Metabolic Decline Research Articles

Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab.

We aimed to analyse TrialNet Anti-CD3 Prevention (TN10) data using oral minimal model (OMM)-derived indices to characterise the natural history of stage 2 type 1 diabetes in placebo-treated individuals, to describe early metabolic responses to teplizumab and to explore the predictive capacity of OMM measures for disease-free survival rate. OMM-estimated insulin secretion, sensitivity and clearance and the disposition index were evaluated at baseline and at 3, 6 and 12 months post randomisation in placebo- and teplizumab-treated groups, and, within each group, in slow- and rapid-progressors (time to stage 3 disease >2 or 2 years). OMM metrics were also compared with the standard AUC C-peptide. Percentage changes in CD8+ T memory cell and programmed death-1 (PD-1) expression were evaluated in each group. Baseline metabolic characteristics were similar between 28 placebo- and 39 teplizumab-treated participants. Over 12 months, insulin secretion declined in placebo-treated and rose in teplizumab-treated participants. Within groups, placebo slow-progressors (n=14) maintained insulin secretion and sensitivity, while both declined in placebo rapid-progressors (n=14). Teplizumab slow-progressors (n=28) maintained elevated insulin secretion, while teplizumab rapid-progressors (n=11) experienced mild metabolic decline. Compared with rapid-progressor groups, insulin clearancesignificantlydecreased between baseline and 3, 6 and 12 months in the slow-progressor groups in both treatment arms. In aggregate, both higher baseline insulin secretion (p=0.027) and reduced 12 month insulin clearance (p=0.045) predicted slower progression. A >25% loss of insulin secretion at 3 months had specificity of 0.95 (95% CI 0.86, 1.00) to identify rapid-progressors and correctly classified the 2 year risk for progression in 92% of participants, with a sensitivity of 0.19 (95% CI 0.08, 0.30). OMM-estimated insulin secretion outperformed AUC C-peptide to differentiate groups by treatment or to predict progression. Metabolic changes were paralleled by relative frequency of change in PD-1+ CD8+ T effector memory cells. OMM measures characterise the metabolic heterogeneity in stage 2 diabetes, identifying differences between rapid- and slow-progressors, and heterogeneous impacts of immunotherapy, suggesting the need to account for these differences when designing and interpreting clinical trials.

Abstract 4139188: Myocardial perfusion, oxidative metabolism and fibrosis in heart failure with preserved ejection fraction

Background: Cardiac remodeling among individuals with heart failure with preserved ejection fraction (HFpEF) and its risk factors is incompletely understood. Non-invasive cardiac imaging can reliably assess myocardial oxidative metabolism, perfusion, fibrosis, systolic and diastolic function. Nevertheless, the interrelationships between these, particularly with oxidative metabolism, remain unresolved from health to HFpEF as most human studies lack complementary multi-modality imaging. Methods: We performed a cross-sectional study using multi-modality cardiovascular imaging in healthy individuals (n=17), those with hypertension (n=15), and patients with HFpEF (n=8). We quantified myocardial oxidative metabolism (K mono ) with 11 C-acetate positron emission tomography (PET), coronary flow reserve (CFR) with 13 N-ammonia PET, fibrosis (extracellular volume [ECV], LVEF and mass with magnetic resonance imaging (MRI), and LV diastolic filling pressure (E/e’) by echocardiography. The associations between myocardial oxidative metabolism, perfusion, and fibrosis across clinical status (health, hypertension, and HFpEF) were examined in multivariable models. Results: From health to HFpEF, we found significant graded declines in oxidative metabolism indexed to workload (K mono /RPP) (β = -1.66 x 10 -6 [95%CI: -3.12 x 10 -6 to -2.10 x 10 -6 ]; p = 0.027) and CFR (β = -0.76 [95% CI: -1.36 to -0.16]; p = 0.021), along with increased fibrosis (ECV) (β = 2.12% [95% CI: 0.10 to 4.14%]; p = 0.041), independent of LVEF, LV mass, E/e’, age, sex, and body mass index. The decline in oxidative metabolism from health to HFpEF was also independent of ECV and CFR (β = -2.98 x 10 -6 [95% CI: -5.62 x 10 -6 to -3.41 x 10 -6 ], p = 0.015). In contrast, the decline in CFR from health to HFpEF was no longer significant (p = 0.30) with further adjustment for ECV. Conclusions: HFpEF and its development involves progressive declines in myocardial oxidative metabolism and perfusion reserve with increase in fibrosis. The decline in myocardial oxidative metabolism from health to HFpEF is independent of fibrosis and perfusion reserve, suggesting oxidative metabolism may be a target for the prevention and treatment of HFpEF.

