Inflammation In Diet-induced Obese Mice Research Articles

Saikosaponin A Ameliorates Metabolic Inflammation and Intestinal Barrier Damage in DIO Mice through the Nrf2/ARE Pathway.

Obesity is linked to impaired intestinal barrier function and inflammation. Saikosaponin A (SSA), a triterpene saponin from Bupleurum chinense, has shown beneficial effects on intestinal colitis in mice. However, the mechanisms underlying SSA's protective effects against obesity are not fully understood. To investigate the effects of SSA on body weight, metabolic disturbances, and intestinal health in diet-induced obese (DIO) mice, and to elucidate the potential mechanisms involved. In the in vivo study, DIO mice were supplemented with SSA. Body weight, fasting blood glucose, and metabolic parameters were measured. Intestinal barrier function and inflammation were assessed. In the in vitro study, intestinal epithelial cells were treated with palmitic acid and lipopolysaccharide to induce inflammation. SSA was then administered to evaluate its effects on cell barrier integrity and inflammatory responses. The role of the nuclear factor-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway was investigated by silencing Nrf2. SSA supplementation significantly (p < 0.05) decreased body weight and fasting blood glucose levels in DIO mice, and markedly improved metabolic disturbances. This treatment also enhanced intestinal barrier function and reduced metabolic inflammation, likely through increased antioxidant capacity of intestinal epithelial cells via activation of the Nrf2/ARE signaling pathway. In vitro, SSA maintained cell barrier integrity and reduced inflammatory responses by activating the Nrf2/ARE signaling pathway, decreasing intracellular reactive oxygen species content, and increasing transepithelial electrical resistance. However, silencing Nrf2 abolished SSA's protective effects. SSA enhances the antioxidant capacity of intestinal epithelial cells, maintains intestinal barrier integrity, and reduces intestinal inflammation in DIO mice through the activation of the Nrf2/ARE signaling pathway. These findings offer new insights into the protective role of SSA in obesity and metabolic diseases.

P31-036-23 Metabolic Effects of Diets Containing Ammoniated Beef on Hepatic Lipid Metabolism and Inflammation in Diet-Induced Obese Mice

P31-036-23 Metabolic Effects of Diets Containing Ammoniated Beef on Hepatic Lipid Metabolism and Inflammation in Diet-Induced Obese Mice

Dietary Sinapic Acid Alleviates Adiposity and Inflammation in Diet-Induced Obese Mice.

Sinapic acid (SA), a hydroxycinnamic acid, is known to confer protection against oxidative stress, inflammation, diabetes, and liver disease. However, the effectiveness of SA in improving obesity remains obscure. Therefore, this study evaluated anti-obesity efficacy of SA and to elucidate its mechanism of action. Male mice were maintained for 16 weeks on high-fat diet (HFD) alone or with SA (0.004%, w/w) and bodyweight, fat mass, adipocyte size, food intake, and biochemical and molecular markers were evaluated. SA-supplemented mice demonstrated markedly decreased fat mass and adipocyte size compared to unsupplemented group, without any changes in bodyweight and food intake between the two groups. Plasma adipocytokines levels including leptin, resistin, monocyte chemoattractant protein (MCP)-1 and interleukin-6 were also markedly reduced by SA supplementation. SA tended to lower plasma insulin level and improved homeostatic index of insulin resistance and intraperitoneal glucose tolerance test in HFD-induced obese mice. The anti-adiposity effect of SA was maybe owing to down-regulation of the mRNA expression of lipogenic genes, including acetyl coenzyme A (CoA) carboxylase, fatty acid synthesis, stearoyl-CoA desaturase 1, and phosphatidate phosphatase, and peroxisome proliferator-activated receptor γ, a transcription factor responsible for governing lipid metabolism, in adipose tissues. SA significantly down-regulated pro-inflammatory nuclear factor kappa B, MCP-1, tumor necrosis factor-α, and Toll-like receptor 4 mRNA expression in adipose tissue. Thus, SA could be beneficial for the development of functional foods or herbal medications to combat obesity.

