Microbiota-Produced N-Formyl Peptide fMLF Promotes Obesity-Induced Glucose Intolerance.
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ABSTRACT:
SUBMITTER: Wollam J
PROVIDER: S-EPMC6609982 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Essentials The role of formyl peptide receptor 1 (FPR1) and its ligand, fMLF, in the regulation of platelet function, hemostasis, and thrombosis is largely unknown. Fpr1-deficient mice and selective inhibitors for FPR1 were used to investigate the function of fMLF and FPR1 in platelets. N-formyl-methionyl-leucyl-phenylalanine primes platelet activation and augments thrombus formation, mainly through FPR1 in platelets. Formyl peptide receptor 1 plays a pivotal role in the regulation of platelet function.BackgroundFormyl peptide receptors (FPRs) play pivotal roles in the regulation of innate immunity and host defense. The FPRs include three family members: FPR1, FPR2/ALX, and FPR3. The activation of FPR1 by its high-affinity ligand, N-formyl-methionyl-leucyl-phenylalanine (fMLF) (a bacterial chemoattractant peptide), triggers intracellular signaling in immune cells such as neutrophils and exacerbates inflammatory responses to accelerate the clearance of microbial infection. Notably, fMLF has been demonstrated to induce intracellular calcium mobilization and chemotaxis in platelets that are known to play significant roles in the regulation of innate immunity and inflammatory responses. Despite a plethora of research focused on the roles of FPR1 and its ligands such as fMLF on the modulation of immune responses, their impact on the regulation of hemostasis and thrombosis remains unexplored.ObjectiveTo determine the effects of fMLF on the modulation of platelet reactivity, hemostasis, and thrombus formation.MethodsSelective inhibitors for FPR1 and Fpr1-deficient mice were used to determine the effects of fMLF and FPR1 on platelets using various platelet functional assays.ResultsN-formyl-methionyl-leucyl-phenylalanine primes platelet activation through inducing distinctive functions and enhances thrombus formation under arterial flow conditions. Moreover, FPR1 regulates normal platelet function as its deficiency in mouse or blockade in human platelets using a pharmacological inhibitor resulted in diminished agonist-induced platelet activation.ConclusionSince FPR1 plays critical roles in numerous disease conditions, its influence on the modulation of platelet activation and thrombus formation may provide insights into the mechanisms that control platelet-mediated complications under diverse pathological settings.
| S-EPMC6617722 | biostudies-literature
Project description:The neuropeptide kisspeptin regulates reproduction by stimulating gonadotropin-releasing hormone (GnRH) neurons via the kisspeptin receptor KISS1R. In addition to GnRH neurons, KISS1R is expressed in other brain areas and peripheral tissues, which suggests that kisspeptin has additional functions beyond reproduction. Here, we studied the energetic and metabolic phenotype in mice lacking kisspeptin signaling (Kiss1r KO mice). Compared with WT littermates, adult Kiss1r KO females displayed dramatically higher BW, leptin levels, and adiposity, along with strikingly impaired glucose tolerance. Conversely, male Kiss1r KO mice had normal BW and glucose regulation. Surprisingly, despite their obesity, Kiss1r KO females ate less than WT females; however, Kiss1r KO females displayed markedly reduced locomotor activity, respiratory rate, and energy expenditure, which were not due to impaired thyroid hormone secretion. The BW and metabolic phenotype in Kiss1r KO females was not solely reflective of absent gonadal estrogen, as chronically ovariectomized Kiss1r KO females developed obesity, hyperleptinemia, reduced metabolism, and glucose intolerance compared with ovariectomized WT females. Our findings demonstrate that in addition to reproduction, kisspeptin signaling influences BW, energy expenditure, and glucose homeostasis in a sexually dimorphic and partially sex steroid-independent manner; therefore, alterations in kisspeptin signaling might contribute, directly or indirectly, to some facets of human obesity, diabetes, or metabolic dysfunction.
