Browsing by Subject "Adiponectin"
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Item Adiponectin pathway activation dampens inflammation and enhances alveolar macrophage fungal killing via LC3-associated phagocytosis(bioRxiv, 2024-08-24) Goli, Sri Harshini; Lim, Joo-Yeon; Basaran-Akgul, Nese; Templeton, Steven P.; Microbiology and Immunology, School of MedicineAlthough innate immunity is critical for antifungal host defense against the human opportunistic fungal pathogen Aspergillus fumigatus, potentially damaging inflammation must be controlled. Adiponectin (APN) is an adipokine produced mainly in adipose tissue that exerts anti-inflammatory effects in adipose-distal tissues such as the lung. We observed 100% mortality and increased fungal burden and inflammation in neutropenic mice with invasive aspergillosis (IA) that lack APN or the APN receptors AdipoR1 or AdipoR2. Alveolar macrophages (AMs), early immune sentinels that detect and respond to lung infection, express both receptors, and APN−/− AMs exhibited an inflammatory/M1 phenotype that was associated with decreased fungal killing. Pharmacological stimulation of AMs with AdipoR agonist AdipoRon partially rescued deficient killing in APN−/− AMs that was dependent on both receptors. Finally, APN-enhanced fungal killing was associated with increased activation of the non-canonical LC3 pathway of autophagy. Thus, our study identifies a novel role for APN in LC3-mediated killing of A. fumigatus.Item Adiponectin receptor fragmentation in mouse models of type 1 and type 2 diabetes(ProBiologists, 2020) Frabutt, Dylan; Stull, Natalie; Pineros, Annie R.; Tersey, Sarah A.; Scheuner, Donalyn; Mastracci, Teresa L.; Pugia, Michael J.; Biology, School of ScienceThe protein hormone adiponectin regulates glucose and fatty acid metabolism by binding to two PAQR-family receptors (AdipoR1 and AdipoR2). Both receptors feature a C-terminal segment which is released by proteolysis to form a freely circulating C-terminal fragment (CTF) found in the plasma of normal individuals but not in some undefined diabetes patients. The AdipoR1-CTF344-376 is a competitive inhibitor of tumor necrosis factor α cleavage enzyme (TACE) but it contains a shorter peptide domain (AdipoR1 CTF351-362) that is a strong non-competitive inhibitor of insulin-degrading enzyme (IDE). The link between adiponectin receptor fragmentation and diabetes pathology is unclear but could lead to new therapeutic strategies. We therefore investigated physiological variations in the concentrations of CTF in non-obese diabetic (NOD/ShiLtJ) mice and C57BL/6 mice with diet-induced obesity (DIO) as models of diabetes types 1 and 2, respectively. We tested for changes in adiponectin receptor signaling, immune responses, disease progression, and the abundance of neutralizing autoantibodies. Finally, we administered exogenous AdipoR1-CTF peptides either containing or lacking the IDE-binding domain. We observed the more pronounced CTF shedding in the TACE-active NOD mice, which represents an inflammatory autoimmune phenotype, but fragmentation was also observed to a lesser extent in the DIO model. Autoantibodies to CTF were detected in both models. Neither exogenous CTF peptide affected IgG-CTF plasma levels, body weight or the conversion of NOD mice to diabetes. The pattern of AdipoR1 fragmentation and autoantibody production under physiological conditions of aging, DIO, and autoimmune diabetes therefore provides insight into the association adiponectin biology and diabetes.Item Integrative metabolomics-genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease(Wiley, 2022) Horgusluoglu, Emrin; Neff, Ryan; Song, Won-Min; Wang, Minghui; Wang, Qian; Arnold, Matthias; Krumsiek, Jan; Galindo-Prieto, Beatriz; Ming, Chen; Nho, Kwangsik; Kastenmüller, Gabi; Han, Xianlin; Baillie, Rebecca; Zeng, Qi; Andrews, Shea; Cheng, Haoxiang; Hao, Ke; Goate, Alison; Bennett, David A.; Saykin, Andrew J.; Kaddurah-Daouk, Rima; Zhang, Bin; Alzheimer's Disease Neuroimaging Initiative (ADNI); Alzheimer Disease Metabolomics Consortium; Radiology and Imaging Sciences, School of MedicineMetabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD‐specific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD. Metabolite co‐expression network analysis of the blood metabolomic data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) shows short‐chain acylcarnitines/amino acids and medium/long‐chain acylcarnitines are most associated with AD clinical outcomes, including episodic memory scores and disease severity. Integration of the gene expression data