Diet-induced Adipose Tissue Inflammation Research Articles

Abstract 18901: Metabolic Regulation of Adipose Tissue Inflammation and Systemic Insulin Sensitivity: A Role for PFKFB3 in Macrophage Polarization

Much evidence demonstrates that macrophages play a pivotal role in the development of overnutrition-associated metabolic diseases, such as cardiovascular disease and type II diabetes. Macrophage inflammatory status (polarization) is a key determinant of systemic insulin resistance, which is under the control of bi-directional regulation: macrophage proinflammatory activation and macrophage alternative activation (anti-inflammatory). It has been previously shown that PFKFB3, a gene that encodes for a key regulatory enzyme of glycolysis, is crucial for the control of systemic insulin sensitivity. In the present study, if and how PFKFB3 alters macrophage polarization in relation to adipose tissue inflammation and systemic insulin sensitivity were examined. Bone marrow cells were isolated from wild-type mice and PFKFB3-disrupted mice and differentiated into macrophages which were referred to as bone marrow-derived macrophages (BMDM). Compared with control cells, the phosphorylation of NF-kB p65 and JNK1/2 is in PFKFB3-disrupted BMDM. Additionally, the expression of proinflammatory cytokines, such as TNF-α and IL-6, was increased in PFKFB3-disrupted BMDM under the stimulation of lipopolysaccharides (LPS, 100 ng/ml). Upon adoptive transfer of bone marrow cells to lethally irradiated wild-type mice, the recipients with PFKFB3-disrupted bone marrow cells displayed a decrease in systemic insulin sensitivity, which was accompanied by an increase in adipose tissue inflammatory responses. The later were evidenced by increases in adipose tissue macrophage infiltration, the phosphorylation of NF-kB p65, and mRNA levels of proinflammatory cytokines. Taken together, PFKFB3 is a metabolic regulator of macrophage polarization, which accounts for the effects of PFKFB3 on protecting against diet-induced adipose tissue inflammation and systemic insulin resistance.

Abstract 18139: Genetic Deficiency of Traf-1 Attenuates Diet-Induced Adipose Tissue Inflammation by Limiting the Pool of Circulating and Splenic Monocytes in Mice

Background: Accumulation of inflammatory leukocytes, such as of macrophages, is a prerequisite of adipose tissue inflammation during the metabolic syndrome. We recently reported that genetic deficiency of Tumor necrosis factor receptor-associated factor (TRAF) -1 attenuated inflammatory cell recruitment in atherosclerosis. Here, we tested the hypothesis that TRAF-1 deficiency modulates adipose tissue inflammation in a model of diet-induced obesity (DIO) in mice. Methods and Results: To test the association of TRAFs and adipose tissue inflammation we screened for expression of different TRAFs in mouse adipose tissue after 20 weeks of feeding with a high fat (HFD) or a control diet. HFD induced up-regulation of TRAF-1, -3, -5, -6, and -7 mRNA. Interestingly, the amplitude of gene regulation was highest for TRAF-1 (4.9-fold, n=8 per group, p=0.002). Also, in human subcutaneous tissue TRAF-1 gene expression correlated with body mass index of donors (r=0.94, p=0.019). To test functional relevance of our findings, WT or TRAF-1-/- mice consumed HFD for 12 weeks (n ≥ 10 mice per group). Interestingly, TRAF-1-/- mice gained less weight during DIO (119 ± 7.5 % vs. 41 ± 3.7 % of starting body weight for WT and TRAF-1-/-, respectively). Accordingly, total body weight, weight of visceral and cardiac fat pads was decreased in TRAF-1-/- mice. Moreover, TRAF-1-/- mice demonstrated lower glucose levels after starving and during weight-adapted intraperitoneal glucose and insulin tolerance tests, suggesting functional involvement of TRAF-1 in insulin and glucose signaling. Finally, inflammatory cell recruitment was impaired in TRAF-1-/- mice with reduced numbers of adipose tissue macrophages. Functionally, circulating and splenic, but not bone marrow monocytes were lowered in TRAF-1-/- mice, proposing that TRAF-1 modulates monocyte mobilization during inflammation. Conclusion: We present the novel finding that TRAF-1 is regulated in obese murine and human adipose tissue. Genetic deficiency of TRAF-1 attenuates adipose tissue inflammation in mice by limiting monocyte recruitment. These findings identify TRAF-1 as a potent mediator at the interface of cardiovascular and metabolic disease.