Regional differences in glucose metabolic decline and tau deposition in the Alzheimer's continuum brain.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and tau proteins, leading to neurofibrillary tangles. A biomarker-based diagnostic method called the ATN system categorizes AD pathology into amyloid-β (A), tau (T), and neurodegeneration (N). The relationship between regional tau deposition and reduced glucose metabolism in the preclinical AD stage is not well understood. We presented voxel-by-voxel metabolic/tau deposition ratio (MTR) images to investigate the effects of tau deposition on metabolism in AD brains on a stage-by-stage basis. We selected 174 subjects who underwent 3D-MRI, FDG-PET, amyloid PET, and tau PET scans. MTR images were created by normalizing FDG-PET toMK6240 PET images. Voxel-wise comparisons among 63 cognitively normal amyloid-negative (CNA) subjects, 49 subjects with AD dementia (ADD), 23 subjects with mild cognitive impairment due to AD (MCA), and 39 preclinical AD (PRC) subjects were conducted. There was reduced glucose metabolism in ADD and MCA groups compared to CNA, predominantly in parietotemporal areas. Tau deposition was observed in wider areas in ADD and restricted to the medial temporal lobes in MCA. MTR exhibited significant reductions in broader regions in ADD and MCA, indicating simultaneous glucose metabolism decrease and tau deposition. At the MCA and PRC stages, glucose metabolism impairment and tau deposition were shown in separate regions by FDG PET and tau PET, respectively, while MTR images showed impairment in both regions. Our findings suggest that MTR imaging provides insights into AD pathophysiology by simultaneously assessing glucose metabolism and tau deposition. In the early stage of the AD continuum (MCA and PRC), metabolic decline and tau deposition occur independently in different brain regions.

Xanthohumol Protects Against Neuronal Excitotoxicity and Mitochondrial Dysfunction in APP/PS1 Mice: An Omics-Based Study.

Background: Neuronal excitotoxicity and metabolic decline, which begin in the early stages of Alzheimer's disease (AD), pose challenges for effective amelioration. Our previous work suggested that the natural compound xanthohumol, the most abundant prenylated flavonoid in hops, prevents memory deficits in APP/PS1 mice; however, the underlying mechanisms remain unclear. Methods: This study utilized APP/PS1 mice and cutting-edge omics techniques to investigate the effects of xanthohumol on hippocampal proteome, serum metabolome, and microbiome. Results: Our findings revealed that xanthohumol reduces the postsynaptic overexpression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, N-methyl-D-aspartate, and metabotropic glutamate receptors, but enhances ATP synthesis and mitophagy in the young AD hippocampus. Further mechanistic analyses suggested systemic regulatory effects, particularly on the decreasing glutamate synthesis in the blood and intestines of AD mice following xanthohumol administration. Conclusions: These results underscore the potential of xanthohumol in mitigating AD pathology through multifaceted mechanisms, sparking interest and curiosity in its preventive and therapeutic potential in AD.

Mirtazapine: A One-Drug Intervention for the Physical and Psychological Symptoms of End-Stage Renal Disease (ESRD).

