Obesity-induced Metabolic Changes Research Articles

Multi-Omics analysis reveals molecular insights into the effects of acute ozone exposure on lung tissues of normal and obese male mice

Certain sub-groups, including men and obese individuals, are more susceptible to ozone (O3) exposure, but the underlying molecular mechanisms remain unclear. In this study, the male mice were divided into two dietary groups: one fed a high-fat diet (HFD), mimicking obesity conditions, and the other fed a normal diet (ND), then exposed to 0.5 ppm and 2 ppm O3 for 4 h per day over two days. The HFD mice exhibited significantly higher body weight and serum lipid biochemical indicators compared to the ND mice. Obese mice also exhibited more severe pulmonary inflammation and oxidative stress. Using a multi-omics approach including proteomics, metabolomics, and lipidomics, we observed that O3 exposure induced significant pulmonary molecular changes in both obese and normal mice, primarily arachidonic acid metabolism and lipid metabolism. Different molecular biomarker responses to acute O3 exposure were also observed between two dietary groups, with immune-related proteins impacted in obese mice and PPAR pathway-related proteins affected in normal mice. Furthermore, although not statistically significant, O3 exposure tended to aggravate HFD-induced disturbances in lung glycerophospholipid metabolism. Overall, this study provides valuable molecular insights into the responses of lung to O3 exposure and highlights the potential impact of O3 on obesity-induced metabolic changes.

338.7: Modeling of obesity-induced metabolic changes by studying the crosstalk between human stem cell-derived pancreatic islets and liver organoids using a pump-less recirculating OoC (rOoC) platform

338.7: Modeling of obesity-induced metabolic changes by studying the crosstalk between human stem cell-derived pancreatic islets and liver organoids using a pump-less recirculating OoC (rOoC) platform

Abstract P010: Molecular mediators of the energy balance-colorectal cancer link: evaluating the gut microbiome and pro-inflammatory biomarkers

Abstract Background: Physical activity and BMI are convincingly associated with colorectal cancer risk, yet the underlying molecular mediators and their interplay in the energy balance-cancer link remain unclear. Possible counteracting effects of physical activity on obesity-induced metabolic changes, including systemic inflammation and changes in the gut microbiome, have yet to be studied. Here, we investigated associations of several combinations of physical activity and BMI with pro-inflammatory biomarkers and the gut microbiome and relationships between these two mediators among patients with colorectal cancer. Methods: N=579 patients with newly diagnosed colorectal cancer (stages I-IV) were included. Physical activity at baseline was assessed using an adapted International Physical Activity Questionnaire (IPAQ) and participants were classified as being ‘active’ or ‘inactive’ based on physical activity guidelines. BMI at baseline was abstracted from medical records and categorized into ‘normal weight’ and ‘overweight/obese’. Pro-inflammatory biomarkers (CRP, SAA, IL-6, IL-8, and TNF-α) were measured in pre-surgery serum samples. In a subset of patients (n=179), 16S rRNA gene sequencing was additionally performed in pre-surgery stool samples. Relative abundances were determined for each taxonomic level and used to calculate diversity metrics. Analyses were adjusted for sex, stage at diagnosis, neoadjuvant treatment, and study site. Results: ‘Obese’ patients had 88% and 17% higher CRP and TNF-α levels compared to ‘normal weight’ patients (p=0.03 and 0.02, respectively). Highest CRP levels were observed among ‘overweight or obese/inactive’ compared to ‘normal weight/active’ patients (p=0.03). Lower gut microbial diversity was observed among ‘inactive’ vs. ‘active’ patients (Shannon index: p=0.01, Simpson: p=0.03), ‘obese’ vs. ‘normal weight’ patients (Shannon index, Simpson, and Observed species: p=0.02, respectively), and ‘overweight or obese/inactive’ vs. ‘normal weight/active’ patients (Shannon index: p=0.02, Observed species: p=0.04). Two phyla and 12 genera (e.g., Actinobacteria and Fusobacteria, and Ruminococcus, Succinivibrio, Succiniclasticum) were differentially abundant across physical activity and BMI groups. High CRP and TNF-α levels were statistically significantly associated with lower alpha diversity metrics (p=0.02-0.05). Conclusions: This is the first evidence indicating that the gut microbiome may be a molecular mediator of the energy balance-colorectal cancer link. We further provide evidence of associations between physical activity and BMI groups with pro-inflammatory biomarkers. While BMI was identified as the key driver of inflammation, biomarker levels were higher among ‘inactive’ patients across BMI groups. Physical activity may offset obesity-induced inflammation and gut microbiome dysbiosis. Our results further provide new insights into the host-microbiome interactions with respect to systemic inflammation. Citation Format: Caroline Himbert, W. Zac Stephens, Biljana Gigic, Tengda Lin, Jennifer Ose, Anjelica Ashworth, Christy Warby, David Nix, Jolanta Jedrzkiewicz, Anita R Peoples, Mary Bronner, Bartley Pickron, Courtney Scaife, Jessica N. Cohan, William M. Grady, Stacey A. Cohen, Mukta Krane, Petra Schrotz-King, Jane C. Figueiredo, Adetunji T. Toriola, Erin M. Siegel, Christopher I. Li, Alexis Ulrich, David Shibata, June L. Round, Lyen C. Huang, Martin Schneider, Sheetal Hardikar, Cornelia M Ulrich. Molecular mediators of the energy balance-colorectal cancer link: evaluating the gut microbiome and pro-inflammatory biomarkers. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P010.