Polycationic PAMAM ameliorates obesity-associated chronic inflammation and focal adiposity

As a surging public health crisis, obesity and overweight predispose individuals to various severe comorbidities contributed by the accompanying chronic inflammation. However, few options exist for tackling chronic inflammation in obesity or inhibiting depot-specific adiposity. Here, we report that polycationic polyamidoamine (PAMAM) treatment can improve both aspects of obesity. With the discovery that the plasma cell-free RNA (cfRNA) level is elevated in obese subjects, we applied the cationic PAMAM generation 3 (P-G3) scavenger to treat diet-induced obese (DIO) mice. Intraperitoneal delivery of P-G3 alleviated the chronic inflammation in DIO mice and reduced their body weight, resulting in improved metabolic functions. To further enhance the applicability of P-G3, we complexed P-G3 with human serum albumin (HSA) to attain a sustained release, which showed consistent benefits in treating DIO mice. Local injection of HSA-PG3 into subcutaneous fat completely restricted the distribution of the complex within the targeted depot and reduced focal adiposity. Our study illuminates a promising cationic strategy to ameliorate chronic inflammation in obesity and target local adiposity.

DNAJB3 Deficiency Exacerbates Diet-Induced Obesity and Insulin Resistance

ObjectivesThe prevalence of obesity and Type 2 Diabetes (T2D) continues to rise worldwide, leading to many other chronic diseases and imposing a large economic burden. DNAJ, also known as HSP40 (Heat Shock Protein-40), subfamily B, member 3 (DNAJB3), is a chaperone protein that can be induced under various stressors. Recent reports implicated DNAJB3 in protection against obesity and T2D. Specifically, DNAJB3 was downregulated in some patients with obesity and T2D; however, precise underlying mechanisms remained unclear. We hypothesized that lack of DNAJB3 will increase body weight and body fat, inflammation, glucose intolerance and insulin resistance in diet-induced obese mice, compared to B6 wild type (WT) littermates fed the same diets. MethodsThree DNAJB3 knockout (KO) mutant lines were generated at the Pennington Biomedical Research Center (KO 30, 44 and 47). Male and female KO and wild type (WT) littermates were fed a high fat diet (45% kcal fat) for 12 weeks. Body weight and composition were measured weekly, and a glucose tolerance test (GTT) was conducted. Following euthanasia, blood, adipose and muscle tissues were harvested and used for serum analyses and tissue gene/protein expression, respectively. ResultsCompared to WT, only DNAJB3 KO male and female mice of line 47 demonstrated significantly higher body weight and fat mass (P < 0.05). Similarly, line 47 also showed a lower rate of glucose clearance as measured by GTT. Consistent with increased body weight and fat mass, male mice in line 47 also exhibited significantly higher mRNA levels of inflammatory markers including TNFα and IL-1β, in gonadal fat, compared to WT and lines 30 and 44. Moreover, similar trends towards increased TNF-α and MCP-1 expression was observed in muscle tissues of KO males of line 47, when compared to WT (P < 0.47), and line 30 (P < 0.15) respectively. ConclusionsAbsence of DNAJB3, increases adiposity, glucose intolerance and inflammation in diet-induced obese mice in both males and females. these findings suggest that DNAJB3 plays an important role in metabolic functions and glucose homeostasis, which warrants further research as a potential therapeutic target for obesity and T2D. Funding SourcesFunded by Qatar National Research Funds, Hamad Bin Khalifa University & Qatar Biomedical Research Institute, Qatar.

Mechanisms Mediating Dose-Dependent Effects of Eicosapentaenoic Acid in White Adipose Tissue From High Fat Diet-Induced Obese Mice

