Development Of Metabolic Inflammation Research Articles

Glibenclamide Prevents Inflammation by Targeting NLRP3 Inflammasome Activation In Vitro

The NLRP3 inflammasome is known to play a significant role in the development of neurodegeneration and physiological aging, as well as the development of metabolic inflammation, which has generated significant interest in the scientific community in finding effective inhibitors of the NLRP3 inflammasome and assessing their effects. The purpose of this study was to evaluate the effect of pharmacological modulation of NLRP3 activity using an indirect NLRP3 inflammasome inhibitor, glibenclamide, on the expression of metaflammasome components in in vitro brain cells obtained from middle-aged mice. The study revealed that glibenclamide reduces the expression of pro-inflammatory markers NLRP3 and IL18 in cell culture, which in turn leads to the prevention of phosphorylation of protein kinases of the metaflammasome complex – PKR and IKKβ. However, we did not observe changes in the expression of pathologically phosphorylated IRS, as well as in the number of senescent cells in cultures after the exposure to glibenclamide.

AGER-1 Long Non-Coding RNA Levels Correlate with the Expression of the Advanced Glycosylation End-Product Receptor, a Regulator of the Inflammatory Response in Visceral Adipose Tissue of Women with Obesity and Type 2 Diabetes Mellitus.

The advanced glycosylation end-product receptor (AGER) is involved in the development of metabolic inflammation and related complications in type 2 diabetes mellitus (T2DM). Tissue expression of the AGER gene (AGER) is regulated by epigenetic mediators, including a long non-coding RNA AGER-1 (lncAGER-1). This study aimed to investigate whether human obesity and T2DM are associated with an altered expression of AGER and lncAGER-1 in adipose tissue and, if so, whether these changes affect the local inflammatory milieu. The expression of genes encoding AGER, selected adipokines, and lncAGER-1 was assessed using real-time PCR in visceral (VAT) and subcutaneous (SAT) adipose tissue. VAT and SAT samples were obtained from 62 obese (BMI > 40 kg/m2; N = 24 diabetic) and 20 normal weight (BMI = 20-24.9 kg/m2) women, while a further 15 SAT samples were obtained from patients who were 18 to 24 months post-bariatric surgery. Tissue concentrations of adipokines were measured at the protein level using an ELISA-based method. Obesity was associated with increased AGER mRNA levels in SAT compared to normal weight status (p = 0.04) and surgical weight loss led to their significant decrease compared to pre-surgery levels (p = 0.01). Stratification by diabetic status revealed that AGER mRNA levels in VAT were higher in diabetic compared to non-diabetic women (p = 0.018). Elevated AGER mRNA levels in VAT of obese diabetic patients correlated with lncAGER-1 (p = 0.04, rs = 0.487) and with interleukin 1β (p = 0.008, rs = 0.525) and resistin (p = 0.004, rs = 0.6) mRNA concentrations. In conclusion, obesity in women is associated with increased expression of AGER in SAT, while T2DM is associated with increased AGER mRNA levels and pro-inflammatory adipokines in VAT.

Cloudberry (Rubus chamaemorus L.) Supplementation Attenuates the Development of Metabolic Inflammation in a High-Fat Diet Mouse Model of Obesity.

Metabolic diseases linked to obesity are an increasing problem globally. They are associated with systemic inflammation, which can be triggered by nutrients such as saturated fatty acids. Cloudberry is rich in ellagitannin and its derivatives, which are known to have anti-inflammatory properties. In the present study, a high-fat-diet-induced mouse model of obesity was used to study the effects of air-dried cloudberry powder on weight gain, systemic inflammation, lipid and glucose metabolism, and changes in gene expression in hepatic and adipose tissues. Cloudberry supplementation had no effect on weight gain, but it prevented the rise in the systemic inflammation marker serum amyloid A (SAA) and the hepatic inflammation/injury marker alanine aminotransferase (ALT), as well as the increase in the expression of many inflammation-related genes in the liver and adipose tissue, such as Mcp1, Cxcl14, Tnfa, and S100a8. In addition, cloudberry supplementation impeded the development of hypercholesterolemia and hyperglycemia. The results indicate that cloudberry supplementation helps to protect against the development of metabolic inflammation and provides partial protection against disturbed lipid and glucose metabolism. These results encourage further studies on the effects of cloudberry and cloudberry-derived ellagitannins and support the use of cloudberries as a part of a healthy diet to prevent obesity-associated metabolic morbidity.

