Lipocalin-2 counteracts metabolic dysregulation in obesity and diabetes.
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ABSTRACT:
SUBMITTER: Mosialou I
PROVIDER: S-EPMC7537391 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Obesity-related asthma is a distinct pediatric asthma phenotype. It is associated with higher disease burden, lower pulmonary function, and suboptimal response to current asthma medications. Recent studies have made inroads into elucidating its pathophysiology. Systemic immune responses in obese children with asthma are skewed to a nonatopic T-helper cell type 1 (Th1) pattern that correlates with pulmonary function deficits. The prevalence of metabolic dysregulation is also higher among obese children with asthma than among normal-weight children with asthma. Insulin resistance and dyslipidemia, particularly low levels of high-density lipoprotein (HDL), are associated with lower airway obstruction and low expiratory reserve volume. These associations are independent of truncal and general adiposity and thereby suggest a direct association between metabolic abnormalities and pulmonary function. Furthermore, insulin resistance is associated with Th1 polarization, whereas low HDL is associated with monocyte activation. Although insulin resistance mediates the association of Th1 polarization with pulmonary function, HDL does not have a similar influence on the association of monocyte activation with pulmonary function. Together, these recent studies have paved the way to the understanding of obesity-related asthma as a distinct asthma phenotype and have begun to identify the complex relationships between metabolic dysregulation, systemic inflammation, and pulmonary function deficits in obese children with asthma. Studies are now needed to elucidate the mechanisms that link metabolic dysregulation and systemic immune responses to pulmonary function.
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Project description:BackgroundChildhood obesity has increased significantly in recent decades.ObjectiveThe objective was to examine the perinatal risk factors related to childhood obesity.DesignIn a prospective study, 89 women with normal glucose tolerance (NGT) or gestational diabetes mellitus (GDM) and their offspring were evaluated at birth and at 8.8 +/- 1.8 y. At birth, obstetrical data, parental anthropometric measures, and neonatal body composition were assessed; at follow-up, diet and activity were assessed and laboratory studies were conducted. Weight was classified by using weight for age and sex, and body composition was measured by using dual-energy X-ray absorptiometry. In childhood, data were analyzed as tertiles and prediction models were developed by using logistic and stepwise regression.ResultsNo significant differences in Centers for Disease Control and Prevention weight percentiles, body composition, and most metabolic measures were observed between children of mothers with NGT and GDM at follow-up. Children in the upper tertile for weight had greater energy intake (P = 0.02), skinfold thickness (P = 0.0001), and leptin concentrations (P < 0.0001) than did those in tertiles 1 and 2. Children in the upper tertile for percentage body fat had greater waist circumference (P = 0.0001), insulin resistance (P = 0.002), and triglyceride (P = 0.009) and leptin (P = 0.0001) concentrations than did children in tertiles 1 and 2. The correlation between body fat at birth and follow-up was r = 0.29 (P = 0.02). The strongest perinatal predictor for a child in the upper tertile for weight was maternal pregravid body mass index (BMI; kg/m(2)) >30 (odds ratio: 3.75; 95% CI: 1.39, 10.10; P = 0.009) and for percentage body fat was maternal pregravid BMI >30 (odds ratio: 5.45; 95% CI: 1.62, 18.41; P = 0.006).ConclusionMaternal pregravid BMI, independent of maternal glucose status or birth weight, was the strongest predictor of childhood obesity.
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Project description:This study is a 6-month randomized controlled trail of diet modification designed to reduce chronic inflammation and reverse metabolic dysfunction among obese individuals with one or more polyps found at a colonoscopy screening. We also will recruit an at least overweight partner, who lives in the same household. To be eligible, participants will be apparently disease-free, obese AAs or EAs who have self-identified a partner who is at least 9 years, with whom they live and who also is at least overweight. Each index participant will: 1) Be AA or EA by self-report; 2) Be ≤55 years old; 3) Have undergone a colonoscopy screening and found to have ≥1 polyp(s); 4) Be free of co-morbid conditions or other factors that would limit participation in this trial; 5) Have a BMI ≥30kg/m2; 6) Be willing to commit to investing the time and effort required to participate in this trial (i.e., willing to complete all assessments and provide biological samples as specified in the consent); and 7) Have no recent antibiotic use. Their partner needs to: 1) Be at least 9 years old; 2) Live in the same household and consumes meals together; 3) Be at least overweight; 4) Agree to all study procedures, including provision of biological samples, body measurements, and self-reported dietary and other assessments; and 5) Have no recent antibiotic use.