ObjectivesObesity is a global epidemic and complex disease associated with an expansion of white adipose tissue (WAT). Obesity is accompanied by chronic low-grade inflammation, characterized by elevated levels of secreted pro-inflammatory cytokines and M1 macrophage infiltration into WAT. Eicosapentaenoic acid (EPA), a long-chain omega-3 polyunsaturated fatty acid, has been reported to have anti-obesity and anti-inflammatory properties. Moreover, we previously showed that EPA dose-dependently improved glucose intolerance, and inflammation in diet-induced obese mice. The objective of this study is to further determine mechanisms underlying these metabolic protective effects of EPA in epididymal WAT (e-WAT). MethodsMale B6 mice were fed a HF diet (45% kcal fat) or a HF diet supplemented with 9, 18, or 36 g/kg of EPA-enriched fish oil (EPA 9, 18 or 36) for 14 weeks. We performed histological assessments in eWAT to determine adipocyte size; and measure macrophage infiltration by immunohistochemistry using galectin-3. RNA was isolated from eWAT for RNA sequencing and gene expression analyses. Data were analyzed using GraphPad Prism software. ResultsEPA36-fed mice had significantly lower body weight and fat percentage, compared to HF (P < 0.05). In addition, EPA18 and 36 significantly decreased weight of e-WAT (P < 0.05) and increased glucose clearance compared to HF (P < 0.05). Moreover, all EPA doses had smaller adipocytes (P < 0.05). Compared to HF, EPA18 and 36 significantly reduced macrophage infiltration in e-7.43 fold, respectively. Consistent with these changes, EPA18 and 36 reduced the mRNA levels of HF-induced inflammatory markers, including arachidonate 5-lipoxygenase (Alox5) and leukotriene B4 receptor (Ltb4r) compared to HF (P < 0.05). RNA Seq analyses revealed that EPA18 attenuated HF-induced inflammation in part by up-regulating cyclic AMP (cAMP)-dependent protein kinase A (PKA) signaling pathways and down-regulating triggering receptor expressed on myeloid cells 1 (TREM1) signaling. ConclusionsEPA dose-dependently ameliorated HF-induced obesity and inflammation by reducing adipocyte size and macrophage infiltration and modulating pro- and anti-inflammatory pathways in e-WAT. These effects were achieved at human equivalent doses, that are currently prescribed for reducing triglycerides. Funding SourcesUSDA NIFA NIH.

Adiponectin receptor agonist AdipoRon ameliorates renal inflammation in diet-induced obese mice and endotoxin-treated human glomeruli ex vivo

Aims/hypothesisChronic low-grade inflammation with local upregulation of proinflammatory molecules plays a role in the progression of obesity-related renal injury. Reduced serum concentration of anti-inflammatory adiponectin may promote chronic inflammation. Here, we investigated the potential anti-inflammatory and renoprotective effects and mechanisms of action of AdipoRon, an adiponectin receptor agonist.MethodsWild-type DBA/2J mice were fed with high-fat diet (HFD) supplemented or not with AdipoRon to model obesity-induced metabolic endotoxaemia and chronic low-grade inflammation and we assessed changes in the glomerular morphology and expression of proinflammatory markers. We also treated human glomeruli ex vivo and human podocytes in vitro with AdipoRon and bacterial lipopolysaccharide (LPS), an endotoxin upregulated in obesity and diabetes, and analysed the secretion of inflammatory cytokines, activation of inflammatory signal transduction pathways, apoptosis and migration.ResultsIn HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-κB p65 subunit (NF-κB-p65) (70%, p < 0.001), TNFα (48%, p < 0.01), IL-1β (51%, p < 0.001) and TGFβ (46%, p < 0.001), renal IL-6 and IL-4 (21% and 20%, p < 0.05), and lowered glomerular F4/80-positive macrophage infiltration (31%, p < 0.001). In addition, AdipoRon ameliorated HFD-induced glomerular hypertrophy (12%, p < 0.001), fibronectin accumulation (50%, p < 0.01) and podocyte loss (12%, p < 0.001), and reduced podocyte foot process effacement (15%, p < 0.001) and thickening of the glomerular basement membrane (18%, p < 0.001). In cultured podocytes, AdipoRon attenuated the LPS-induced activation of the central inflammatory signalling pathways NF-κB-p65, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38-MAPK) (30%, 36% and 22%, respectively, p < 0.001), reduced the secretion of TNFα (32%, p < 0.01), and protected against podocyte apoptosis and migration. In human glomeruli ex vivo, AdipoRon reduced the LPS-induced secretion of inflammatory cytokines IL-1β, IL-18, IL-6 and IL-10.Conclusions/interpretationAdipoRon attenuated the renal expression of proinflammatory cytokines in HFD-fed mice and LPS-stimulated human glomeruli, which apparently contributed to the amelioration of glomerular inflammation and injury. Mechanistically, based on assays on cultured podocytes, AdipoRon reduced LPS-induced activation of the NF-κB-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNFα. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation.Graphical abstract

Therapeutic potential of garlic chive-derived vesicle-like nanoparticles in NLRP3 inflammasome-mediated inflammatory diseases.