Dietary inclusion of ruminally protected linseed oil as a means to mitigate heat and slaughter-induced stress in feedlot cattle.

There is evidence of a relationship between increased energy intake and the development of metabolic inflammation and insulin resistance (IR), and between the aforementioned metabolic state and impaired tolerance to heat stress. Based on the anti-inflammatory properties and mitigating effects on IR and stress of n-3 polyunsaturated fatty acids (n-3 PUFA), an experiment was performed to evaluate the effect of n-3 PUFA supplementation to feedlot-finished steers during summer on animal performance, physiological and biochemical variables associated with glucose metabolism, heat and preslaughter-induced stress, and meat quality. A total of 48 Angus steers (388±2kg) were fed one of three corn-based finishing diets containing (dry matter basis) 0% added oil (CON; negative control), or 1.90% of sunflower oil-calcium salt (SUN; positive control), or 1.92% of linseed oil-calcium salt (LIN). There was a trend (P = 0.08) for greater dry matter intake (DMI) and greater (P = 0.02) average daily gain (ADG) in LIN-fed animals compared with the average between those that received the CON or SUN diets, whereas no differences (P ≥ 0.34) were observed between the latter. No other performance, physiological, or carcass variables were affected (P ≥ 0.12) by treatment. Blood glucose and insulin were similar (P ≥ 0.14), though the homeostatic model assessment (HOMA) which gauges IR tended (P = 0.06) to be reduced for LIN-fed animals compared with the average between those that received the CON or SUN diets. Blood insulin and HOMA increased linearly (P ≤ 0.01) with days on feed. An interaction between the study phase (feeding period or slaughter) and treatment was observed (P ≤ 0.05) for glucose and cortisol. While the magnitude of glucose increase (P < 0.01) from the end of the feeding period to slaughter was greater for CON- and SUN-fed animals compared with LIN-fed ones, cortisol increased (P < 0.05) only in animals that received CON or SUN diets. Meat quality attributes were not affected (P ≥ 0.16) by treatment. The concentration of n-3 PUFA was greater (P < 0.01) and n-6:n-3 ratio was lesser (P < 0.01) in meat from LIN-fed animals compared with that resulting from the average between the animals that received the negative (CON) or positive (SUN) control diets. Results suggest that n-3 PUFA supplementation mitigated metabolic alterations associated with IR and preslaughter-related stress. It may have also improved tolerance to heat, resulting in greater DMI and ADG of steers fed a high-energy diet during summer. Results also indicate that glucose metabolism and heat stress tolerance worsen with time when feeding concentrate-based diets.

Development of metabolic inflammation during pre-hibernation fattening in 13-lined ground squirrels (Ictidomys tridecemlineatus).

Obesity is a worldwide pandemic with significant comorbidities. It is often accompanied by mild inflammation of the intestine followed by inflammation of metabolic tissues such as liver, adipose tissue, and skeletal muscle. Several laboratory models of obesity exist, but seasonal models like hibernators may be valuable for understanding the pathogenesis of obesity independent of genetic or high-fat diet-induced changes. As part of their annual cycle, obligate hibernators, like the 13-lined ground squirrel (Ictidomys tridecemlineatus), undergo a rapid shift from a lean to an obese state to store energy in the form of fat for their prolonged winter fast. Here, we show that ground squirrels gained mass steadily throughout the active season despite a drop in energy intake starting around 9weeks post-hibernation. Glucose tolerance tests revealed a significant decrease in tolerance late in the active season. In visceral adipose, we found increases in adipocyte size, tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels. IL-6 levels also increased in liver and muscle and TNF-α increased in the ileum late in the active season. Levels of the anti-inflammatory cytokine, IL-10, decreased in visceral adipose and colon tissues around the same time. These data suggest metabolic inflammation develops along with adiposity late in the squirrels' active season.

Ceramide kinase regulates TNF-\u03b1-induced immune responses in human monocytic cells