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Project description:ContextBreast cancer is increasing in prevalence in parallel with rising rates of obesity worldwide. Obesity is recognized as a leading modifiable risk factor for the development of breast cancer; however, this association varies considerably by clinicopathologic features, and the underlying mechanisms are complex.Evidence acquisitionPubmed literature search using combinations of "obesity," "breast cancer risk," "diet," "exercise," "weight gain," "weight loss," "adipose tissue inflammation," "crown-like structure," "immune markers," "metformin," "gliflozins," "SGLT-2i," "GLP1-RA," and related terms.Evidence synthesisElevated body mass index and weight gain are associated with increased risk of postmenopausal, hormone receptor-positive breast cancer. Emerging evidence suggests that adverse measures of body composition in individuals of any weight can also confer increased breast cancer risk. Mechanistically, various factors including altered adipokine balance, dysfunctional adipose tissue, dysregulated insulin signaling, and chronic inflammation contribute to tumorigenesis. Weight loss and more specifically fat mass loss through lifestyle and pharmacologic interventions improve serum metabolic and inflammatory markers, sex hormone levels, and measures of breast density, suggesting a link to decreased breast cancer risk.ConclusionIncorporating markers of metabolic health and body composition measures with body mass index can capture breast cancer risk more comprehensively. Further studies of interventions targeting body fat levels are needed to curb the growing prevalence of obesity-related cancer.
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Project description:BackgroundMetabolomics, the study of small-molecule metabolites, has increased understanding of human metabolic diseases, but has not been used to study equine metabolic syndrome (EMS).Objectives(1) To examine the serum metabolome of Welsh Ponies with and without insulin dysregulation before and during an oral sugar test (OST). (2) To identify differences in metabolites in ponies with insulin dysregulation, obesity, or history of laminitis.AnimalsTwenty Welsh Ponies (mean ± SD; 13.8 ± 9.0 years) classified as non-insulin dysregulated [CON] (n = 10, insulin < 30 mU/L) or insulin dysregulated [ID] (n = 10, insulin > 60 mU/L) at 75 minutes after administration of Karo syrup, obese (n = 6) or nonobese (n = 14), and history of laminitis (n = 9) or no history of laminitis (n = 11).MethodsCase-control study. Metabolomic analysis was performed on serum obtained at 0 minutes (baseline) and 75 minutes during the OST. Data were analyzed with multivariable mixed linear models with significance set at P ≤ .05.ResultsMetabolomic analysis of 646 metabolites (506 known) detected significant metabolite differences. At baseline, 55 metabolites (insulin response), 91 metabolites (obesity status), and 136 metabolites (laminitis history) were different. At 75 minutes, 51 metabolites (insulin response), 102 metabolites (obesity status), and 124 metabolites (laminitis history) were different.Conclusions and clinical importanceUse of metabolomics could have diagnostic utility for early detection of EMS and provide new knowledge regarding the pathophysiology of metabolic perturbations associated with this condition that might lead to improved clinical management.
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Project description:Thyroid hormone (TH) is a thermogenic activator with anti-obesity potential. However, systemic TH administration has no obvious clinical benefits on weight reduction. Herein we selectively delivered triiodothyronine (T3) to adipose tissues by encapsulating T3 in liposomes modified with an adipose homing peptide (PLT3). Systemic T3 administration failed to promote thermogenesis in brown and white adipose tissues (WAT) due to a feedback suppression of sympathetic innervation. PLT3 therapy effectively obviated this feedback suppression on adrenergic inputs, and potently induced browning and thermogenesis of WAT, leading to alleviation of obesity, glucose intolerance, insulin resistance, and fatty liver in obese mice. Furthermore, PLT3 was much more effective than systemic T3 therapy in reducing hypercholesterolemia and atherosclerosis in apoE-deficient mice. These findings uncover WAT as a viable target mediating the therapeutic benefits of TH and provide a safe and efficient therapeutic strategy for obesity and its complications by delivering TH to adipose tissue.