Aberrant activation of the nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome drives the development of many complex inflammatory diseases, such as obesity, Alzheimer's disease, and atherosclerosis. However, no medications specifically targeting the NLRP3 inflammasome have become clinically available. Therefore, we aim to identify new inhibitors of the NLRP3 inflammasome in this study.Methods: Vesicle-like nanoparticles (VLNs) were extracted from garlic chives and other Allium vegetables and their effects on the NLRP3 inflammasome were evaluated in primary macrophages. After garlic chive-derived VLNs (GC-VLNs) were found to exhibit potent anti-NLRP3 inflammasome activity in cell culture, such function was further assessed in a murine acute liver injury disease model, as well as in diet-induced obesity. Finally, GC-VLNs were subjected to omics analysis to identify the active components with anti-NLRP3 inflammasome function.Results: GC-VLNs are membrane-enclosed nanoparticles containing lipids, proteins, and RNAs. They dose-dependently inhibit pathways downstream of NLRP3 inflammasome activation, including caspase-1 autocleavage, cytokine release, and pyroptotic cell death in primary macrophages. The inhibitory effects of GC-VLNs on the NLRP3 inflammasome are specific, considering their marginal impact on activation of other inflammasomes. Local administration of GC-VLNs in mice alleviates NLRP3 inflammasome-mediated inflammation in chemical-induced acute liver injury. When administered orally or intravenously, GC-VLNs accumulate in specific tissues and suppress activation of the NLRP3 inflammasome and chronic inflammation in diet-induced obese mice. The phospholipid 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) in GC-VLNs has been identified to inhibit NLRP3 inflammasome activation.Conclusions: Identification of GC-VLNs and their active component DLPC as potent inflammasome inhibitors provides new therapeutic candidates in the treatment of NLRP3 inflammasome-driven diseases.

2311-PUB: Metformin Improves Hepatic Inflammation in Diet-Induced Obese Mice through Downregulating CYP7B1

Metformin is an antidiabetic drug widely used to treat type 2 diabetes. Although it has been found for a very long time, its mechanism remains to be discovered. Recently, metformin has been reported to be effective in other disease, such as obesity and tumor. However, whether metformin is beneficial in nonalcoholic fatty liver disease remains controversial. CYP7B1, a cholesterol hydroxylase, has been reported to be upregulated in the inflammatory diseases. We investigated whether CYP7B1 plays an important role in the effect of metformin on the hepatic inflammation in diet-induced obese mice. In this study, eight-week-old C57BL/6 mice were subjected to a chow diet or a high fat diet (HFD) for 12 weeks. After the diet intervention, mice on an HFD were randomly divided into HFD group and HFD+Metformin group (HFDM group) for 4 weeks. The results showed that the body weight, fasting blood glucose, body fat mass, glucose metabolism and insulin sensitivity were remarkably improved by metformin. The histological results including H&amp;E staining and oil red O staining showed that metformin significantly ameliorated fatty liver induced by HFD. And the quantification of liver triglyceride also proved that. The histological results also revealed that adipocytes of epididymal adipose tissue and subcutaneous adipose tissue were smaller after metformin treatment. Meanwhile, metformin also ameliorated the whitening of brown adipose tissue according to the H&amp;E staining. Compared to HFD group, the mRNA levels of CYP7B1 and pro-inflammatory markers (TNFα, IL-1, F4/80 and MCP1) in liver were downregulated in HFDM group. How CYP7B1 functions in the beneficial effect of metformin on improving hepatic inflammation is going to be further studied. Disclosure W. Guo: None. W. Wang: None. X. Zheng: None. F. Xu: None.