Abstract 14007: Sodium-Dependent Glucose Transporters 2 Inhibition Ameliorates Obesity-Induced Metabolic Changes and Cardiomyopathy

Introduction: Inhibition of renal sodium-glucose cotransporter-2 (SGLT2) reduces urinary glucose reabsorption to decrease glycemia. Recent large-scale trials have shown that SGLT2 inhibitors provide cardio protection beyond lowering glucose. Hypothesis: Treating SGLT2 inhibitor (SGLT2i) reduces the cardiovascular risk in type 2 diabetes that indicates the potential correlation of SGLT2i in cardiomyopathy mediating metabolic effects. Methods: Male 8 weeks old C57/BL6 mice were fed high fat diet (> 60% of fat) for 4 months, and treated SGLT2i, canagliflozin (CANA) in the third and the fourth month. Measured its blood glucose, body weight and echocardiology every month. Moreover, analyzed the lipid contents in its plasma, the adipose tissue, liver and heart, and also examine the cardiomyopathy markers and its potential signaling pathways. Furthermore, palmitate acid (PA) was treated to H9c2 cells to mimic a high lipid environment, and validate its potential signaling pathways. Results: Treatments of high fat diet-induced obese mice with the CANA reduced blood glucose, body weight and adiposity. Moreover, CANA reversed the obesity-induced cardiomyopathy including heart weight ratio, echocardiology and cardiomyopathy markers ( Col1 , Col4 , Icam1 and Myh7 ). Furthermore, CANA increased AKT phosphorylation which is the one of the key pathways, and reduces apoptosis in cardiomyopathy. To investigate the potential mechanisms of metabolic changes in cardiomyopathy by CANA, we searched the hepatic RNA expression from high fat diet induced obesity mice by GEO profiles online. FGF21, a hepatokine increased in CANA action by hepatic and adipose tissue lipolysis, next circulated to the heart, and induced AKT phosphorylation to reduce apoptosis. CANA increased plasma and hepatic FGF21 in obese mice. Further treating recombinant FGF21 in H9c2 differentiated cardiomyocyte like cells with palmitic acid, FGF21 reduced cardiomyocyte apoptosis via AKT phosphorylation. Conclusions: These data demonstrated that SGLT2 inhibition ameliorates metabolic changes and apoptosis via FGF21-AKT pathway in cardiomyopathy.

Intermittent Fasting Attenuates High-Fat Diet-Induced Cerebellar Changes in Rats: Involvement of TNF-α, Autophagy, and Oxidative Stress