Patients with end-stage renal disease (ESRD), especially those on dialysis, experience myriad medical and psychological symptoms that impact theirquality of life. These symptoms range from nausea, emesis, and insomnia to pruritus, anxiety, depression, and loss of appetite. These symptoms often require multiple medications (e.g., anticholinergics, antihistamines, tricyclics, benzodiazepines, and Z-drugs), which can lead to polypharmacy, medication non-adherence, and potentially harmful drug-drug interactions, especially in older ESRD patients, a population with an age-related decline in drug metabolism, multimorbidity, and polypharmacy. The current perspective article will discuss evidence from extant literature supporting mirtazapine (a noradrenergic antagonist and selective serotonin antagonist, NASSA) as a potentially useful one-stop pharmacologic agent to alleviate multiple symptoms that ESRD patients face. A one-stop strategy has the potential to decrease polypharmacy, reduce adverse drug-drug and drug-disease interactions, reduce healthcare costs, and improve the quality of life in ESRD patients. Mirtazapine use in an ESRD setting merits a large randomized pragmatic double-blinded controlled trial to evaluate its efficacy as a potential pharmacotherapeutic agent for the management of multiple disabling gastrointestinal and other neuropsychological symptoms in older adults living with ESRD.

Downregulation of glucose-energy metabolism via AMPK signaling pathway in granulosa cells of diminished ovarian reserve patients

Glucose metabolism plays a crucial role in the function of granulosa cells (GCs) and the development of follicles. In cases of diminished ovarian reserve (DOR), alterations in these processes can impact female fertility. This study aims to investigate changes in glucose-energy metabolism in GCs of young DOR patients aged 20 to 35 years and their correlation with the onset and progression of DOR. 72 DOR cases and 75 women with normal ovarian reserve (NOR) as controls were included based on the POSEIDON and Bologna criteria. Samples of GCs and follicular fluid (FF) were collected for a comprehensive analysis involving transcriptomics, metabolomics, RT-qPCR, JC-1 staining, and flow cytometry. The study identified differentially expressed genes and metabolites in GCs of DOR and NOR groups, revealing 7 common pathways related to glucose-energy metabolism, along with 11 downregulated genes and 14 metabolites. Key substances in the glucose-energy metabolism pathway, such as succinate, lactate, NADP, ATP, and ADP, showed decreased levels, with the DOR group exhibiting a reduced ADP/ATP ratio. Downregulation of genes involved in glycolysis (HK, PGK, LDH1), the TCA cycle (CS), and gluconeogenesis (PCK) was observed, along with reduced glucose content and expression of glucose transporter genes (GLUT1 and GLUT3) in DOR GCs. Additionally, decreased AMPK pathway activity and impaired mitochondrial function in DOR suggest a connection between mitochondrial dysfunction and disrupted energy metabolism. Above all, the decline in glucose-energy metabolism in DOR is closely associated with its onset and progression. Reduced glucose uptake and impaired mitochondrial function in DOR GCs lead to internal energy imbalances, hindering the AMPK signaling pathway, limiting energy production and supply, and ultimately impacting follicle development and maturation.

Long-Term Administration of Nicotinamide Mononucleotide Mitigates High-Fat-Diet-Induced Physiological Decline in Aging Mice

BackgroundNicotinamide adenine dinucleotide (NAD+) levels decline with age, and boosting it can improve multi-organ functions and lifespan. ObjectivesNicotinamide mononucleotide (NMN) is a natural NAD+ precursor with the ability to enhance NAD+ biosynthesis. Numerous studies have shown that a high-fat diet (HFD) can accelerate the process of aging and many diseases. We hypothesized that long-term administration of NMN could exert protective effects on adipose, muscle, and kidney tissues in mice on an HFD act by affecting the autophagic pathway. MethodsMice at 14 mo of age were fed an HFD, and NMN was added to their drinking water at a dose of 400 mg/kg for 7 mo. The locomotor ability of the mice was assessed by behavioral experiments such as grip test, wire hang test, rotarod, and beam-walking test. At the end of the behavioral experiments, the pathological changes of each peripheral organ and the expression of autophagy-related proteins, as well as the markers of the senescence and inflammaging were analyzed by pathological staining, immunohistochemical staining, and western blotting, respectively. ResultsWe found that NMN supplementation increased NAD+ levels and ultimately attenuated age- and diet-related physiological decline in mice. NMN inhibited HFD-induced obesity, promoted physical activity, improved glucose and lipid metabolism, improved skeletal muscle function and renal damage, as well as mitigated the senescence and inflammaging as demonstrated by p16, interleukin 1β, and tumor necrosis factor α levels. In addition, the present study further emphasizes the potential mechanisms underlying the bidirectional relationship between NAD+ and autophagy. We detected changes in autophagy levels in various tissue organs, and NMN may play a protective role by inhibiting excessive autophagy induced by HFD. ConclusionsOur findings demonstrated that NMN administration attenuated HFD-induced metabolic disorders and physiological decline in aging mice.