Dietary Eriodictyol Alleviates Adiposity, Hepatic Steatosis, Insulin Resistance, and Inflammation in Diet-Induced Obese Mice.

The present study aimed to investigate the molecular mechanisms underlying the anti-obesity effect of flavonoid eriodictyol (ED) supplementation in mice fed with a high-fat diet (HFD). C57BL/6N mice were fed with normal diet (ND), HFD (40 kcal% fat), or HFD + 0.005% (w/w) ED for 16 weeks. In HFD-induced obese mice, dietary ED supplementation significantly alleviated dyslipidemia and adiposity by downregulating the expression of lipogenesis-related genes in white adipose tissue (WAT), while enhancing fecal lipid excretion. ED additionally improved hepatic steatosis and decreased the production of pro-inflammatory cytokines by downregulating the expression of hepatic enzymes and the genes involved in lipogenesis and upregulating the expression of hepatic fatty acid oxidation-related enzymes and genes. In addition, ED improved insulin resistance (IR) by suppressing hepatic gluconeogenesis, enhancing glucose utilization, and modulating the production and release of two incretin hormones, namely gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Taken together, the current findings indicated that ED can protect against diet-induced obesity and related metabolic disturbances, including dyslipidemia, inflammation, fatty liver disease, and IR in diet-induced obese mice.

Angiopoietin-like 8 Improves Insulin Resistance and Attenuates Adipose Tissue Inflammation in Diet-Induced Obese Mice

Angiopoietin-like 8 (ANGPTL8) is closely linked to obesity-associated metabolic diseases and insulin resistance. The aim of the current study was to investigate the ability of ANGPTL8 to reverse insulin resistance in obese mice. The administration of ANGPTL8 reduced weight gain and improved glucose tolerance in mice with diet-induced obesity. In addition, ANGPTL8 administration modified macrophage infiltration, reduced monocyte chemoattractant protein-1 (MCP-1) and interleukin-1β(IL-1β) levels, and increased adiponectin gene expression in inguinal white adipose tissue (iWAT). Moreover, the exposure of a cultured peritoneal macrophage line to ANGPTL8 reduced the mRNA expression of M1 macrophage markers (TNF-α and IL-1β) upon stimulation with lipopolysaccharides in a dose-dependent manner. By contrast, when incubated with IL-4, exposure of macrophages to ANGPTL8 increased the mRNA expression of M2 macrophage markers (Arg1 and Chi3l3) in a dose-dependent manner. Collectively, the results of the present study demonstrated that treatment with ANGPTL8 can attenuate adipose tissue inflammation through regulation of macrophage polarization, and thus, it could be useful for improving insulin resistance.

Milk: Bioactive Components and Role in Human Nutrition

In the current Special Issue, numerous and different aspects related to milk, an important component of a well-balanced diet, are presented.[...]

Natural product celastrol suppressed macrophage M1 polarization against inflammation in diet-induced obese mice via regulating Nrf2/HO-1, MAP kinase and NF-κB pathways.

Macrophage polarization is implicated in the inflammation in obesity. The aim of the present study was to examine the anti-inflammatory activities of botanical triterpene celastrol against diet-induced obesity. We treated diet-induced obese C57BL/6N male mice with celastrol (5, 7.5 mg/kg/d) for 3 weeks, and investigated macrophage M1/M2 polarization in adipose and hepatic tissues. Celastrol reduced fat accumulation and ameliorated glucose tolerance and insulin sensitivity. Celastrol down-regulated the mRNA levels of macrophage M1 biomarkers (e.g., IL-6, IL-1β, TNF-α, iNOS) in cell culture and in mice. The underlying mechanisms were investigated in murine macrophage RAW264.7 cells. Our results demonstrated that celastrol might control macrophage polarization through modulating the cross-talk between the following three mechanisms: 1) suppressing LPS-induced activation of MAP kinases (e.g., ERK1/2, p38, JNK) in a concentration dependent manner; 2) attenuating LPS-induced nuclear translocation of NF-κB p65 subunit in a time dependent manner; 3) activating Nrf2 and subsequently inducing HO-1 expression. HO-1 inhibitor SnPP diminished the inhibitory effects of celastrol on the activation of NF-κB pathway and the pro-inflammatory M1 macrophage polarization. Taken together, celastrol exhibited anti-obesity effects via suppressing pro-inflammatory M1 macrophage polarization. Thus, our results provide new evidence for the potential of celastrol in the treatment of obesity.

