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Characterization of metabolic alterations in the lean metabolically unhealthy alpha defensin transgenic mice.

ABSTRACT: Inflammation is consistently linked to dysmetabolism. In transgenic mice (Def^+/+) model the neutrophilic peptide, alpha defensin, proved atherogenic. This phenotype occurred despite favorable cholesterol and glucose levels, and lower body weight and blood pressure. In this study, integration of metabolic&behavioral phenotyping system, endocrine, biochemical and mitochondrial assessment, pathological and immunohistochemical tests, and multiple challenge tests was established to explore the metabolic impact of alpha defensin. Compared to the control group, Def^+/+ mice exhibited lower total energy expenditure and carbohydrate utilization, and higher fat oxidation. Their ACTH-cortisol and thyroid profiles were intact. Intriguingly, they had low levels of glucagon, with high ammonia, uric acid, triglyceride, and lactate. Mitochondrial evaluations were normal. Overall, defensin-induced hypoglucagonemia is associated with lipolysis, restricted glucose oxidation, and enhanced wasting. Def^+/+ mice may be a useful model for studying the category of lean, apparently metabolically healthy, and atherosclerotic phenotype, with insight into a potential inflammatory-metabolic link.

SUBMITTER: Higazi AA

PROVIDER: S-EPMC10839648 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Characterization of metabolic alterations in the lean metabolically unhealthy alpha defensin transgenic mice.

Higazi Abd Al-Roof AA Maraga Emad E Baraghithy Saja S Udi Shiran S Azar Shahar S Saada Ann A Glaser Benjamin B Avrahami Dana D Abdeen Suhair S Hamdan Zenab Z Tam Joseph J Fanne Rami Abu RA

iScience 20240112 2

Inflammation is consistently linked to dysmetabolism. In transgenic mice (Def<sup>+/+</sup>) model the neutrophilic peptide, alpha defensin, proved atherogenic. This phenotype occurred despite favorable cholesterol and glucose levels, and lower body weight and blood pressure. In this study, integration of metabolic&behavioral phenotyping system, endocrine, biochemical and mitochondrial assessment, pathological and immunohistochemical tests, and multiple challenge tests was established to explore ...[more]

PMID: 38318380

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Project description:BackgroundMetabolically healthy obesity (MHO) and its transition to unhealthy metabolic status have been associated with risk of cardiovascular disease (CVD) in Western populations. However, it is unclear to what extent metabolic health changes over time and whether such transition affects risks of subtypes of CVD in Chinese adults. We aimed to examine the association of metabolic health status and its transition with risks of subtypes of vascular disease across body mass index (BMI) categories.Methods and findingsThe China Kadoorie Biobank was conducted during 25 June 2004 to 15 July 2008 in 5 urban (Harbin, Qingdao, Suzhou, Liuzhou, and Haikou) and 5 rural (Henan, Gansu, Sichuan, Zhejiang, and Hunan) regions across China. BMI and metabolic health information were collected. We classified participants into BMI categories: normal weight (BMI 18.5-23.9 kg/m²), overweight (BMI 24.0-27.9 kg/m²), and obese (BMI ≥ 28 kg/m²). Metabolic health was defined as meeting less than 2 of the following 4 criteria (elevated waist circumference, hypertension, elevated plasma glucose level, and dyslipidemia). The changes in obesity and metabolic health status were defined from baseline to the second resurvey with combination of overweight and obesity. Among the 458,246 participants with complete information and no history of CVD and cancer, the mean age at baseline was 50.9 (SD 10.4) years, and 40.8% were men, and 29.0% were current smokers. During a median 10.0 years of follow-up, 52,251 major vascular events (MVEs), including 7,326 major coronary events (MCEs), 37,992 ischemic heart disease (IHD), and 42,951 strokes were recorded. Compared with metabolically healthy normal weight (MHN), baseline MHO was associated with higher hazard ratios (HRs) for all types of CVD; however, almost 40% of those participants transitioned to metabolically unhealthy status. Stable metabolically unhealthy overweight or obesity (MUOO) (HR 2.22, 95% confidence interval [CI] 2.00-2.47, p < 0.001) and transition from metabolically healthy to unhealthy status (HR 1.53, 1.34-1.75, p < 0.001) were associated with higher risk for MVE, compared with stable healthy normal weight. Similar patterns were observed for MCE, IHD, and stroke. Limitations of the analysis included lack of measurement of lipid components, fasting plasma glucose, and visceral fat, and there might be possible misclassification.ConclusionsAmong Chinese adults, MHO individuals have increased risks of MVE. Obesity remains a risk factor for CVD independent of major metabolic factors. Our data further suggest that metabolic health is a transient state for a large proportion of Chinese adults, with the highest vascular risk among those remained MUOO.