Profilin-1 Haploinsufficiency Protects Against Obesity-Associated Glucose Intolerance and Preserves Adipose Tissue Immune Homeostasis

Metabolic inflammation may contribute to the pathogenesis of obesity and its comorbidities, including type 2 diabetes and cardiovascular disease. Previously, we showed that the actin-binding protein profilin-1 (pfn) plays a role in atherogenesis because pfn heterozygote mice (PfnHet) exhibited a significant reduction in atherosclerotic lesion burden and vascular inflammation. In the current study, we tested whether pfn haploinsufficiency would also limit diet-induced adipose tissue inflammation and insulin resistance (IR). First, we found that a high-fat diet (HFD) upregulated pfn expression in epididymal and subcutaneous white adipose tissue (WAT) but not in the liver or muscle of C57BL/6 mice compared with normal chow. Pfn expression in WAT correlated with F4/80, an established marker for mature macrophages. Of note, HFD elevated pfn protein levels in both stromal vascular cells and adipocytes of WAT. We also found that PfnHet were significantly protected from HFD-induced glucose intolerance observed in pfn wild-type mice. With HFD, PfnHet displayed blunted expression of systemic and WAT proinflammatory cytokines and decreased accumulation of adipose tissue macrophages, which were also preferentially biased toward an M2-like phenotype; this correlated with preserved frequency of regulatory T cells. Taken together, the findings indicate that pfn haploinsufficiency protects against diet-induced IR and inflammation by modulating WAT immune homeostasis.

Impact of caspase‐11 non‐canonical inflammasome on adipose tissue inflammation and obesity induced insulin resistance

Sterile inflammation in the absence of overt infection contributes to insulin‐resistance and type 2 diabetes. IL‐1β mediates sustained tissue damage during the development of type 2 diabetes and is controlled by caspase‐1. Caspase‐1 is activated by multiple inflammasome protein complexes. We have shown that canonical Nlrp3 inflammasome activation participates in high‐fat diet induced adipose tissue inflammation and insulin‐resistance. Caspase‐11 has recently been identified as a non‐canonical inflammasome that leads to caspase‐1 activation in response to gram‐negative bacteria. Intestinal barrier function may be impaired during obesity and diabetes, making caspase‐11 a potential mediator of chronic inflammation during these diseases. Therefore we tested the hypothesis that caspase‐11 contributes to inflammasome activation, IL‐1β production and adipose tissue lymphocytosis during obesity. Our findings suggest that that high‐fat fed caspase‐11 −/− mice are not protected from lymphocytosis, adipose tissue inflammation and glucose and insulin intolerance. These data suggest that the caspase‐11 non‐canonical inflammasome is not the major innate immune sensor of obesity‐associated changes in endogenous gut microbial species that drive inflammation and insulin‐resistance. This research was supported in part by NIH DK090556, and RWG is supported by NIH DK064584.

Lack of ST2 enhances high-fat diet-induced visceral adiposity and inflammation in BALB/c mice