Danggui Shaoyao San Alleviates Early Cognitive Impairment in Alzheimer's Disease Mice Through IRS1/GSK3β/Wnt3a-β-Catenin Pathway.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by Amyloid plaques and neurofibrillary tangles. We explored the potential mechanism by which Danggui Shaoyao San (DSS) modulates central glucose metabolism via the insulin receptor substrate 1 (IRS1)/glycogen synthase kinase-3β (GSK3β)/Wnt3a-β-catenin pathway, thereby exerting protective effects on cognitive functions. In vitro, HT22 cells were induced with streptozotocin (STZ) to investigate the impact of GSK3β on pathway transduction. The active components in the DSS stock solution were validated using mass spectrometry. Subsequently, an AD model in C57BL/6J mice was established through STZ injection into both ventricles. The success of the model was validated behaviorally and pathologically. The Morris Water Maze (MWM) test, immunohistochemistry, Western blotting, quantitative reverse transcription-PCR, and 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) were employed to evaluate the influence of DSS on memory and pathological changes in AD. The DSS stock solution, rich in active components, ameliorated the memory deficits in AD mice in the MWM. In vitro, GSK3β exhibited regulatory control over Wnt and β-catenin, with GSK3β inhibition mitigating β-amyloid and tau redundancies at protein and gene levels, facilitating signal transduction. In vivo, DSS impacted key targets in the IRS1/GSK3β/Wnt3a-β-catenin pathway, mitigated senile plaques resulting from amyloid β (Aβ) deposition and neurofiber tangles induced by tau hyperphosphorylation, and alleviated the decline in central glucose metabolism observed in FDG-PET. Our findings suggest that DSS potentially confers cognitive protection by alleviating central hypoglycemia through the IRS1/GSK3β/Wnt3a-β-catenin pathway. This may serve as a promising therapeutic avenue for AD.

Comparative analysis of reproductive hormones, serum biochemical indexes and ovarian metabolites in Muscovy breeder duck at different laying stages

The hypothalamic-pituitary-gonadal (HPG) axis regulates egg laying through control hormones secretion in poultry. In this study, the serum hormones (12 samples per stage), serum biochemical indexes (12 samples per stage), and ovarian metabolites (8 samples per stage) of Muscovy breeder ducks were detected at prelaying stage (PT), start of laying stage (ST), high laying stage (HT), and the end of laying stage (ET). The serum hormones of Muscovy ducks were measured at 8:00, 13:00, 18:00, 23:00, and 4:00 within 1 d. The TG, TP, ALB, and GLB were significantly increased, while HDL-C was significantly decreased at ST as compared to PT (P < 0.05). Serum Na, Cl, Ca, P, and K showed significant rise at ST as compared to PT. Serum Na, Cl, Ca, and K were significantly declined, while P was significantly increased at ET as compared to HT (P < 0.05). Serum FSH, LH, PRL, E2, P4 levels peaked at ST (P < 0.05) with only FSH and LH fluctuated significantly within 1 ovulation cycle at ST (P < 0.05). Differential metabolites showed continued ovarian aging. The decline of nucleic acid metabolism occured in ST, the decline of sugar metabolism occurred in ET, and the decline of amino acid metabolism continued at all stages. Temporal expression patterns and correlation analyses indicated a high correlation between ovarian cAMP and serum reproductive hormone levels across different reproductive stages. In conclusion, this study revealed the changes in serum hormones, serum biochemical indicators, and ovarian metabolites, as well as the relationship between serum hormones and ovarian metabolites.