Ceramide kinase (CERK) phosphorylates ceramide to produce ceramide-1-phosphate (C1P), which is involved in the development of metabolic inflammation. TNF-α modulates inflammatory responses in monocytes associated with various inflammatory disorders; however, the underlying mechanisms remain not fully understood. Here, we investigated the role of CERK in TNF-α-induced inflammatory responses in monocytes. Our results show that disruption of CERK activity in monocytes, either by chemical inhibitor NVP-231 or by small interfering RNA (siRNA), results in the defective expression of inflammatory markers including CD11c, CD11b and HLA-DR in response to TNF-α. Our data show that TNF-α upregulates ceramide phosphorylation. Inhibition of CERK in monocytes significantly reduced the secretion of IL-1β and MCP-1. Similar results were observed in CERK-downregulated cells. TNF-α-induced phosphorylation of JNK, p38 and NF-κB was reduced by inhibition of CERK. Additionally, NF-κB/AP-1 activity was suppressed by the inhibition of CERK. Clinically, obese individuals had higher levels of CERK expression in PBMCs compared to lean individuals, which correlated with their TNF-α levels. Taken together, these results suggest that CERK plays a key role in regulating inflammatory responses in human monocytes during TNF-α stimulation. CERK may be a relevant target for developing novel therapies for chronic inflammatory diseases.

5‐Aminosalicylic Acid Treatment Affects the Rate of Caloric Intake in Fattening Ground Squirrels

Obesity is the second leading cause of preventable death in the United States. Though prevalent, very little is known about the biological mechanisms that lead to obesity. A connection between increased gut permeability and the consequent immune response in systemic tissues exists in obese humans and mice. Systemic inflammation brought on by this immune response has been shown to decrease tissue efficacy and lead to adverse effects, such as insulin resistance. Recently, it was shown in mice on a high‐fat diet that 5‐aminosalicylic acid (5‐ASA, mesalazine), a gut‐specific anti‐inflammatory drug, attenuated insulin resistance and metabolic inflammation. We used a natural model of rapid adiposity, fattening 13‐lined ground squirrels (Ictidomys tridecemlineatus) during their active season, to examine the effects of 5‐ASA on caloric intake, body mass, glucose tolerance and inflammation. These squirrels normally double their adipose mass during their active season in preparation for hibernation. We found that the rate of caloric intake was significantly affected by 5‐ASA treatment and that these squirrels tended to eat more while gaining equal or less mass during the same period. Adipose depot mass was not different between groups but did differ between males and females. Despite a trend in the early weeks of 5‐ASA treatment, glucose tolerance did not differ between treated and control squirrels. Examination of pro‐ and anti‐inflammatory cytokines in white adipose depots and gut tissues revealed trends toward increased IL‐4 and TNF in visceral adipose of treated squirrels. Our results suggest that 5‐ASA treatment has different effects on development of metabolic inflammation in ground squirrels versus mice. Further studies are needed to determine if a higher dose would prove more effective in these seasonal hibernators.Support or Funding InformationSupported by NIH award 1R15GM124586‐01A1

NOD1: An Interface Between Innate Immunity and Insulin Resistance.

Insulin resistance is driven, in part, by activation of the innate immune system. We have discussed the evidence linking nucleotide-binding oligomerization domain (NOD)1, an intracellular pattern recognition receptor, to the onset and progression of obesity-induced insulin resistance. On a molecular level, crosstalk between downstream NOD1 effectors and the insulin receptor pathway inhibits insulin signaling, potentially through reduced insulin receptor substrate action. In vivo studies have demonstrated that NOD1 activation induces peripheral, hepatic, and whole-body insulin resistance. Also, NOD1-deficient models are protected from high-fat diet (HFD)-induced insulin resistance. Moreover, hematopoietic NOD1 deficiency prevented HFD-induced changes in proinflammatory macrophage polarization status, thus protecting against the development of metabolic inflammation and insulin resistance. Serum from HFD-fed mice activated NOD1 signaling ex vivo; however, the molecular identity of the activating factors remains unclear. Many have proposed that an HFD changes the gut permeability, resulting in increased translocation of bacterial fragments and increased circulating NOD1 ligands. In contrast, others have suggested that NOD1 ligands are endogenous and potentially lipid-derived metabolites produced during states of nutrient overload. Nevertheless, that NOD1 contributes to the development of insulin resistance, and that NOD1-based therapy might provide benefit, is an exciting advancement in metabolic research.