| S-EPMC4071390 | biostudies-literature
Project description:We previously demonstrated that cellular aging signals upregulated a secreted class 3 semaphorin E (Sema3E) and its receptor plexinD1 in the adipose tissue of a murine model of dietary obesity and that Sema3E was a chemoattractant, mediating its biological effects by inducing infiltration of plexinD1-positive inflammatory macrophages into the visceral white adipose tissue. This study was performed to develop a peptide vaccine for Sema3E and test its therapeutic potential in a murine model of dietary obesity. Two antigenic peptides were selected to generate neutralizing antibodies for a vaccine. These peptides were conjugated to keyhole limpet hemocyanin (KLH), and were administered with Freund's adjuvant to obese wild-type male mice. The Sema3E antibody titer was analyzed by ELISA, and the biological effects of the peptides were tested in mice with dietary obesity. Among the two candidate peptides, the Sema3E antibody titer was significantly increased by injection of KLH-conjugated HKEGPEYHWS (Sema3E vaccine). Administration of Sema3E vaccine suppressed the infiltration of plexinD1-positive cells, ameliorated chronic inflammation in visceral white adipose tissue, and improved systemic glucose intolerance in mice with dietary obesity, suggesting that Sema3E vaccine has the potential to become a next generation therapy for obesity and diabetes.
| S-EPMC6405888 | biostudies-literature
Project description:ObjectiveBreakthroughs in HIV treatment, especially combination antiretroviral therapy (ART), have massively reduced AIDS-associated mortality. However, ART administration amplifies the risk of non-AIDS defining illnesses including obesity, diabetes, and cardiovascular disease, collectively known as metabolic syndrome. Initial reports suggest that ART-associated risk of metabolic syndrome correlates with socioeconomic status, a multifaceted finding that encompasses income, race, education, and diet. Therefore, determination of causal relationships is extremely challenging due to the complex interplay between viral infection, ART, and the many environmental factors.MethodsIn the current study, we employed a mouse model to specifically examine interactions between ART and diet that impacts energy balance and glucose metabolism. Previous studies have shown that high-fat feeding induces persistent low-grade systemic and adipose tissue inflammation contributing to insulin resistance and metabolic dysregulation via adipose-infiltrating macrophages. Studies herein test the hypothesis that ART potentiates the inflammatory effects of a high-fat diet (HFD). C57Bl/6J mice on a HFD or standard chow containing ART or vehicle, were subjected to functional metabolic testing, RNA-sequencing of epididymal white adipose tissue (eWAT), and array-based kinomic analysis of eWAT-infiltrating macrophages.ResultsART-treated mice on a HFD displayed increased fat mass accumulation, impaired glucose tolerance, and potentiated insulin resistance. Gene set enrichment and kinomic array analyses revealed a pro-inflammatory transcriptional signature depicting granulocyte migration and activation.ConclusionThe current study reveals a HFD-ART interaction that increases inflammatory transcriptional pathways and impairs glucose metabolism, energy balance, and metabolic dysfunction.
| S-EPMC6001921 | biostudies-literature
Project description:Since metabolic process differs between humans and mice, studies were performed in hamsters, which are generally considered to be a more appropriate animal model for studies of obesity-related metabolic disorders. The modulation of gut microbiota, bile acids and the farnesoid X receptor (FXR) axis is correlated with obesity-induced insulin resistance and hepatic steatosis in mice. However, the interactions among the gut microbiota, bile acids and FXR in metabolic disorders remained largely unexplored in hamsters. In the current study, hamsters fed a 60% high-fat diet (HFD) were administered vehicle or an antibiotic cocktail by gavage twice a week for four weeks. Antibiotic treatment alleviated HFD-induced glucose intolerance, hepatic steatosis and inflammation accompanied with decreased hepatic lipogenesis and elevated thermogenesis in subcutaneous white adipose tissue (sWAT). In the livers of antibiotic-treated hamsters, cytochrome P450 family 7 subfamily B member 1 (CYP7B1) in the alternative bile acid synthesis pathway was upregulated, contributing to a more hydrophilic bile acid profile with increased tauro-?-muricholic acid (T?MCA). The intestinal FXR signaling was suppressed but remained unchanged in the liver. This study is of potential translational significance in determining the role of gut microbiota-mediated bile acid metabolism in modulating diet-induced glucose intolerance and hepatic steatosis in the hamster.