ABSTRACT Obesity and obesity related disorders are strongly associated with chronic low-grade inflammation originating from growing visceral adipose tissue during nutrient excess. Although interleukin (IL)-33 may have protective role in obesity and atherosclerosis, the impact of IL-33/ST2 axis in metabolic disorders needs to be elucidated. In this study, we investigated the role of IL-33/ST2 pathway in high-fat diet (HFD)-induced obesity using ST2-deficient (ST2 -/- ) and wild type mice on BALB/c background. The deletion of ST2 enhanced systemic and visceral adipose tissue (VAT) inflammation and was associated with significantly higher weight gain and amount of total VAT in ST2 -/- mice fed with HFD for 18 weeks. More numerous classically activated M1 macrophages and markedly decreased alternatively activated M2 macrophages were observed in VAT of HFD-fed ST2 -/- mice. Additionally, VAT of ST2 -/- mice fed with HFD had increased percentage of CD3 + T cells with lower incidence of CD4 + CD25 + FoxP3 + T regulatory cells in comparison with low-fat diet fed controls. The incidence of CD3 + IL-17 + and IL-5 positive VAT-derived mononuclear cells was significantly lower in HFD-fed ST2 -/- mice. Serum levels of proinflammatory cytokines IL-1β and IFN-γ were increased in HFD-fed ST2 -/- mice, while the levels of IL-6 and CRP did not differ among groups. Importantly, the levels of anti-inflammatory IL-10 and IL-13 were significantly lower in the sera of ST2 -/- mice compared with wild-type controls. Our findings suggest that protective role of IL33/ST2 signaling in high-fat diet-induced adipose tissue inflammation. ST2 deficiency related to nutrient excess is associated with polarization of macrophages toward M1 phenotype and the induction Th1-mediated immune response. Key words: ST2, obesity, high-fat diet, visceral adipose tissue, inflammation

Apolipoprotein E4 Impairs Macrophage Efferocytosis and Potentiates Apoptosis by Accelerating Endoplasmic Reticulum Stress

Apolipoprotein (apo) E4 is a major genetic risk factor for a wide spectrum of inflammatory metabolic diseases, including atherosclerosis, diabetes, and Alzheimer disease. This study compared diet-induced adipose tissue inflammation as well as functional properties of macrophages isolated from human APOE3 and APOE4 mice to identify the mechanism responsible for the association between apoE4 and inflammatory metabolic diseases. The initial study confirmed previous reports that APOE4 gene replacement mice were less sensitive than APOE3 mice to diet-induced body weight gain but exhibited hyperinsulinemia, and their adipose tissues were similarly inflamed as those in APOE3 mice. Peritoneal macrophages isolated from APOE4 mice were defective in efferocytosis compared with APOE3 macrophages. Increased cell death was also observed in APOE4 macrophages when stimulated with LPS or oxidized LDL. Western blot analysis of cell lysates revealed that APOE4 macrophages displayed elevated JNK phosphorylation indicative of cell stress even under basal culturing conditions. Significantly higher cell stress due mainly to potentiation of endoplasmic reticulum (ER) stress signaling was also observed in APOE4 macrophages after LPS and oxidized LDL activation. The defect in efferocytosis and elevated apoptosis sensitivity of APOE4 macrophages was ameliorated by treatment with the ER chaperone tauroursodeoxycholic acid. Taken together, these results showed that apoE4 expression causes macrophage dysfunction and promotes apoptosis via ER stress induction. The reduction of ER stress in macrophages may be a viable option to reduce inflammation and inflammation-related metabolic disorders associated with the apoE4 polymorphism.

Correction: CD40L Deficiency Attenuates Diet-Induced Adipose Tissue Inflammation by Impairing Immune Cell Accumulation and Production of Pathogenic IgG-Antibodies

Correction: CD40L Deficiency Attenuates Diet-Induced Adipose Tissue Inflammation by Impairing Immune Cell Accumulation and Production of Pathogenic IgG-Antibodies

Scavenger Receptor CD36 Expression Contributes to Adipose Tissue Inflammation and Cell Death in Diet-Induced Obesity

ObjectiveThe enlarged adipose tissue in obesity is characterized by inflammation, including the recruitment and infiltration of macrophages and lymphocytes. The objective of this study was to investigate the role of the scavenger receptor CD36 in high fat diet-induced obesity and adipose tissue inflammation and cell death.Experimental ApproachObesity and adipose tissue inflammation was compared in CD36 deficient (CD36 KO) mice and wild type (WT) mice fed a high fat diet (60% kcal fat) for 16 weeks and the inflammatory response was studied in primary adipocytes and macrophages isolated from CD36 KO and WT mice.ResultsCompared to WT mice, CD36 KO mice fed a high fat diet exhibited reduced adiposity and adipose tissue inflammation, with decreased adipocyte cell death, pro-inflammatory cytokine expression and macrophage and T-cell accumulation. In primary cell culture, the absence of CD36 expression in macrophages decreased pro-inflammatory cytokine, pro-apoptotic and ER stress gene expression in response to lipopolysaccharide (LPS). Likewise, CD36 deficiency in primary adipocytes reduced pro-inflammatory cytokine and chemokine secretion in response to LPS. Primary macrophage and adipocyte co-culture experiments showed that these cell types act synergistically in their inflammatory response to LPS and that CD36 modulates such synergistic effects.ConclusionsCD36 enhances adipose tissue inflammation and cell death in diet-induced obesity through its expression in both macrophages and adipocytes.