Reversing Pdgfrβ signaling restores metabolically active beige adipocytes by alleviating ILC2 suppression in aged and obese mice

ObjectivePlatelet Derived Growth Factor Receptor Beta (Pdgfrβ) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if deleting Pdgfrβ in aged mice could rejuvenate metabolically active beige adipocytes by activating group 2 innate lymphoid cells (ILC2), and whether this effect could counteract diet-induced obesity-associated beige fat decline. MethodsWe employed Pdgfrβ gain-of-function and loss-of-function mouse models targeting beige adipocyte progenitor cells (APCs). Our approach included cold exposure, metabolic cage analysis, and age and diet-induced obesity models to examine beige fat development and metabolic function under varied Pdgfrβ activity. ResultsAcute cold exposure alone enhanced metabolic benefits in aged mice, irrespective of beige fat generation. However, Pdgfrβ deletion in aged mice reestablished the formation of metabolically functional beige adipocytes, enhancing metabolism. Conversely, constitutive Pdgfrβ activation in young mice stymied beige fat development. Mechanistically, Pdgfrβ deletion upregulated IL-33, promoting ILC2 recruitment and activation, whereas Pdgfrβ activation reduced IL-33 levels and suppressed ILC2 activity. Notably, diet-induced obesity markedly increased Pdgfrβ expression and Stat1 signaling, which inhibited IL-33 induction and ILC2 activation. Genetic deletion of Pdgfrβ restored beige fat formation in obese mice, improving whole-body metabolism. ConclusionsThis study reveals that cold temperature exposure alone can trigger metabolic activation in aged mammals. However, reversing Pdgfrβ signaling in aged and obese mice not only restores beige fat formation but also renews metabolic function and enhances the immunological environment of white adipose tissue (WAT). These findings highlight Pdgfrβ as a crucial target for therapeutic strategies aimed at combating age- and obesity-related metabolic decline.

Interactions between mild depressive symptoms and amyloid pathology on the trajectory of neurodegeneration, cognitive decline, and risk of Alzheimer's disease

BackgroundAlzheimer's disease (AD) was driven by the interplay between modifiable environmental factors and β-amyloid (Aβ) pathology. We aimed to investigate the interaction effects of mild depressive symptoms (MDS) with Aβ on AD development. MethodsLongitudinal data of 1746 non-demented adults (mean age = 73 years, female = 53 %, maximum = 10 years) were derived from the Alzheimer's Disease Neuroimaging Initiative cohort. MDS was separately defined by the baseline status, longitudinal latent class, and average intensity during follow-up. Amyloid-positive (A+) status was determined based on cerebrospinal fluid levels of β-amyloid. Regression models were employed to analyze the interactive effects of MDS with A+ on cognitive decline, neurodegeneration, and AD incidence. ResultsIndividuals with both A+ status and MDS at baseline experienced the fastest neurodegeneration (p < 0.01), cognitive decline (p < 0.05), and a higher risk of developing AD (HR = 5.23, p < 0.001). Furthermore, A+ participants with the trajectory of increasing depressive symptoms demonstrated more pronounced neurodegeneration (p < 0.001), cognitive decline (p < 0.01), and elevated risk of AD (HR = 10.45, p < 0.001). Finally, A+ status in combination with a higher average intensity of depressive symptoms was associated with faster brain atrophy (p < 0.01) and brain metabolism decline (p < 0.05), cognitive decline (p < 0.05), and higher AD risk (HR = 13.99, p < 0.001). ConclusionThese findings emphasized that the MDS-Aβ interaction relationship should be considered in risk stratification, prediction, and early management of neurodegeneration and cognitive decline in the pre-dementia stage.