Gut microbiota and immune crosstalk in metabolic disease

The aim of the review is to discuss about the role played by the defence crosstalk between the gut microbiota and the intestinal immune system, in the development of metabolic disease focusing on obesity and diabetes. Starting from physiological and pathological stand points and based on the latest published data, this review is addressing how the concept of the hologenome theory of evolution can drive the fate of metabolic disease. The notion of "metabolic infection" to explain the "metabolic inflammation" is discussed. This imply comments about the process of bacterial translocation and impaired intestinal immune defense against commensals. Eventually this review sets the soil for personalized medicine. The monthly increase in the number of publications on the gut microbiota to intestinal immune defense and the control of metabolism demonstrate the importance of this field of investigation. The notion of commensal as "self or non-self" has to be reevaluated in the light of the current data. Furthermore, data demonstrate the major role played by short chain fatty acids, secondary bile acids, LPS, peptidoglycans, indole derivatives, and other bacteria-related molecules on the shaping of cells involved in the intestinal protection against commensals is now becoming a central player in the incidence of metabolic diseases. The literature demonstrates that the onset of metabolic diseases and some specific co-morbidities can be explained by a gut microbiota to intestinal immune system crosstalk. Therefore, one should now consider this avenue of investigation as a putative source of biomarkers and therapeutic targets to personalize the treatment of metabolic disease and its co-morbidities. Gut microbiota is considered as a major regulator of metabolic disease. This reconciles the notion of metabolic inflammation and the epidemic development of the disease. In addition to evidence showing that a specific gut microbiota characterizes patients with obesity, type 2 diabetes, and hepatic steatosis, the mechanisms causal to the disease could be related to the translocation of microbiota from the gut to the tissues, which induces inflammation. The mechanisms regulating such a process are based on the crosstalk between the gut microbiota and the host immune system. The hologenome theory of evolution supports this concept and implies that therapeutic strategies aiming to control glycemia should take into account both the gut microbiota and the host immune system. This review discusses the latest evidence regarding the bidirectional impact of the gut microbiota on host immune system crosstalk for the control of metabolic disease, hyperglycemia, and obesity. To avoid redundancies with the literature, we will focus our attention on the intestinal immune system, identifying evidence for the generation of novel therapeutic strategies, which could be based on the control of the translocation of gut bacteria to tissues. Such novel strategies should hamper the role played by gut microbiota dysbiosis on the development of metabolic inflammation. Recent evidence in rodents allows us to conclude that an impaired intestinal immune system characterizes and could be causal in the development of metabolic disease. The fine understanding of the molecular mechanisms should allow for the development of a first line of treatment for metabolic disease and its co-morbidities.

Intestinal RORrt-generated Th17 cells control type 2 diabetes: A first antidiabetic target identified from the host to microbiota crosstalk

The recent discovery of the role played by gut microbiota on the control of metabolic disease opens novel routes for the identification of the causes of type 2 diabetes and obesity. This paradigm could explain the infiltration, by innate and adaptive immune cells, of the adipose tissue, liver, and islets of Langerhans which is responsible for the metabolic inflammation state that leads to impaired insulin action and secretion, and therefore, type 2 diabetes. The identification of the causal role of circulating lipopolysaccharides LPS and peptidoglycans in the development of metabolic inflammation, due to an increased intestinal permeability, led to the leaky gut hypothesis. In addition, whole live bacteria were found in metabolic tissues establishing a tissue microbiota which upon a fat-enriched diet becomes dysbiotic. The process of intestinal bacterial translocation was responsible for the onset of a leaky gut causal to the disease. The translocation of selective sets of intestinal bacteria to the blood could be identified. These blood bacterial 16SrRNA-DNA sequences are considered as biomarkers of the bacterial translocation process. An increased of the corresponding bacterial DNA concentration was predicting the occurrence of type 2 diabetes. Associated to the dysbiotic microbiota translocation, an impaired intestinal immune defense was identified as a cause of the selective leaky gut. The change in small intestine mucosal microbiota induced by a fat-enriched diet reduces the number of IL17-secreting CD4 T cells within the lamina propria of the intestine. This loss of IL17-secreting CD4 T cells is the consequence of an impaired capacity of intestinal antigen presenting cells to activate and trigger the expression of RORgt and the production of IL17 by CD4 T cells. Altogether, an impaired intestinal immune defense, notably the reduced differentiation of RORgt expressing IL17-producing CD4 T cells, favors the onset of a leaky gut leading to the translocation of bacterial factors and live bacteria towards tissues triggering metabolic inflammation; insulin resistance and type 2 diabetes. Hence, the triggering of intestinal defense surrounding RORgt pathway now appears as a potential target mechanism for the control of type 2 diabetes.