The Radioprotective 105/MD-1 Complex Contributes to Diet-induced Obesity and Adipose Tissue Inflammation (172.23)

Abstract Accumulating evidence suggest that innate immunity is associated with obesity-induced chronic inflammation and metabolic disorders. For example, the TLR4/MD-2 complex recognizes free fatty acids (FAAs) derived from adipose tissue and promotes adipose tissue inflammation and insulin resistance. The RP105/MD-1 complex is a homolog of the TLR4/MD-2 complex. However, the roles of RP105/MD-1 complex in adipose tissue inflammation have remained elusive. We now report that the RP105/MD-1 complex contributes to high-fat diet (HFD)-induced obesity, adipose tissue inflammation, and insulin resistance independent of TLR4 signaling. RP105 mRNA expression is dramatically increased by HFD in stromal vascular fraction of epididymal white adipose tissue (eWAT) in wild-type (WT) mice. In human, RP105 mRNA expression is also increased in the visceral adipose tissue of obese subjects. The RP105/MD-1 complex is expressed by most adipose tissue macrophages (ATMs). HFD increases RP105/MD-1 expression on the M1 ATMs in eWAT. Increased RP105 and MD-1 mRNA expression in macrophages is induced by co-culture with 3T3L-1 adipocytes. RP105 KO and MD-1 KO mice have less HFD-induced adipose tissue inflammation, hepatic steatosis and insulin resistance compared to these in WT and TLR4 KO mice. Finally, the saturated FAAs palmitic and stearic acids activate TLR4/MD-2 but not RP105/MD-1. Thus, the RP105/MD-1 complex is a major mediator of adipose tissue inflammation independent of TLR4 signaling.

CD40L deficiency attenuates diet-induced adipose tissue inflammation by impairing immune cell accumulation and production of pathogenic IgG-antibodies.

BackgroundAdipose tissue inflammation fuels the metabolic syndrome. We recently reported that CD40L – an established marker and mediator of cardiovascular disease – induces inflammatory cytokine production in adipose cells in vitro. Here, we tested the hypothesis that CD40L deficiency modulates adipose tissue inflammation in vivo.Methodology/Principal FindingsWT or CD40L−/− mice consumed a high fat diet (HFD) for 20 weeks. Inflammatory cell recruitment was impaired in mice lacking CD40L as shown by a decrease of adipose tissue macrophages, B-cells, and an increase in protective T-regulatory cells. Mechanistically, CD40L-deficient mice expressed significantly lower levels of the pro-inflammatory chemokine MCP-1 both, locally in adipose tissue and systemically in plasma. Moreover, levels of pro-inflammatory IgG-antibodies against oxidized lipids were reduced in CD40L−/− mice. Also, circulating low-density lipoproteins and insulin levels were lower in CD40L−/− mice. However, CD40L−/− mice consuming HFD were not protected from the onset of diet-induced obesity (DIO), insulin resistance, and hepatic steatosis, suggesting that CD40L selectively limits the inflammatory features of diet-induced obesity rather than its metabolic phenotype. Interestingly, CD40L−/− mice consuming a low fat diet (LFD) showed both, a favorable inflammatory and metabolic phenotype characterized by diminished weight gain, improved insulin tolerance, and attenuated plasma adipokine levels.ConclusionWe present the novel finding that CD40L deficiency limits adipose tissue inflammation in vivo. These findings identify CD40L as a potential mediator at the interface of cardiovascular and metabolic disease.

