipid profiles, and markers of inflammation (C-reactive protein, interleukin-6, and tumor necrosis factor alpha), insulin resistance (serum insulin and adiponectin, oral glucose tolerance test and homeostatic model of insulin resistance) and oxidative stress (total antioxidant status and thiobarbituric acid reactive species) in the serum and liver were determined, while mRNA levels of hepatic antioxidant and inflammation genes were also quantified. Serum levels of alanine transaminase, aspartate transaminase, alkaline phosphatase, urea, creatinine and uric acid were also assessed.ResultsHFD feeding caused hyperlipidemia and insulin resistance, and worsened liver and kidney functions. HFD feeding also potentiated inflammation and oxidative stress, partly through modulation of hepatic gene expression, while Neu5Ac especially at higher doses and simvastatin attenuated HFD-induced changes, although Neu5Ac showed better outcomes.ConclusionsBased on the present results, we surmised that Neu5Ac can prevent HFD-induced inflammation and oxidative stress, and may in fact be useful in the prevention of hyperlipidemia-associated inflammation and oxidative stress. However, the translational implications of these findings can only be determined after long-term effects are established. Hence, the use of Neu5Ac on obesity-related diseases requires additional attention.

Odontella aurita-enriched diet prevents high fat diet-induced liver insulin resistance.

The beneficial effect of polyunsaturated omega-3 fatty acid (w-3 FA) consumption regarding cardiovascular diseases, insulin resistance and inflammation has been widely reported. Fish oil is considered as the main source of commercialized w-3 FAs, and other alternative sources have been reported such as linseed or microalgae. However, despite numerous reports, the underlying mechanisms of action of w-3 FAs on insulin resistance are still not clearly established, especially those from microalgae. Here, we report that Odontella aurita, a microalga rich in w-3 FAs eicosapentaenoic acid, prevents high fat diet-induced insulin resistance and inflammation in the liver of Wistar rats. Indeed, a high fat diet (HFD) increased plasma insulin levels associated with the impairment of insulin receptor signaling and the up-regulation of toll-like receptor 4 (TLR4) expressions. Importantly, Odontella aurita-enriched HFD (HFOA) reduces body weight and plasma insulin levels and maintains normal insulin receptor expression and responsiveness. Furthermore, HFOA decreased TLR4 expression, JNK/p38 phosphorylation and pro-inflammatory factors. In conclusion, we demonstrate for the first time, to our knowledge, that diet supplementation with whole Ondontella aurita overcomes HFD-induced insulin resistance through the inhibition of TLR4/JNK/p38 MAP kinase signaling pathways.

Edible Bird's Nest attenuates high fat diet-induced oxidative stress and inflammation via regulation of hepatic antioxidant and inflammatory genes.

BackgroundEdible Bird’s nest (EBN) is an antioxidant-rich supplement that is popular in many parts of Asia. Its antioxidant and anti-inflammatory properties have been reported using in vitro system. This paper aimed to determine the antioxidant and anti-inflammatory effects of EBN in in high fat diet induced rats model.MethodsWe evaluate if those properties can be translated in rats. High fat diet (HFD) was fed to rats for 12 weeks to determine its effects on oxidative stress and inflammation, and compared with HFD + Simvastatin and HFD + EBN (2.5 or 20 %). Weights were measured weekly, while serum and hepatic markers of oxidative stress (total antioxidant status and TBARS) and inflammation (interleukin 6 [IL-6], C-reactive protein [CRP] and tumor necrosis factor alpha [TNF-α]) were determined at the end of the intervention. In addition, transcriptional changes in hepatic antioxidant (superoxide dismutase, glutathione reductase, glutathione peroxidase) and inflammation (C-reactive protein, chemokine [C-C] motif 2, nuclear factor kappa beta 1 and tumor necrosis factor alpha) genes were evaluated.ResultsThe results showed increases in oxidative stress (raised TBARS and lowered total antioxidant status) and inflammatory markers (raised CRP, IL-6 and TNF-α) in HFD induced rats with corresponding attenuation of antioxidant gene expression and potentiation of inflammatory gene expression. EBN on the other hand attenuated the HFD-induced inflammation and oxidative stress and produced overall better outcomes in comparison with simvastatin.ConclusionsIn aggregate, the results support the evidence-based utilization of EBN as a supplement for preventing obesity-related inflammation and oxidative stress in rats. These promising results can open up opportunities for translating the benefits of EBN to humans.