Project description:ObjectivesTo analyze sex differences in the prevalence of obesity phenotypes and their risk factors among children and adolescents aged 7-18 years in China.MethodsWe enrolled 15,114 children and adolescents aged 7-18 years into the final analysis. Obesity phenotypes were classified by body mass index (BMI) and metabolic status as metabolically healthy or unhealthy obesity. In addition, we collected four possible influencing factors on obesity phenotypes through questionnaires, including demographic, parental, early life, and lifestyle indicators. Multinomial logistic regression analysis in a generalized linear mixed model (GLMM) was selected to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for identifying risk factors and control the cluster effects of schools. More importantly, the interaction terms of sex and each indicator were established to demonstrate the sex differences.ResultsThe prevalence of metabolically healthy obesity (MHO), metabolically unhealthy obesity (MUO), metabolically healthy overweight and obesity (MHOO), and metabolically unhealthy overweight and obesity (MUOO) were 3.5%, 5.6%, 11.1%, and 13.0% respectively, with higher prevalence in boys (5.3% vs. 1.6%, 7.9% vs. 3.1%, 14.3% vs. 7.7%, 15.6% vs. 10.1%). In addition, younger ages, single children, parental smoking, parental history of diseases (overweight, hypertension, diabetes), caesarean, premature, and delayed delivery time, high birth weight, insufficient sleep time, and excessive screen time were considered as important risk factors of MHO and MUO among children and adolescents (p < 0.05). More notably, boys were at higher risks of MUO when they were single children (boys: OR = 1.56, 95% CI: 1.24-1.96; girls: OR = 1.12, 95% CI: 0.82-1.54), while girls were more sensitive to MUO with parental smoking (girls: OR = 1.34, 95% CI: 1.02-1.76; boys: OR = 1.16, 95% CI: 0.97-1.39), premature delivery (girls: OR = 3.11, 95% CI: 1.59-6.07; boys: OR = 1.22, 95% CI: 0.67-2.22), high birth weight (girls: OR = 2.45, 95% CI: 1.63-3.69; boys: OR = 1.28, 95% CI: 0.96-1.70), and excessive screen time (girls: OR = 1.47, 95% CI: 1.06-2.04; boys: OR = 0.97, 95% CI: 0.79-1.20), with significant interaction term for sex difference (pinteraction < 0.05).ConclusionsMHO and MUO are becoming prevalent among Chinese children and adolescents. Significant sex differences in the prevalence of obesity phenotypes as well as their environmental and genetic risk factors suggest it might be necessary to manage obesity phenotypes problems from a sex perspective.

Project description:Obesity and obesity-related low-grade inflammation are common findings in polycystic ovary syndrome (PCOS), the most common endocrine-metabolic disorder-affecting women in reproductive age. The terms metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO) have been introduced to define individuals with obesity in whom cardio-metabolic risk factors are absent or present, respectively. To date, evidence investigating differences in body composition and adherence to the Mediterranean diet (MD) between MHO and MUO-PCOS women are lacking. Aim of this study was to better characterize the determinants of the metabolic health status in PCOS patients with obesity according to MHO and MUO phenotypes by evaluating endocrine-metabolic profile, inflammatory status, adherence to the MD, and body composition. The study population consisted of 94 treatment-naïve women with PCOS and obesity (BMI = 38.23 ± 6.62 kg/m2 and age = 24.12 ± 3.68 years). Compared PCOS MHO with PCOS MUO patients, the latter had higher levels of high-sensitivity C-reactive protein (hs-CRP) (p < 0.001), testosterone (p < 0.001), and insulin (p < 0.001), worse metabolic parameters, and higher Homeostatic Model Assessment of Insulin Resistance (HoMA-IR), Visceral Adiposity Index (VAI), and Fatty liver Index (FLI) (p < 0.001). Furthermore, PCOS MUO patients had lower adherence to the MD (p < 0.001) in spite of the same total energy intake (p = 0.102) as compared to PCOS MHO. The presence of MUO was associated with highest hs-CRP levels (OR = 1.49, p < 0.001), more severe hyperandrogenism and cardio-metabolic indices (p < 0.001). On the contrary, being PCOS MUO was associated with lower adherence to the MD (OR = 0.28, p < 0.001), and smaller PhAs (OR = 0.04, p < 0.001). Using a regression linear analysis model PREDIMED score entered at the first step (p < 0.001), followed by VAI (p < 0.001), and FLI (p = 0.032) in this analysis. At ROC analysis, a PREDIMED score of ≤4 (p < 0.001, AUC 0.926) could serve as a threshold for a significantly increased risk of presence the MUO-PCOS phenotype. To the best of our knowledge, this is the first study that characterized MHO and MUO-PCOS women on the basis of their adherence to the MD, body composition, and cardio-metabolic indices, providing evidence of the usefulness of adjunctive diagnostic parameters to better differentiate the MHO/MHO phenotypes in this cohort of PCOS patients with obesity.

Dataset Information

Characterization of metabolic alterations in the lean metabolically unhealthy alpha defensin transgenic mice.

Publications

Characterization of metabolic alterations in the lean metabolically unhealthy alpha defensin transgenic mice.

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