in both the blood from the ADNI and the brain from the Accelerating Medicines Partnership Alzheimer's Disease (AMP‐AD) program reveals ABCA1 and CPT1A are involved in the regulation of acylcarnitines and amino acids in AD. Gene co‐expression network analysis of the AMP‐AD brain RNA‐seq data suggests the CPT1A‐ and ABCA1‐centered subnetworks are associated with neuronal system and immune response, respectively. Increased ABCA1 gene expression and adiponectin protein, a regulator of ABCA1, correspond to decreased short‐chain acylcarnitines and amines in AD in the ADNI. In summary, our integrated analysis of large‐scale multiomics data in AD systematically identifies novel metabolites and their potential regulators in AD and the findings pave a way for not only developing sensitive and specific diagnostic biomarkers for AD but also identifying novel molecular mechanisms of AD pathogenesis.Item Non-traditional biomarkers and incident diabetes in the Diabetes Prevention Program: comparative effects of lifestyle and metformin interventions(Springer Verlag, 2018-10-17) Goldberg, Ronald B.; Bray, George A.; Marcovina, Santica M.; Mather, Kieren J.; Orchard, Trevor J.; Perreault, Leigh; Temprosa, Marinella; Medicine, School of MedicineWe compared the associations of circulating biomarkers of inflammation, endothelial and adipocyte dysfunction and coagulation with incident diabetes in the placebo, lifestyle and metformin intervention arms of the Diabetes Prevention Program, a randomised clinical trial, to determine whether reported associations in general populations are reproduced in individuals with impaired glucose tolerance, and whether these associations are independent of traditional diabetes risk factors. We further investigated whether biomarker-incident diabetes associations are influenced by interventions that alter pathophysiology, biomarker concentrations and rates of incident diabetes. METHODS: The Diabetes Prevention Program randomised 3234 individuals with impaired glucose tolerance into placebo, metformin (850 mg twice daily) and intensive lifestyle groups and showed that metformin and lifestyle reduced incident diabetes by 31% and 58%, respectively compared with placebo over an average follow-up period of 3.2 years. For this study, we measured adiponectin, leptin, tissue plasminogen activator (as a surrogate for plasminogen activator inhibitor 1), high-sensitivity C-reactive protein, IL-6, monocyte chemotactic protein 1, fibrinogen, E-selectin and intercellular adhesion molecule 1 at baseline and at 1 year by specific immunoassays. Traditional diabetes risk factors were defined as family history, HDL-cholesterol, triacylglycerol, BMI, fasting and 2 h glucose, HbA1c, systolic blood pressure, inverse of fasting insulin and insulinogenic index. Cox proportional hazard models were used to assess the effects of each biomarker on the development of diabetes assessed semi-annually and the effects of covariates on these. RESULTS: E-selectin, (HR 1.19 [95% CI 1.06, 1.34]), adiponectin (0.84 [0.71, 0.99]) and tissue plasminogen activator (1.13 [1.03, 1.24]) were associated with incident diabetes in the placebo group, independent of diabetes risk factors. Only the association between adiponectin and diabetes was maintained in the lifestyle (0.69 [0.52, 0.92]) and metformin groups (0.79 [0.66, 0.94]). E-selectin was not related to diabetes development in either lifestyle or metformin groups. A novel association appeared for change in IL-6 in the metformin group (1.09 [1.021, 1.173]) and for baseline leptin in the lifestyle groups (1.31 [1.06, 1.63]). CONCLUSIONS/INTERPRETATION: These findings clarify associations between an extensive group of biomarkers and incident diabetes in a multi-ethnic cohort with impaired glucose tolerance, the effects of diabetes risk factors on these, and demonstrate differential modification of associations by interventions. They strengthen evidence linking adiponectin to diabetes development, and argue against a central role for endothelial dysfunction. The findings have implications for the pathophysiology of diabetes development and its prevention.Item Reciprocal Inhibition of Adiponectin and Innate Lung Immune Responses to Chitin and Aspergillus fumigatus(Frontiers, 2019-05-10) Amarsaikhan, Nansalmaa; Stolz, Dylan J.; Wilcox, Amber; Sands, Ethan M.; Tsoggerel, Angar; Gravely, Haley; Templeton, Steven P.; Microbiology and Immunology, School of MedicineChitin is a structural biopolymer found in numerous organisms, including pathogenic fungi, and recognized as an immune-stimulating pathogen