Abstract P231: High Fat Diet-induced Er Stress and Inflammation in the Kidney: Role of Trpv1-positive Afferent Renal Nerves

Chronic high fat diet (HFD) intake may lead to enhancement in endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) production, and inflammation in the kidney, but the mechanisms of HD effects are largely unknown. This study tests the hypothesis that HFD impairs afferent renal nerves expressing the transient receptor potential vanilloid 1 (TRPV1) channels, and that stimulating/preserving TRPV1-positive afferent renal nerves prevents against HFD-induced increases in ER stress, ROS production, and inflammation in the kidney. HFD decreased levels of TRPV1 in the kidney, levels of urinary calcitonin-gene related peptide (CGRP) and substance P (SP), and responses of afferent renal nerve activity (ARNA) to capsaicin, a TRPV1 agonist, perfused into the renal pelvis. HFD increased ER stress (XBP-1, CREB2, GRP78, p-JNK), ROS production (urinary 8-isoprostane), and inflammation (TNF-α, IL-1β) in the kidney. N-oleoyldopamine (OLDA, a TRPV1 agonist, 1 ng/kg, daily) or vehicle was given intrathecally (i.t.) via indwelled catheters to segments (T8-L3) supplying the kidneys of rats fed a HFD or normal fat diet (Con) for 8 weeks. OLDA prevented HFD-induced decreases in the levels of renal TRPV1, urinary CGRP and SP, and ARNA responses to capsaicin, as well as HFD-induced increases in renal ER stress, ROS production, and inflammation. OLDA-induced protection during HFD was abolished by degeneration of TRPV1-positive afferent renal nerves by topical application of resiniferatoxin (RTX, 2 μg/ml x 2 times), a potent TRPV1 agonist, on renal nerves (TNF-α, Con: 0.17±0.02, HFD: 0.41±0.03, HFD+OLDA: 0.21±0.02, HFD+OLDA+RTX: 0.46±0.04, p<0.05; 8-isoprostane, Con: 8.8±1.2, HFD: 17±2, HFD+OLDA: 11±1, HFD+OLDA+RTX: 22±3 ng/day, p<0.05). Thus, our data show that HFD impairs TRPV1-positive afferent renal nerves, and chronic stimulation of TRPV1 via intrathecal injection of OLDA to T8-L3 segments preserves TRPV1-positive afferent renal nerves to against HFD-induced ER stress, ROS production, and inflammation in the kidney given that impairment of this population of afferent renal nerves abolishes OLDA effects. These data indicate that TRPV1-positive afferent renal nerves play a counteractive role against HFD-induced renal injury.

Rice bran prevents high-fat diet-induced inflammation and macrophage content in adipose tissue.

The inflammatory process associated with obesity mainly arises from white adipose tissue (WAT) alterations. In the last few years, nutritional-based strategies have been positioned as promising alternatives to pharmacological approaches against these pathologies. Our aim was to determine the potential of a rice bran enzymatic extract (RBEE)-supplemented diet in the prevention of metabolic, biochemical and functional adipose tissue and macrophage changes associated with a diet-induced obesity (DIO) in mice. C57BL/6J mice were fed high-fat diet (HF), 1 and 5% RBEE-supplemented high-fat diet (HF1% and HF5%, respectively) and standard diet as control. Serum cardiometabolic parameters, adipocytes size and mRNA expression of pro-inflammatory biomarkers and macrophage polarization-related genes from WAT and liver were evaluated. RBEE administration significantly decreased insulin resistance in obese mice. Serum triglycerides, total cholesterol, glucose, insulin, adiponectin and nitrites from treated mice were partially restored, mainly by 1% RBEE-enriched diet. The incremented adipocytes size observed in HF group was reduced by RBEE treatment, being 1% more effective than 5% RBEE. Pro-inflammatory biomarkers in WAT such as IL-6 and IL-1β were significantly decreased in RBEE-treated mice. Adiponectin, PPARγ, TNF-α, Emr1 or M1/M2 levels were significantly restored in WAT from HF1% compared to HF mice. RBEE-supplemented diet attenuated insulin resistance, dyslipidemia and morphological and functional alterations of adipose tissue in DIO mice. These benefits were accompanied by a modulating effect in adipocytes secretion and some biomarkers associated with macrophage polarization. Therefore, RBEE may be considered an alternative nutritional complement over metabolic syndrome and its complications.

Acute Exercise Improves Indices Of High Fat Diet-Induced Brain Inflammation And Neurodegeneration