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Project description:During the past forty years there has been an inexplicable increase in chronic inflammatory disorders, including obesity. One theory, the 'hygiene hypothesis', involves dysregulated immunity arising after too few beneficial early life microbe exposures. Indeed, earlier studies have shown that gut microbe-immune interactions contribute to smoldering inflammation, adiposity, and weight gain. Here we tested a safe and well-established microbe-based immune adjuvant to restore immune homeostasis and counteract inflammation-associated obesity in animal models. We found that consuming Vibrio cholerae exotoxin subunit B (ctB) was sufficient to inhibit age-associated obesogenic outcomes in wild type mice, including reduced crown-like structures (CLS) and granulomatous necrosis histopathology in fat depots. Administration of cholera toxin reduced weight gain irrespective of age during administration; however, exposure during youth imparted greater slenderizing effects when compared with animals receiving ctB for the first time during adulthood. Beneficial effects were transplantable to other obesity-prone animals using immune cells alone, demonstrating an immune-mediated mechanism. Taken together, we concluded that oral vaccination with cholera toxin B helps stimulate health-protective immune responses that counteract age-associated obesity.
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Project description:Obesity-related inflammation-induced insulin resistance and metabolic dysregulation were investigated in retrospective analysis of placebo hematologic and metabolic laboratory data from trials associated with increasing chronic low-grade inflammation and body mass index. Studies included healthy subjects and those with progressive stages of metabolic dysregulation, including type 2 diabetes mellitus with uncontrolled hemoglobin A1c. Intrasubject variances in erythroid and metabolic values increased with metabolic dysregulation. Random effects were demonstrated in treatment-naïve diabetes for erythroid, glucose, and HbA1c fluctuations. The anti-inflammatory insulin sensitizer, HE3286, was tested for its ability to decrease obesity-related inflammation-induced insulin resistance and metabolic dysregulation in diabetes. HE3286 significantly decreased erythroid and metabolic variances and improved 1,5-anhydroglucitol (a surrogate of postprandial glucose) compared to the placebo group. HE3286 HbA1c decrease correlated with weight loss and inversely with baseline monocyte chemoattractant protein-1 (MCP-1) in metformin-treated diabetics. Normalization of HbA1c to the 84-day average hemoglobin revealed that HE3286 HbA1c decrease correlated with high baseline MCP-1 and MCP-1 decrease in treatment-naïve diabetics. HE3286 decreased insulin resistance, increased the frequency of decreased day 84 HbA1c in metformin-treated subjects, and decreased day 112 HbA1c in treatment-naïve diabetics. HE3286 may be useful to restore metabolic homeostasis in type 2 diabetes.
| S-EPMC3572652 | biostudies-literature
Project description:Rationale: Early pathogenesis of lung adenocarcinoma (LUAD) remains largely unknown. We found that, relative to wild-type littermates, the innate immunomodulator Lcn2 (lipocalin-2) was increased in normal airways from mice with knockout of the airway lineage gene Gprc5a (Gprc5a-/-) and that are prone to developing inflammation and LUAD. Yet, the role of LCN2 in lung inflammation and LUAD is poorly understood.Objectives: Delineate the role of Lcn2 induction in LUAD pathogenesis.Methods: Normal airway brushings, uninvolved lung tissues, and tumors from Gprc5a-/- mice before and after tobacco carcinogen exposure were analyzed by RNA sequencing. LCN2 mRNA was analyzed in public and in-house data sets of LUAD, lung squamous cancer (LUSC), chronic obstructive pulmonary disease (COPD), and LUAD/LUSC with COPD. LCN2 protein was immunohistochemically analyzed in a tissue microarray of 510 tumors. Temporal lung tumor development, gene expression programs, and host immune responses were compared between Gprc5a-/- and Gprc5a-/-/Lcn2-/- littermates.Measurements and Main Results: Lcn2 was progressively elevated during LUAD development and positively correlated with proinflammatory cytokines and inflammation gene sets. LCN2 was distinctively elevated in human LUADs, but not in LUSCs, relative to normal lungs and was associated with COPD among smokers and patients with LUAD. Relative to Gprc5a-/- mice, Gprc5a-/-/Lcn2-/- littermates exhibited significantly increased lung tumor development concomitant with reduced T-cell abundance (CD4+) and richness, attenuated antitumor immune gene programs, and increased immune cell expression of protumor inflammatory cytokines.Conclusions: Augmented LCN2 expression is a molecular feature of COPD-associated LUAD and counteracts LUAD development in vivo by maintaining antitumor immunity.
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