Non-human primate model of long-COVID identifies immune associates of hyperglycemia

Hyperglycemia, and exacerbation of pre-existing deficits in glucose metabolism, are manifestations of the post-acute sequelae of SARS-CoV-2. Our understanding of metabolic decline after acute COVID-19 remains unclear due to the lack of animal models. Here, we report a non-human primate model of metabolic post-acute sequelae of SARS-CoV-2 using SARS-CoV-2 infected African green monkeys. Using this model, we identify a dysregulated blood chemokine signature during acute COVID-19 that correlates with elevated and persistent hyperglycemia four months post-infection. Hyperglycemia also correlates with liver glycogen levels, but there is no evidence of substantial long-term SARS-CoV-2 replication in the liver and pancreas. Finally, we report a favorable glycemic effect of the SARS-CoV-2 mRNA vaccine, administered on day 4 post-infection. Together, these data suggest that the African green monkey model exhibits important similarities to humans and can be utilized to assess therapeutic candidates to combat COVID-related metabolic defects.

Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1–7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK–AMPK–mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.

Temporal metabolomics analysis reveals the metabolic patterns in goat cumulus cells during oocyte maturation

Cumulus cells play a crucial role in the oocyte growth and maturation processes through providing necessary nutrients and growth signals by gap junction communication. However, a global overview of metabolic events in goat cumulus cells is still lacking. In the present study, we collected cumulus cells from goat cumulus-oocyte complexes (COCs) at different developmental stages. Metabolomics analysis was performed to investigate the global metabolic patterns in cumulus cells during oocyte in vitro maturation. In particular, we revealed the several significantly altered metabolic pathways and metaboliccharacteristics in goat cumulus cells, including the accumulation of fatty acids, steroid hormones metabolism, active catabolism of arginine during meiotic resumption, and a progressive decline in nucleotide metabolism. In conclusion, the dataset generated by our metabolomic profiling will provide valuable information to understand the key metabolic pathways and metabolites involved in COCs development.

Unveiling the impact of glutathione (GSH) and p53 gene deletion on tumor cell metabolism by amino acid and proteomics analysis.

Tumor cell inhibition is a pivotal focus in anti-cancer research, and extensive investigations have been conducted regarding the role of p53. Numerous studies have highlighted its close association with reactive oxygen species (ROS). However, the precise impact of the antioxidant glutathione (GSH) in this context remains inadequately elucidated. Here, we will elucidate the anti-cancer mechanisms mediated by p53 following treatment with GSH. In this study, we employed a p53 gene knockout approach in SW480 colorectal cells and conducted comprehensive analyses of 20 amino acids and proteomics using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). These analyses unveiled profound alterations in amino acids and proteins triggered by GSH treatment, shedding light on novel phenomena and delineating the intricate interplay between GSH and cellular proteins. The deletion of the p53 gene exerts a profound influence on tumor cell proliferation. Moreover, tumor cell proliferation is significantly affected by elevated GSH levels. Importantly, in the absence of the p53 gene, cells exhibit heightened sensitivity to GSH, leading to inhibited cell growth. The combined therapeutic approach involving GSH and p53 gene deletion expedites the demise of tumor cells. It is noteworthy that this treatment leads to a marked decline in amino acid metabolism, particularly affecting the down-regulation of methionine (Met) and phenylalanine (Phe) amino acids. Among the 41 proteins displaying significant changes, 8 exhibit consistent alterations, with 5 experiencing decreased levels and 3 demonstrating increased quantities. These proteins primarily participate in crucial cellular metabolic processes and immune functions. In conclusion, the concurrent administration of GSH treatment and p53 gene deletion triggers substantial modifications in the amino acid and protein metabolism of tumor cells, primarily characterized by down-regulation. This, in turn, compromises cell metabolic activity and immune function, ultimately culminating in the demise of tumor cells. These newfound insights hold promising implications and could pave the way for the development of straightforward and efficacious anti-cancer treatments.