Dietary Milk Sphingomyelin Reduces Systemic Inflammation in Diet-Induced Obese Mice and Inhibits LPS Activity in Macrophages

High-fat diets (HFD) increase lipopolysaccharide (LPS) activity in the blood and may contribute to systemic inflammation with obesity. We hypothesized that dietary milk sphingomyelin (SM), which reduces lipid absorption and colitis in mice, would reduce inflammation and be mediated through effects on gut health and LPS activity. C57BL/6J mice were fed high-fat, high-cholesterol diets (HFD, n = 14) or the same diets with milk SM (HFD-MSM, 0.1% by weight, n = 14) for 10 weeks. HFD-MSM significantly reduced serum inflammatory markers and tended to lower serum LPS (p = 0.08) compared to HFD. Gene expression related to gut barrier function and macrophage inflammation were largely unchanged in colon and mesenteric adipose tissues. Cecal gut microbiota composition showed greater abundance of Acetatifactor genus in mice fed milk SM, but minimal changes in other taxa. Milk SM significantly attenuated the effect of LPS on pro-inflammatory gene expression in RAW264.7 macrophages. Milk SM lost its effects when hydrolysis was blocked, while long-chain ceramides and sphingosine, but not dihydroceramides, were anti-inflammatory. Our data suggest that dietary milk SM may be effective in reducing systemic inflammation through inhibition of LPS activity and that hydrolytic products of milk SM are important for these effects.

Eicosapentaenoic acid shows anti-inflammatory effect via GPR120 in 3T3-L1 adipocytes and attenuates adipose tissue inflammation in diet-induced obese mice

BackgroundSaturated fatty acids have been shown to cause insulin resistance and low-grade chronic inflammation, whereas unsaturated fatty acids suppress inflammation via G-protein coupled receptor 120 (GPR120) in macrophages. However, the anti-inflammatory effects of unsaturated fatty acids in adipocytes have yet to be elucidated. Hence, the aims of the present study were to evaluate the anti-inflammatory effects of eicosapentaenoic acid (EPA) via GPR120 in adipocytes.MethodsWe used 250 μM palmitate as a representative saturated fatty acid. 3T3-L1 adipocytes were used for in vitro studies. We further evaluated the effect of EPA supplementation in a high-fat/high-sucrose (HFHS) diet-induced adipose tissue inflammatory mouse model.ResultsEPA attenuated palmitate-induced increases in inflammatory gene expression and NF-κB phosphorylation in 3T3-L1 adipocytes. Silencing of GPR120 abolished the anti-inflammatory effects of EPA. In GPR120 downstream signal analysis, EPA was found to decrease palmitate-induced increases in TAK1/TAB1 complex expression. EPA supplementation suppressed HFHS-induced crown-like structure formation in epididymal adipose tissue and altered macrophage phenotypes from M1 to M2 in the stromal vascular fraction. Moreover, the EPA-containing diet attenuated increases in adipose p-JNK and phospho-p65 NF-κB levels.ConclusionsIn conclusion, the findings of the present study demonstrate that EPA suppresses palmitate-induced inflammation via GPR120 by inhibiting the TAK1/TAB1 interaction in adipocytes. EPA supplementation reduced HFHS diet-induced inflammatory changes in mouse adipose tissues. These results demonstrate adipose GPR120 as a potential therapeutic target for decreasing inflammation.