Obesity and type 2 diabetes are significant risk factors in the development of neurodegenerative diseases, such as Alzheimer’s disease (AD). A variety of cellular mechanisms, such as altered AKT, AMPK, and increased inflammatory signaling contribute to neurodegeneration. Exercise has beneficial effects on cognition and can improve markers of neurodegeneration but the underlying mechanisms remain largely unknown. PURPOSE: To determine the effects of a single bout of exercise on markers of neurodegeneration and inflammation in brains from mice fed a high fat diet. METHODS: Male C57BL/6 mice were fed a low (LFD, 10% kcals from lard) or a high fat diet (HFD, 60% kcals from lard) for 7 weeks. HFD mice then underwent an acute bout of exercise (treadmill running: 15 m/min, 5% incline, 120 min) followed by a recovery period of 2. Results: The HFD resulted in increased body mass (LFD 30.0±0.81 vs HFD 43.1±1.18 g; p<0.05) and glucose intolerance (AUC LFD 958.7±45.6 vs HFD 1806±119.4; p<0.05). This was accompanied by an ∼2 fold increase in the activation of AKT, ERK, and GSK in the cerebral cortex (p<0.05). Following exercise, AKT, ERK, and GSK phosphorylation were decreased to a level similar to that of the LFD mice (p<0.05). Further, AMPK phosphorylation was reduced 2 hours post-exercise, indicative of a decline in cellular stress (HFD 1.5±0.29 vs 2h 0.4±0.06 A.U.; p<0.05). Together this was accompanied by a decrease in beta-site amyloid precursor protein cleaving enzyme 1 (BACE) content post-exercise (HFD 1.2±0.1 vs 2h 0.78±0.05; p<0.05). There were no apparent effects of HFD or exercise on gliosis, assessed as total protein content of GFAP or IBa1. CONCLUSION: Findings from this study provide evidence to suggest that a single, acute bout of exercise may have beneficial neuro-protective effects in obesity. These protective effects may be mediated through reduced AKT, ERK, GSK, and AMPK signaling in the cortex. Supported by Alzheimer Society Canada.

Medium-chain triglyceride ameliorates insulin resistance and inflammation in high fat diet-induced obese mice.

The aim of the present study was to investigate the in vivo effects of dietary medium-chain triglyceride (MCT) on inflammation and insulin resistance as well as the underlying potential molecular mechanisms in high fat diet-induced obese mice. Male C57BL/6J mice (n = 24) were fed one of the following three diets for a period of 12 weeks: (1) a modified AIN-76 diet with 5 % corn oil (normal diet); (2) a high-fat control diet (17 % w/w lard and 3 % w/w corn oil, HFC); (3) an isocaloric high-fat diet supplemented with MCT (17 % w/w MCT and 3 % w/w corn oil, HF-MCT). Glucose metabolism was evaluated by fasting blood glucose levels and intraperitoneal glucose tolerance test. Insulin sensitivity was evaluated by fasting serum insulin levels and the index of homeostasis model assessment-insulin resistance. The levels of serum interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α were measured by ELISA, and hepatic activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways was determined using western blot analysis. Compared to HFC diet, consumption of HF-MCT did not induce body weight gain and white adipose tissue accumulation in mice. HFC-induced increases in serum fasting glucose and insulin levels as well as glucose intolerance were prevented by HF-MCT diet. Meanwhile, HF-MCT resulted in significantly lower serum IL-6 level and higher IL-10 level, and lower expression levels of inducible nitric oxide synthase and cyclooxygenase-2 protein in liver tissues when compared to HFC. In addition, HF-MCT attenuated HFC-triggered hepatic activation of NF-κB and p38 MAPK. Our study demonstrated that MCT was efficacious in suppressing body fat accumulation, insulin resistance, inflammatory response, and NF-κB and p38 MAPK activation in high fat diet-fed mice. These data suggest that MCT may exert beneficial effects against high fat diet-induced insulin resistance and inflammation.

The effects of high fat diet and moderate exercise on TGFβ1 and collagen deposition in mouse skeletal muscle

Obesity is a primary cause of muscle insulin resistance and is also associated with morphological and functional changes in the skeletal muscle including fibrosis. Studies suggest that macrophages in obese skeletal muscle may be primed to secrete transforming growth factor β1 (TGFβ1), a factor that can stimulate type I collagen gene expression via Smad3 activation but the extent to which exercise could modulate high fat (HF) diet-induced inflammation and fibrosis in skeletal muscle remains to be determined. The purpose of this study was to determine the extent to which moderate intensity exercise training can attenuate pro-inflammatory cytokine gene expression and markers of fibrosis in skeletal muscle in response to concomitant HF diet. Male C57BL/6J mice (6 wk old) were randomly assigned to one of four treatment groups: (1) Control diet-No Exercise (CON-No Ex), (2) CON-Ex, (3) HF-No Ex, or (4) HF-Ex. Mice were exercised on a motorized treadmill 40min/day at 12m/min, 5% grade, 5days/wk, for 12weeks. Macrophage (F4/80, CD11c, CD206), inflammatory cytokine (TNFα, IL-6, IL-10), TGFβ1, and collagen (Col1α) gene expression were evaluated in skeletal muscle by qPCR. Frozen muscle sections were stained to assess collagen content and fiber cross sectional area (CSA). F4/80, CD206 and IL-6 gene expression were increased by HF diet, and exercise only attenuated the increase in F4/80 and IL-6 (p<0.05). No differences in CD11c, TNFα and IL-10 gene expression were found between the groups. HF diet increased TGFβ1 protein expression, Smad3 activation, and collagen deposition in skeletal muscle, and exercise attenuated TGFβ1 protein expression and collagen deposition in skeletal muscle (p<0.05). Muscle fiber CSA was not different between the groups. The results from this study suggest that HF diet can increase skeletal muscle macrophage gene expression and fibrosis and that exercise can attenuate these changes.