Nrf2 deficiency in myeloid cells is not sufficient to protect mice from high-fat diet-induced adipose tissue inflammation and insulin resistance

Activation of the transcription factor NF-E2-related factor 2 (Nrf2) by oxidative stress induces the expression of a variety of antioxidant and anti-inflammatory genes. Yet, genetic ablation of Nrf2 was shown to protect mice from high-fat diet (HFD)-induced obesity and insulin resistance. The mechanisms that underlie this seemingly paradoxical finding remain largely unexplored. Here we examined whether Nrf2 deficiency in myeloid cells contributes to protection against HFD-induced metabolic changes by decreasing adipose tissue inflammation. In vitro, induction of IL-1β by inflammatory stimuli was significantly reduced in Nrf2-deficient macrophages. Whereas inflammatory gene expression in the stromal vascular fraction was reduced in both global and chimeric Nrf2 KO mice, only global Nrf2-deficient, and not bone marrow-transplanted Nrf2 chimeric, mice were protected against HFD-induced adipose tissue inflammation. Whereas global Nrf2 deficiency resulted in significantly decreased expression of inflammatory genes and PPARγ2, there was no difference when Nrf2 was absent only from myeloid cells. In vitro coculture with adipocytes demonstrated that macrophage Nrf2 regulated inflammatory gene expression in macrophages; however, it was not required to induce inflammatory gene expression in adipocytes. Finally, in contrast to global Nrf2 knockout, Nrf2 deficiency in myeloid cells did not protect against HFD-induced insulin resistance. Together, our data demonstrate a dominant role for nonmyeloid Nrf2 in controlling HFD-induced adipose tissue inflammation and the development of insulin resistance.

High-glycemic index carbohydrates abrogate the antiobesity effect of fish oil in mice

Fish oil rich in n-3 polyunsaturated fatty acids is known to attenuate diet-induced obesity and adipose tissue inflammation in rodents. Here we aimed to investigate whether different carbohydrate sources modulated the antiobesity effects of fish oil. By feeding C57BL/6J mice isocaloric high-fat diets enriched with fish oil for 6 wk, we show that increasing amounts of sucrose in the diets dose-dependently increased energy efficiency and white adipose tissue (WAT) mass. Mice receiving fructose had about 50% less WAT mass than mice fed a high fish oil diet supplemented with either glucose or sucrose, indicating that the glucose moiety of sucrose was responsible for the obesity-promoting effect of sucrose. To investigate whether the obesogenic effect of sucrose and glucose was related to stimulation of insulin secretion, we combined fish oil with high and low glycemic index (GI) starches. Mice receiving the fish oil diet containing the low-GI starch had significantly less WAT than mice fed high-GI starch. Moreover, inhibition of insulin secretion by administration of nifedipine significantly reduced WAT mass in mice fed a high-fish oil diet in combination with sucrose. Our data show that the macronutrient composition of the diet modulates the effects of fish oil. Fish oil combined with sucrose, glucose, or high-GI starch promotes obesity, and the reported anti-inflammatory actions of fish oil are abrogated. In conclusion, our data indicate that glycemic control of insulin secretion modulates metabolic effects of fish oil by demonstrating that high-GI carbohydrates attenuate the antiobesity effects of fish oil.

Stevioside ameliorates high-fat diet-induced insulin resistance and adipose tissue inflammation by downregulating the NF-κB pathway

Accumulating evidence suggests that adipose tissue is the main source of pro-inflammatory molecules that predispose individuals to insulin resistance. Stevioside (SVS) is a widely used sweetener with multiple beneficial effects for diabetic patients. In this study, we investigated the effect of SVS on insulin resistance and the pro-inflammatory state of adipose tissue in mice fed with a high-fat diet (HFD). Oral administration of SVS for 1month had no effect on body weight, but it significantly improved fasting glucose, basal insulin levels, glucose tolerance and whole body insulin sensitivity. Interestingly, these changes were accompanied with decreased expression levels of several inflammatory cytokines in adipose tissue, including TNF-α, IL6, IL10, IL1β, KC, MIP-1α, CD11b and CD14. Moreover, macrophage infiltration in adipose tissue was remarkably reduced by SVS. Finally, SVS significantly suppressed the nuclear factor-kappa b (NF-κB) signaling pathway in adipose tissue. Collectively, these results suggested that SVS may ameliorate insulin resistance in HFD-fed mice by attenuating adipose tissue inflammation and inhibiting the NF-κB pathway.