Licochalcone F alleviates glucose tolerance and chronic inflammation in diet-induced obese mice through Akt and p38 MAPK

Licochalcone (lico) F is a novel synthetic retrochalcone. In this study, we investigated the anti-inflammatory effects of lico F invitro, and its effects on obesity-induced chronic inflammation, glucose intolerance, and fatty liver invivo. The inhibitory effects of lico F on TNFα-induced inflammation were investigated using NF-κB luciferase reporter assay and RT-PCR. Diet-induced obese mice were treated orally, once per day, with vehicle or lico F (10mg/kg/day), for 3 weeks, and blood, liver, and adipose tissues were analyzed. Lico F inhibited TNFα-induced NF-κB activation and mRNA expression of TNFα, COX-2, IL-6, IL-1β, and NOS2. In obese mice, lico F administration significantly alleviated glucose tolerance without changes in body weight gain and food intake. Lico F reduced adipocyte size and macrophage infiltration into white adipose tissue and improved hepatic lesions, by decreasing fat droplets and glycogen deposition. The mRNA expression levels of TNFα, MCP-1, and CD68 in white adipose tissue also decreased markedly. Moreover, lico F enhanced Akt signaling, but reduced p38 MAPK signaling in white adipose tissue. Lico F had anti-inflammatory effects and showed beneficial effects on glucose metabolism, which could be partially caused by activation of the Akt signal pathway and obesity-induced chronic inflammation, probably by downregulating p38 signal pathway. Moreover, lico F could be used as a potential novel therapeutic compound against type 2 diabetes and obesity-induced chronic inflammation without the deleterious effects of body weight gain and fatty liver.

Polyphenol-rich blackcurrant extract prevents inflammation in diet-induced obese mice

Obesity is closely associated with chronic, low-grade inflammation. We investigated if polyphenol-rich blackcurrant extract (BCE) can prevent inflammation in vivo. Male C57BL/6J mice were fed a modified AIN-93M control diet containing high fat/high cholesterol (16% fat, 0.25% cholesterol by weight) or the control diet supplemented with 0.1% BCE (wt/wt) for 12 weeks. In BCE-fed mice, the percentage of body weight and adipocyte size of the epididymal fat were significantly lower than those of control mice. There were fewer crown-like structures (CLS) with concomitant decreases in F4/80, cluster of differentiation 68 and inhibitor of nuclear factor κB kinase ε (IKKε) mRNA in the epididymal adipose of BCE-fed mice. F4/80 and IKKε mRNA levels were positively correlated with CLS number. In the skeletal muscle of mice fed with BCE, mRNA expression of genes involved in energy expenditure and mitochondrial biogenesis, including PPARα, PPARδ, UCP-2, UCP-3 and mitochondrial transcription factor A, were significantly increased. When splenocytes from BCE-fed mice were stimulated by lipopolysaccharides, tumor necrosis factor α and interleukin-1β mRNA were significantly lower than control splenocytes. Together, the results suggest that BCE supplementation decreases obesity-induced inflammation in adipose tissue and splenocytes, at least in part, by modulating energy metabolism in skeletal muscle.

Curcuma longa Extract Associated with White Pepper Lessens High Fat Diet-Induced Inflammation in Subcutaneous Adipose Tissue

BackgroundSupra-nutritional doses of curcumin, derived from the spice Curcuma longa, have been proposed as a potential treatment of inflammation and metabolic disorders related to obesity. The aim of the present study was to test whether Curcuma longa extract rich in curcumin and associated with white pepper (Curcuma-P®), at doses compatible with human use, could modulate systemic inflammation in diet-induced obese mice. We questioned the potential relevance of changes in adiposity and gut microbiota in the effect of Curcuma-P® in obesity.Methodology/Principal FindingsMice were fed either a control diet (CT), a high fat (HF) diet or a HF diet containing Curcuma longa extract (0.1 % of curcumin in the HF diet) associated with white pepper (0.01 %) for four weeks. Curcumin has been usually combined with white pepper, which contain piperine, in order to improve its bioavailability. This combination did not significantly modify body weight gain, glycemia, insulinemia, serum lipids and intestinal inflammatory markers. Tetrahydrocurcumin, but not curcumin accumulated in the subcutaneous adipose tissue. Importantly, the co-supplementation in curcuma extract and white pepper decreased HF-induced pro-inflammatory cytokines expression in the subcutaneous adipose tissue, an effect independent of adiposity, immune cells recruitment, angiogenesis, or modulation of gut bacteria controlling inflammation.Conclusions/SignificanceThese findings support that nutritional doses of Curcuma longa, associated with white pepper, is able to decrease inflammatory cytokines expression in the adipose tissue and this effect could be rather linked to a direct effect of bioactive metabolites reaching the adipose tissue, than from changes in the gut microbiota composition.