| S-EPMC6664038 | biostudies-literature
Project description:Background Breakthroughs in HIV treatment, especially antiretroviral therapy (ART), have massively reduced mortality. However, ART-treated individuals display elevated rates of obesity, diabetes, and cardiovascular disease, collectively known as metabolic syndrome. These co-morbidities represent a considerable threat to long-term survival and quality of life. Previous studies have shown that high-fat feeding induces persistent low-grade systemic and adipose tissue inflammation contributing to insulin resistance and metabolic dysregulation via adipose-infiltrating macrophages. Methods and Results Studies herein test the hypothesis that ART potentiates the inflammatory effects of a high-fat diet (HFD). C57Bl/6J mice on a HFD or standard chow containing ART or vehicle, were subjected to functional metabolic testing, RNA-sequencing of epididymal white adipose tissue (eWAT), and array-based kinomic analysis of eWAT-infiltrating macrophages. ART-treated mice on a HFD displayed fat mass accumulation, impaired glucose tolerance, and potentiated insulin resistance. Gene set enrichment and kinomic array analyses revealed a pro-inflammatory transcriptional signature depicting granulocyte migration and activation. Conclusions The current study reveals a HFD-ART interaction that increases inflammatory transcriptional pathways in eWAT consistent with macrophage infiltration, resulting in impaired glucose metabolism, energy balance, and metabolic dysfunction.
2018-09-14 | GSE110035 | GEO
Project description:Aims/hypothesisAngiopoietin-like 4 (ANGPTL4) is an important regulator of triacylglycerol metabolism, carrying out this role by inhibiting the enzymes lipoprotein lipase and pancreatic lipase. ANGPTL4 is a potential target for ameliorating cardiometabolic diseases. Although ANGPTL4 has been implicated in obesity, the study of the direct role of ANGPTL4 in diet-induced obesity and related metabolic dysfunction is hampered by the massive acute-phase response and development of lethal chylous ascites and peritonitis in Angptl4-/- mice fed a standard high-fat diet. The aim of this study was to better characterise the role of ANGPTL4 in glucose homeostasis and metabolic dysfunction during obesity.MethodsWe chronically fed wild-type (WT) and Angptl4-/- mice a diet rich in unsaturated fatty acids and cholesterol, combined with fructose in drinking water, and studied metabolic function. The role of the gut microbiota was investigated by orally administering a mixture of antibiotics (ampicillin, neomycin, metronidazole). Glucose homeostasis was assessed via i.p. glucose and insulin tolerance tests.ResultsMice lacking ANGPTL4 displayed an increase in body weight gain, visceral adipose tissue mass, visceral adipose tissue lipoprotein lipase activity and visceral adipose tissue inflammation compared with WT mice. However, they also unexpectedly had markedly improved glucose tolerance, which was accompanied by elevated insulin levels. Loss of ANGPTL4 did not affect glucose-stimulated insulin secretion in isolated pancreatic islets. Since the gut microbiota have been suggested to influence insulin secretion, and because ANGPTL4 has been proposed to link the gut microbiota to host metabolism, we hypothesised a potential role of the gut microbiota. Gut microbiota composition was significantly different between Angptl4-/- mice and WT mice. Interestingly, suppression of the gut microbiota using antibiotics largely abolished the differences in glucose tolerance and insulin levels between WT and Angptl4-/- mice.Conclusions/interpretationDespite increasing visceral fat mass, inactivation of ANGPTL4 improves glucose tolerance, at least partly via a gut microbiota-dependent mechanism.