Abstract 17934: MicroRNA-223 Regulates Macrophage Polarization and Protects Mice from Diet-Induced Insulin Resistance and Adipose Tissue Inflammation

Macrophage-mediated adipose tissue inflammation is a crucial contributor to the risk of Cardiovascular disease (CVD) associated obesity. microRNAs are important regulators for various basic cell functions, such as proliferation, differentiation and apoptosis. We found that miR-223, a microRNA with high abundance in the bone marrow, can regulate adipose tissue inflammation by modulating macrophage polarization. In order to elucidate how miR-223 regulates the function of macrophages, we generated bone marrow-derived macrophage (BMDM) and tested their response to different stimuli. Our results showed that miR-223 deficiency did not affect macrophage formation in mice. However, miR-223 deficiency enhanced the classical activation (M1) but delayed alternative activation (M2) in macrophages. When stimulated by LPS, miR-223 -/- BMDMs exhibited stronger response compared to wild type control cells at various time points, accompanied by increased phosphorylation of p65, suggesting enhanced NF-κB signaling. On the contrary, alternative stimulation by IL-4 led to delayed response in BMDM with miR-223 deficiency judged by surface marker detection using FACS analysis. Consequently, co-culture of miR223-deficient macrophages with wild-type adipocytes led to increased adipocyte inflammatory response and decreased insulin signaling. In addition we investigated the modulation of adipose tissue inflammation by miR-223 in vivo. Upon high-fat diet (HFD) feeding, miR223-deficient mice exhibited a greater increase in the severity of systemic insulin resistance compared to wild-type littermates. Additionally, miR223-deficient mice exhibited a marked increase in HFD-induced adipose tissue inflammatory response. Using a combination of computational prediction and luciferase reporter assays, we identified several genes that are crucial for macrophage activation as miR-223 targets, including Nfat5 and Pknox1. Our findings suggest that miR223 protect against diet-induced adipose tissue inflammatory response by modulating macrophage polarization. thus provides a new layer of regulatory circuit in the network governing adipose tissue inflammation.

Lack of Interleukin-1 Receptor I (IL-1RI) Protects Mice From High-Fat Diet–Induced Adipose Tissue Inflammation Coincident With Improved Glucose Homeostasis

OBJECTIVEHigh-fat diet (HFD)-induced adipose tissue inflammation is a critical feature of diet-induced insulin resistance (IR); however, the contribution of interleukin-1 receptor I (IL-1RI)-mediated signals to this phenotype has not been defined. We hypothesized that lack of IL-1RI may ameliorate HFD-induced IR by attenuating adipose tissue inflammation.RESEARCH DESIGN AND METHODSGlucose homeostasis was monitored in chow- and HFD-fed wild-type (WT) and IL-1RI−/− mice by glucose tolerance and insulin tolerance tests. Macrophage recruitment and cytokine signature of adipose tissue macrophages was evaluated. Insulin sensitivity and cytokine secretion from adipose explants was quantified. Cytokine secretion and adipocyte insulin sensitivity was measured in cocultures of WT or IL-1RI−/− macrophages with 3T3L1 adipocytes. Synergistic effects of IL-1β with tumor necrosis factor (TNF)-α on inflammation was monitored in WT and IL-1RI−/− bone-marrow macrophages and adipose explants.RESULTSLean and obese IL-1RI−/− animals exhibited enhanced glucose homeostasis by glucose tolerance test and insulin tolerance test. M1/M2 macrophage number in adipose tissue was comparable between genotypes; however, TNF-α and IL-6 secretion was lower from IL-1RI−/− adipose tissue macrophages. IL-1RI−/− adipose exhibited enhanced insulin sensitivity, elevated pAKT, lower cytokine secretion, and attenuated induction of phosphorylated signal transducer and activator of transcription 3 and suppressor of cytokine signaling molecule 3 after HFD. Coculture of WT, but not IL-1RI−/− macrophages, with 3T3L1 adipocytes enhanced IL-6 and TNF-α secretion, reduced adiponectin secretion, and impaired adipocyte insulin sensitivity. TNF-α and IL-1β potently synergized to enhance inflammation in WT macrophages and adipose, an effect lost in the absence of IL-1RI.CONCLUSIONSLack of IL-1RI protects against HFD-induced IR coincident with reduced local adipose tissue inflammation, despite equivalent immune cell recruitment.