Thermoneutral Housing Accelerates Metabolic Inflammation to Potentiate Atherosclerosis but Not Insulin Resistance

Chronic, low-grade inflammation triggered by excess intake of dietary lipids has been proposed to contribute to the pathogenesis of metabolic disorders, such as obesity, insulin resistance, type 2 diabetes, and atherosclerosis. Although considerable evidence supports a causal association between inflammation and metabolic diseases, most tests of this link have been performed in cold-stressed mice that are housed below their thermoneutral zone. We report here that thermoneutral housing of mice has a profound effect on the development of metabolic inflammation, insulin resistance, and atherosclerosis. Mice housed at thermoneutrality develop metabolic inflammation in adipose tissue and in the vasculature at an accelerated rate. Unexpectedly, this increased inflammatory response contributes to the progression of atherosclerosis but not insulin resistance. These findings not only suggest that metabolic inflammation can be uncoupled from obesity-associated insulin resistance, but also point to how thermal stress might limit our ability to faithfully model human diseases in mice.

The fractalkine/Cx3CR1 system is implicated in the development of metabolic visceral adipose tissue inflammation in obesity

Diet-induced obesity and related peripheral and central inflammation are major risk factors for metabolic, neurological and psychiatric diseases. The chemokine fractalkine (Cx3CL1) and its receptor Cx3CR1 play a pivotal role in recruitment, infiltration and proinflammatory polarization of leukocytes and micoglial cells, however, the role of fractalkine signaling in the development of metabolic inflammation is not fully resolved. To address this issue, fractalkine receptor deficient (Cx3CR1 gfp/gfp) mice were exposed to normal or fat-enriched diet (FatED) for 10weeks and physiological-, metabolic- and immune parameters were compared to those animals in which the fractalkine signaling is maintained by the presence of one functioning allele (Cx3CR1 +/gfp). Mice with intact fractalkine signaling develop obesity characterized by increased epididymal white fat depots and mild glucose intolerance, recruit leukocytes into the visceral adipose tissue and display increased expression of subset of pro- and anti-inflammatory cytokines when exposed to fat-enriched diet. By contrast, Cx3CR1-deficient (gfp/gfp) mice gain significantly less weight on fat-enriched diet and have smaller amount of white adipose tissue (WAT) in the visceral compartment than heterozygote controls. Furthermore, Cx3CR1 gfp/gfp mice fed a fat-enriched diet do not develop glucose intolerance, recruit proportionally less number of gfp-positive cells and express significantly less MCP-1, IL-1α and TNFα in the WAT than control animals with fat-enriched diet induced obesity. Furthermore, heterozygote obese, but not fractalkine receptor deficient mice express high levels of anti-inflammatory IL-10 and arginase1 markers in the visceral fat. The effect of fat-enriched diet on cytokine expression pattern was specific for the WAT, as we did not detect significant elevation of interleukin-1, tumor necrosis factor-alpha and monocyte chemotacting protein (MCP-1) expression in the liver or in the hypothalamus in either genotype. These results highlight the importance of fractalkine signaling in recruitment and polarization of adipose tissue immune cells and identify fractalkine as a target to fight obesity-induced inflammatory complications.

Adiponectin: Are Measurements Clinically Useful in Pregnancy?

Adiponectin (AdpN) is an abundant protein that circulates in blood in microgram quantities. Although AdpN is primarily produced by adipose tissue, the paradox of AdpN is that plasma concentrations decrease with increasing adiposity (1,2). AdpN concentrations are decreased in obesity (3) and obesity-related complications—for example, diabetes, cardiovascular diseases, nonalcoholic fatty liver disease, and in pregnancy (4,5). AdpN exerts pleiotropic actions including potent insulin sensitizing properties. Studies in obesity, type 2 diabetes, and gestational diabetes mellitus (GDM) suggest that the deficiency of AdpN triggers the progression to insulin resistance and the development of metabolic inflammation (recently reviewed in ref. 6). This has encouraged numerous groups to investigate whether AdpN could serve as a systemic biomarker that would predict the risk of diabetes. A link between hypoadiponectinemia and reduced insulin action also exists in pregnancy. In healthy women, AdpN levels reach their lowest concentrations in the third trimester when maternal insulin resistance is greatest (5,7). The low AdpN concentrations in the third trimester are further accentuated in GDM (8). Total AdpN and high molecular weight AdpN and the high molecular weight-to-AdpN ratio are inversely related to insulin resistance as estimated by clamp studies in early and late pregnancy (5). Maternal AdpN does not cross the placenta and consequently does not contribute to fetal adiponectinemia (9). Contrary to other cytokines, AdpN is not expressed nor produced by the placenta (10–12). Similar to the nonpregnant state, these characteristics underscore that maternal adipose tissue is the major source of maternal plasma AdpN, which thus can be assessed as an independent maternal biomarker (Fig. 1). …