| S-EPMC6449003 | biostudies-literature
Project description:Serine hydrolases are a large family of multifunctional enzymes known to influence obesity. Here, we performed activity-based protein profiling to assess the functional level of serine hydrolases in liver biopsies from lean and obese humans in order to gain mechanistic insight into the pathophysiology of metabolic disease. We identified reduced hepatic activity of carboxylesterase 2 (CES2) and arylacetamide deacetylase (AADAC) in human obesity. In primary human hepatocytes, CES2 knockdown impaired glucose storage and lipid oxidation. In mice, obesity reduced CES2, whereas adenoviral delivery of human CES2 reversed hepatic steatosis, improved glucose tolerance, and decreased inflammation. Lipidomic analysis identified a network of CES2-regulated lipids altered in human and mouse obesity. CES2 possesses triglyceride and diacylglycerol lipase activities and displayed an inverse correlation with HOMA-IR and hepatic diacylglycerol concentrations in humans. Thus, decreased CES2 is a conserved feature of obesity and plays a causative role in the pathogenesis of obesity-related metabolic disturbances.
| S-EPMC5276805 | biostudies-other
Project description:BackgroundThe cardiac hormones atrial (ANP) and B-type natriuretic peptides (BNP) moderate arterial blood pressure and improve energy metabolism as well as insulin sensitivity via their shared cGMP-producing guanylyl cyclase-A (GC-A) receptor. Obesity is associated with impaired NP/GC-A/cGMP signaling, which possibly contributes to the development of type 2 diabetes and its cardiometabolic complications. In vitro, synthetic ANP, via GC-A, stimulates glucose-dependent insulin release from cultured pancreatic islets and β-cell proliferation. However, the relevance for systemic glucose homeostasis in vivo is not known. To dissect whether the endogenous cardiac hormones modulate the secretory function and/or proliferation of β-cells under (patho)physiological conditions in vivo, here we generated a novel genetic mouse model with selective disruption of the GC-A receptor in β-cells.MethodsMice with a floxed GC-A gene were bred to Rip-CreTG mice, thereby deleting GC-A selectively in β-cells (β GC-A KO). Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion were monitored in normal diet (ND)- and high-fat diet (HFD)-fed mice. β-cell size and number were measured by immunofluorescence-based islet morphometry.ResultsIn vitro, the insulinotropic and proliferative actions of ANP were abolished in islets isolated from β GC-A KO mice. Concordantly, in vivo, infusion of BNP mildly enhanced baseline plasma insulin levels and glucose-induced insulin secretion in control mice. This effect of exogenous BNP was abolished in β GC-A KO mice, corroborating the efficient inactivation of the GC-A receptor in β-cells. Despite this under physiological, ND conditions, fasted and fed insulin levels, glucose-induced insulin secretion, glucose tolerance and β-cell morphology were similar in β GC-A KO mice and control littermates. However, HFD-fed β GC-A KO animals had accelerated glucose intolerance and diminished adaptative β-cell proliferation.ConclusionsOur studies of β GC-A KO mice demonstrate that the cardiac hormones ANP and BNP do not modulate β-cell's growth and secretory functions under physiological, normal dietary conditions. However, endogenous NP/GC-A signaling improves the initial adaptative response of β-cells to HFD-induced obesity. Impaired β-cell NP/GC-A signaling in obese individuals might contribute to the development of type 2 diabetes.
| S-EPMC6048747 | biostudies-literature
Project description:As the prevalence of obesity-induced type 2 diabetes mellitus (T2DM) and nonalcoholic steatohepatitis (NASH) continue to increase, the need for pharmacologic therapies becomes urgent. However, endeavors to identify and develop novel therapeutic strategies for these chronic conditions are balanced by the need for safety, impeding clinical translation. One shared pathology of these two diseases is a maladaptive reactivation of the Notch signaling pathway in liver. Notch antagonism with γ-secretase inhibitors effectively suppresses hepatic glucose production and reduces liver fibrosis in NASH, but its extrahepatic side effects, particularly goblet cell metaplasia, limit therapeutic utility. To overcome this barrier, we developed a nanoparticle-mediated delivery system to target γ-secretase inhibitor to liver (GSI NPs). GSI NP application reduced hepatic glucose production in diet-induced obese mice and reduced hepatic fibrosis and inflammation in mice fed a NASH-provoking diet, without apparent gastrointestinal toxicity. By changing the delivery method, these results provide proof-of-concept for the repurposing of a previously intolerable medication to address unmet needs in the clinical landscape for obesity-induced T2DM and NASH.
| S-EPMC7444843 | biostudies-literature