Diet-Induced Adipose Tissue Inflammation and Liver Steatosis Are Prevented by DPP-4 Inhibition in Diabetic Mice

OBJECTIVEDiet composition alters the metabolic states of adipocytes and hepatocytes in diabetes. The effects of dipeptidyl peptidase-4 (DPP-4) inhibition on adipose tissue inflammation and fatty liver have been obscure. We investigated the extrapancreatic effects of DPP-4 inhibition on visceral fat and the liver.RESEARCH DESIGN AND METHODSWe investigated diet-induced metabolic changes in β-cell–specific glucokinase haploinsufficient (Gck+/−) diabetic mice. We challenged animals with a diet containing a combination of sucrose and oleic acid (SO) or sucrose and linoleic acid (SL). Next, we assessed the effects of a DPP-4 inhibitor, des-fluoro-sitagliptin, on adipose tissue inflammation and hepatic steatosis.RESULTSThe epididymal fat weight and serum leptin level were significantly higher in Gck+/− mice fed SL than in mice fed SO, although no significant differences in body weight or adipocyte size were noted. Compared with SO, SL increased the numbers of CD11c+ M1 macrophages and CD8+ T-cells in visceral adipose tissue and the expression of E-selectin, P-selectin, and plasminogen activator inhibitor-1 (PAI-1). DPP-4 inhibition significantly prevented adipose tissue infiltration by CD8+ T-cells and M1 macrophages and decreased the expression of PAI-1. The production of cytokines by activated T-cells was not affected by DPP-4 inhibition. Furthermore, DPP-4 inhibition prevented fatty liver in both wild-type and Gck+/− mice. DPP-4 inhibition also decreased the expressions of sterol regulatory element–binding protein-1c, stearoyl-CoA desaturase-1, and fatty acid synthase, and increased the expression of peroxisome proliferator–activated receptor-α in the liver.CONCLUSIONSOur findings indicated that DPP-4 inhibition has extrapancreatic protective effects against diet-induced adipose tissue inflammation and hepatic steatosis.

12/15-Lipoxygenase Is Required for the Early Onset of High Fat Diet-Induced Adipose Tissue Inflammation and Insulin Resistance in Mice

BackgroundRecent understanding that insulin resistance is an inflammatory condition necessitates searching for genes that regulate inflammation in insulin sensitive tissues. 12/15-lipoxygenase (12/15LO) regulates the expression of proinflammatory cytokines and chemokines and is implicated in the early development of diet-induced atherosclerosis. Thus, we tested the hypothesis that 12/15LO is involved in the onset of high fat diet (HFD)-induced insulin resistance.Methodology/Principal FindingsCells over-expressing 12/15LO secreted two potent chemokines, MCP-1 and osteopontin, implicated in the development of insulin resistance. We assessed adipose tissue inflammation and whole body insulin resistance in wild type (WT) and 12/15LO knockout (KO) mice after 2–4 weeks on HFD. In adipose tissue from WT mice, HFD resulted in recruitment of CD11b+, F4/80+ macrophages and elevated protein levels of the inflammatory markers IL-1β, IL-6, IL-10, IL-12, IFNγ, Cxcl1 and TNFα. Remarkably, adipose tissue from HFD-fed 12/15LO KO mice was not infiltrated by macrophages and did not display any increase in the inflammatory markers compared to adipose tissue from normal chow-fed mice. WT mice developed severe whole body (hepatic and skeletal muscle) insulin resistance after HFD, as measured by hyperinsulinemic euglycemic clamp. In contrast, 12/15LO KO mice exhibited no HFD-induced change in insulin-stimulated glucose disposal rate or hepatic glucose output during clamp studies. Insulin-stimulated Akt phosphorylation in muscle tissue from HFD-fed mice was significantly greater in 12/15LO KO mice than in WT mice.ConclusionsThese results demonstrate that 12/15LO mediates early stages of adipose tissue inflammation and whole body insulin resistance induced by high fat feeding.