Obesity has become a prevalent global health issue, and recently it has been reported to be intimately associated with neuronal health. Obesity triggers peripheral inflammatory responses concomitant with neuroinflammation, elevated oxidative stress, and compromised autophagy. Intermittent fasting (IF) positively influences lowering body weight and improving the metabolic changes accompanying obesity. IF also has a beneficial impact on neuronal function; however, no studies have discussed this effect on high-fat diet (HFD)-induced cerebellar damage. This study examines the effect of IF on the cerebellum of HFD-fed rats. Male Wister Albino rats (n = 16) were fed HFD for 16 weeks (HFD group); half of them were subjected to IF alternating with HFD for 6 weeks starting at the 11th week till the end of the experiment (fasting + HFD group). The control group of rats (n = 8) was kept on a basal diet. The animals were euthanized after 16 weeks. Their tissue was harvested and processed for morphology using H&E, cresyl violet, and luxol fast stains, and immunohistochemical staining was carried out for inflammatory marker (TNF-α), gliosis marker (GFAP), and autophagy markers (LC3 II and P62). Oxidative stress markers (SOD, MDA) were measured, and protein expression of phosphorylated-AMP-activated protein kinase (p-AMPK) and phosphorylated-rapamycin complex (p-mTOR) in cerebellar tissue was detected via western blotting. IF mitigated HFD-induced cerebellar morphological changes, reduced cerebellar TNF-α expression, decreased oxidative stress markers, and balanced p-AMPK and p-mTOR with autophagy improvement. Moreover, a decrease in body weight and ameliorated obesity-induced metabolic changes in the serum levels of glucose, insulin, cholesterol, and triglyceride were seen. These observations suggest that IF can improve both peripheral and central changes prompted by HFD through attenuating inflammation, oxidative stress, and reestablishing the autophagy balance.

Transgenic mice expressing human IL-32 develop adipokine profiles resembling those of obesity-induced metabolic changes

Low-grade inflammation is associated with the development of insulin resistance in obese individuals. The present study aims to provide additional evidence strengthening the role of interleukin (IL)-32 in this key process. Using an IL-32 transgenic (IL-32tg) mouse model, we observed that IL-32tg fed a normal diet had greater body weight, due to greater accumulation of white adipose tissue (WAT) along with larger sized adipocytes. This led to metabolic consequences, with significant higher leptin levels and a trend towards hyperinsulinemia, indicating a phenotype resembling the metabolic syndrome. Adipocytes of IL-32tg mice were more prone to induce a pro-inflammatory response locally, which would be expected when predisposed to insulin resistance and type2 diabetes mellitus (T2D). In conclusion, our study provides novel evidence of a direct contribution of IL-32 to pathophysiological perturbations within the adipose tissue, possibly contributing to the metabolic syndrome that precedes frank insulin resistance and T2D. Future research should focus on the role of IL-32 in the obesity epidemic.

Obesity and cancer: A mechanistic overview of metabolic changes in obesity that impact genetic instability.

Obesity, defined as a state of positive energy balance with a body mass index exceeding 30 kg/m2 in adults and 95th percentile in children, is an increasing global concern. Approximately one-third of the world's population is overweight or obese, and in the United States alone, obesity affects one in six children. Meta-analysis studies suggest that obesity increases the likelihood of developing several types of cancer, and with poorer outcomes, especially in children. The contribution of obesity to cancer risk requires a better understanding of the association between obesity-induced metabolic changes and its impact on genomic instability, which is a major driving force of tumorigenesis. In this review, we discuss how molecular changes during adipose tissue dysregulation can result in oxidative stress and subsequent DNA damage. This represents one of the many critical steps connecting obesity and cancer since oxidative DNA lesions can result in cancer-associated genetic instability. In addition, the by-products of the oxidative degradation of lipids (e.g., malondialdehyde, 4-hydroxynonenal, and acrolein), and gut microbiota-mediated secondary bile acid metabolites (e.g., deoxycholic acid and lithocholic acid), can function as genotoxic agents and tumor promoters. We also discuss how obesity can impact DNA repair efficiency, potentially contributing to cancer initiation and progression. Finally, we outline obesity-related epigenetic changes and identify the gaps in knowledge to be addressed for the development of better therapeutic strategies for the prevention and treatment of obesity-related cancers.

Brain Innate Immune Response in Diet-Induced Obesity as a Paradigm for Metabolic Influence on Inflammatory Signaling.