Abstract 81: Pharmacological Inhibition of Calpain Attenuates Adipose Tissue Apoptosis, Macrophage Accumulation and Inflammation in Diet-induced Obese Mice

Background and Objective Obesity is associated with low-grade chronic inflammation and apoptosis that contributes to development of insulin resistance and other metabolic complications. Adipose tissue macrophages have been proposed as a link between obesity and insulin resistance. However, the mechanisms underlying these processes are not defined. Calpains are calcium-dependent neutral cysteine proteases that are essential for multiple cellular functions, such as cytoskeletal remodeling and apoptotic cell death. Recent studies have demonstrated that activated calpain promotes adipocyte differentiation in vitro, and enhances macrophage recruitment during nephropathy. However, the functional role of calpain activation in adipose tissue macrophage accumulation and obesity remains to be elucidated. The purpose of this study was to define whether pharmacological inhibition of calpain influences diet-induced obesity and adipose tissue macrophage accumulation in mice. Methods and Results Male C57BL/6 mice (8 weeks old; n=10 per group) were fed either low (10% kcal) or high (60% kcal) fat diet for 12 weeks. Calpeptin, a calpain inhibitor (2.5 mg/kg/day) or vehicle (DMSO) was administered daily by osmotic mini-pumps for 12 weeks. Calpeptin administration did not influence high fat diet induced body weight and fat mass gain throughout the study. Calpain inhibition had no effect on glucose and insulin tolerance in obese mice. However, calpain inhibition highly reduced adipocyte apoptosis, adipose tissue collagen and macrophage accumulation as evident by TUNEL, Picro Sirius and CD68 immunostaining. Real-time PCR analysis showed that calpain inhibition significantly suppressed inflammatory cytokines (TNFα, IL-6, MCP-1, F4/80) expression in adipose tissue (P&lt;0.05 vs vehicle). In addition, Oil Red O staining revealed that calpain inhibition also suppressed accumulation of hepatic fat. Conclusion Pharmacological inhibition of calpain attenuated macrophage accumulation, adipocyte apoptosis, fibrosis and inflammation in diet-induced obese mice without influencing body weight gain and insulin tolerance.

Combined Ethanol Extract of Grape Pomace and Omija Fruit Ameliorates Adipogenesis, Hepatic Steatosis, and Inflammation in Diet-Induced Obese Mice

The aim of this study was to evaluate the long-term effects of grape pomace ethanol extract (GPE) with or without omija fruit ethanol extract (OFE) on adiposity, hepatic steatosis, and inflammation in diet-induced obese mice. Male C57BL/6J mice were fed a high-fat diet (HFD) as the control diet and HFD plus GPE (0.5%, w/w) with or without OFE (0.05%, w/w) as the experimental diet for 12 weeks. GPE alone did not significantly affect adipogenesis and hepatic steatosis. However, the supplementation of GPE + OFE significantly lowered body weight gain, white adipose tissue weight, adipocyte size, and plasma free fatty acid and adipokines (leptin, PAI-1, IL-6, and MCP-1) levels in HFD-fed mice compared to those of the control group. These beneficial effects of GPE + OFE were partly related to the decreased expression of lipogenic and inflammatory genes in white adipose tissue. GPE + OFE supplementation also significantly lowered liver weight and ameliorated fatty liver by inhibiting expression of hepatic genes involved in fatty acid and cholesterol syntheses as well as inflammation and by activating hepatic fatty acid oxidation. These findings suggest that the combined ethanol extract of grape pomace and omija fruit has the potential to improve adiposity and fatty liver in diet-induced obese mice.