associated molecular pattern by pattern recognition molecules of the host immune system. However, programming and regulation of lung innate immunity to chitin inhalation in the context of inhalation of fungal pathogens such as Aspergillus fumigatus is complex and our understanding incomplete. Here we report that the systemic metabolism-regulating cytokine adiponectin is decreased in the lungs and serum of mice after chitin inhalation, with a concomitant decrease in surface expression of the adiponectin receptor AdipoR1 on lung leukocytes. Constitutive lung expression of acidic mammalian chitinase resulted in decreased inflammatory cytokine gene expression and neutrophil recruitment, but did not significantly affect lung adiponectin transcription. Exogenous recombinant adiponectin specifically dampened airway chitin-mediated eosinophil recruitment, while adiponectin deficiency resulted in increased airway eosinophils. The presence of adiponectin also resulted in decreased CCL11-mediated migration of bone marrow-derived eosinophils. In contrast to purified chitin, aspiration of viable conidia from the high chitin-expressing A. fumigatus isolate Af5517 resulted in increased neutrophil recruitment and inflammatory cytokine gene expression in adiponectin-deficient mice, while no significant changes were observed in response to the isolate Af293. Our results identify a novel role for the adiponectin pathway in inhibition of lung inflammatory responses to chitin and A. fumigatus inhalation.Item Regulation of lung inflammation by adiponectin(Frontiers Media, 2023-09-01) Lim, Joo-Yeon; Templeton, Steven P.; Microbiology and Immunology, School of MedicineAdiponectin is an insulin sensitizing hormone that also plays a role in the regulation of inflammation. Although adiponectin can exert pro-inflammatory effects, more studies have reported anti-inflammatory effects, even in non-adipose tissues such as the lung. Obesity is considered an inflammatory disease, is a risk factor for lung diseases, and is associated with decreased levels of plasma adiponectin. The results of recent studies have suggested that adiponectin exerts anti-inflammatory activity in chronic obstructive pulmonary disease, asthma and invasive fungal infection. The signaling receptors of adiponectin, AdipoR1 and AdipoR2, are expressed by epithelial cells, endothelial cells, and immune cells in the lung. In this mini-review, we discuss the anti-inflammatory mechanisms of adiponectin in lung cells and tissues.Item Systematic review of marine-derived omega-3 fatty acid supplementation effects on leptin, adiponectin, and the leptin-to-adiponectin ratio(Elsevier, 2021-01-01) Rausch, Jamie; Gillespie, Shannon; Orchard, Tonya; Tan, Alai; School of Nursing, IU Fort WayneIncreasing evidence suggests that adipokines, leptin and adiponectin, produced and secreted by adipocytes, are involved in regulating systemic inflammation and may be important targets for interventions to reduce the chronic systemic inflammation linked to some conditions common in aging (e.g., atherosclerosis). Lower leptin levels and higher adiponectin levels in peripheral circulation have been associated with less systemic inflammation. While some studies have shown that marine-derived omega-3 fatty acids (eicosapentaenoic acid [EPA] and/or docosahexaenoic acid [DHA]) have effects on leptin and adiponectin in the context of inflammation, the extent of their effects remain unclear. The purpose of this systematic review was to summarize findings from randomized, controlled trials that measured effects of EPA+DHA supplementation on circulating levels of leptin and adiponectin to determine the state of the science. PubMed, CINAHL, Web of Science, Scopus, and Cochrane Trials were searched up to June 2018 for studies meeting inclusion criteria. Thirty-one studies included in this review were conducted in 16 countries. Eighteen studies reported lower leptin and/or higher adiponectin levels with EPA+DHA supplementation versus placebo at study end point (9 reported statistically significant differences), but doses, supplementation duration, and population characteristics varied across studies. In 9 studies reporting significantly lower leptin and/or higher adiponectin levels the EPA+DHA dose was 0.52 to 4.2 g/day for 4 to 24 weeks. Additional studies are warranted which assess dose parameters and patient populations similar to studies reporting significant effects of EPA+DHA on leptin or adiponectin in order to evaluate the extent of reproducibility before recommending EPA+DHA as a therapy to target these adipokines.