Obesity is a predisposing factor for numerous morbidities, including those affecting the central nervous system. Hypothalamic inflammation is a hallmark of obesity and is believed to participate in the onset and progression of the obese phenotype, by promoting changes in neuronal functions involved in the control of metabolism. The activation of brain immune cells in the hypothalamus, which are represented by microglia and brain macrophages, is associated with obesity and has been the focus of intense research. Despite the significant body of knowledge gathered on this topic, obesity-induced metabolic changes in brain cells involved in innate immune responses are still poorly characterized due, at least in part, to limitations in the existing experimental methods. Since the metabolic state influences immune responses of microglia and other myeloid cells, the understanding and characterization of the effects of cellular metabolism on the functions of these cells, and their impact on brain integrity, are crucial for the development of efficient therapeutic interventions for individuals exposed to a long-term high fat diet (HFD). Here we review and speculate on the cellular basis that may underlie the observed changes in the reactivity and metabolism of the innate immune cells of the brain in diet-induced obesity (DIO), and discuss important points that deserve further investigation.

Effect of simvastatin on IL-6 and adiponectin secretion and mRNA expression in 3T3-L1 adipocytes

In order to investigate the effects of simvastatin on secretion and mRNA expression of interleukin-6 (IL-6) and adiponectin in 3T3-L1 adipocytes, mouse 3T3-L1 adipocytes were stimulated with lipopolysaccharide (LPS). Production and mRNA expression of IL-6 and adiponectin in 3T3-L1 adipocytes were measured using enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (RT-PCR), respectively. The results showed that simvastatin could significantly suppress LPS-induced IL-6 production and mRNA expression in adipocytes (P<0.05), but increase the LPS-induced adiponectin secretion and mRNA expression in a dose-dependent manner (P<0.05). It was suggested that simvastatin could exert beneficial effects on prevention of obesity-induced metabolic changes in adipocytes.

260. Effects of diet-induced obesity on ovarian function and female fertility

Obesity and its related complications (metabolic syndrome, Type II diabetes and polycystic ovary syndrome) are increasingly associated with female infertility. Our research is focused on understanding how diet-induced obesity, which triggers insulin resistance and symptoms of chronic inflammation, directly impacts ovarian function and female fertility. Female mice were maintained on a “Western style” diet (22% fat, 0.15% cholesterol) or a matched control diet. Body weights were monitored weekly and after 16 weeks fasting insulin levels and glucose tolerance were assessed. Mice were then paired with males and tissues collected on day 1 on pregnancy. Blood samples were taken to determine levels of progesterone, metabolites (glucose, HDL/LDL) and inflammatory cytokines. Tissue weights (fat pads, liver, kidney, spleen, pancreas, ovary and uterus) were recorded and the reproductive tissues were fixed for analysis of histology and gene expression. Zygotes were isolated from the oviduct, cultured in vitro and scored for on-time development and differentially stained to assess blastocyst quality. Indices of ovarian function, including ovulation rate, steroid production and oocyte quality/blastocyst development will then be correlated with degrees of insulin resistance, dyslipidemia and inflammation. Five strains of mice were tested (CBA, Balb/c, C57, SV129 and Swiss) and showed significant differences in susceptibility to diet-induced obesity and insulin resistance. In CBA mice, the first group to be completed, the high fat diet significantly increased body weight, but did not result in overtly impaired glucose tolerance. The number of days to mating was slightly extended compared to mice on the control diet. Interestingly, the high fat diet did not affect ovulation rate but resulted in dramatically impaired blastocyst development. The results of this study will reveal how ovarian folliculogenesis, oocyte competence and ovulation are affected by obesity-induced metabolic changes, which are increasingly affecting women of reproductive age.

Troglitazone corrects metabolic changes but not vascular dysfunction in dietary-obese rats

Insulin resistance has been attributed to the defect in vascular function associated with obesity, type 2 diabetes and dyslipidaemia. We have investigated vascular effects of chronic (3-week) administration of troglitazone on female Wistar rats with moderate dietary obesity. Compared with lean controls, untreated obese rats had significantly higher body weights, fat pad masses, plasma triglycerides, free fatty acids and leptin levels (for all P<0.01). These metabolic changes were corrected by troglitazone treatment. In mesenteric arteries, responses to noradrenaline or KCl were similar in all groups. However, in noradrenaline-preconstricted arteries, vasorelaxations to acetylcholine and insulin were significantly (50–60% less than in lean, P<0.001) attenuated in both untreated and troglitazone-treated obese rats. Relaxations to sodium nitroprusside showed similar but lesser impairment in both untreated and troglitazone-treated obese animals. Our data show that although troglitazone markedly improved obesity-induced metabolic changes, it failed to correct vascular dysfunction associated with obesity in female Wistar rats.