Reversing Pdgfrβ Signaling Restores Metabolically Active Beige Adipocytes by Alleviating ILC2 Suppression in Aged and Obese Mice.

Platelet Derived Growth Factor Receptor Beta (Pdgfrβ) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if deleting Pdgfrβ in aged mice could rejuvenate metabolically active beige adipocytes by activating group 2 innate lymphoid cells (ILC2), and whether this effect could counteract diet-induced obesity-associated beige fat decline. We employed Pdgfrβ gain-of-function and loss-of-function mouse models targeting beige adipocyte progenitor cells (APCs). Our approach included cold exposure, metabolic cage analysis, and age and diet-induced obesity models to examine beige fat development and metabolic function under varied Pdgfrβ activity. Acute cold exposure alone enhanced metabolic benefits in aged mice, irrespective of beige fat generation. However, Pdgfrβ deletion in aged mice reestablished the formation of metabolically functional beige adipocytes, enhancing metabolism. Conversely, constitutive Pdgfrβ activation in young mice stymied beige fat development. Mechanistically, Pdgfrβ deletion upregulated IL-33, promoting ILC2 recruitment and activation, whereas Pdgfrβ activation reduced IL-33 levels and suppressed ILC2 activity. Notably, diet-induced obesity markedly increased Pdgfrβ expression and Stat1 signaling, which inhibited IL-33 induction and ILC2 activation. Genetic deletion of Pdgfrβ restored beige fat formation in obese mice, improving whole-body metabolism. This study reveals that cold temperature exposure alone can trigger metabolic activation in aged mammals. However, reversing Pdgfrβ signaling in aged and obese mice not only restores beige fat formation but also renews metabolic function and enhances the immunological environment of white adipose tissue (WAT). These findings highlight Pdgfrβ as a crucial target for therapeutic strategies aimed at combating age- and obesity-related metabolic decline.

Daily white tea intake reprograms hepatic metabolism and improves the enzymatic antioxidant defence system of rats with prediabetes

BackgroundPrediabetes (PrDM) poses a significant risk for the development of Diabetes Mellitus (DM). Preventing the transition to type 2 DM is of utmost importance, and identifying novel dietary agents with both antioxidant and antidiabetic properties is crucial. This study aims to assess the potential of regular white tea (WTEA) consumption in alleviating the detrimental effects of PrDM on hepatic metabolism and redox state. MethodsTo achieve this, we divided 18 male Wistar rats into three groups: a control group and two prediabetes (PrDM) groups. In one of the PrDM groups, water consumption was replaced with white tea (WTEA). After a two-month period, we evaluated the hepatic metabolic profile using 1H NMR. Additionally, we measured total antioxidant potential, the activities of antioxidant enzymes, and various oxidative parameters, including protein nitration and carbonylation, lipid peroxidation, and levels of H2A.X and phosphorylated H2A.X. ResultsPrDM induced a decline in hepatic catabolic metabolism and the activities of key antioxidant enzymes, including superoxide dismutase, glutathione reductase, catalase, and levels of phosphorylated H2A.X. However, when PrDM rats consumed WTEA, a remarkable restoration occurred. Specifically, WTEA intake reinstated glutathione reductase and catalase activities and elevated superoxide dismutase activity in the liver compared to normoglycemic conditions. Moreover, enhancements were noted in overall antioxidant capacity and a reduction in lipid peroxidation in the rat liver. ConclusionPrDM significantly impacts liver metabolism and antioxidant defenses, but the consumption of WTEA, a plant-based functional beverage, exhibits potent hepatoprotective capabilities against PrDM-induced oxidative stress.

T cells in obesity-associated inflammation: The devil is in the details.

Obesity presents a significant health challenge, affecting 41% of adults and 19.7% of children in the United States. One of the associated health challenges of obesity is chronic low-grade inflammation. In both mice and humans, T cells in circulation and in the adipose tissue play a pivotal role in obesity-associated inflammation. Changes in the numbers and frequency of specific CD4+ Th subsets and their contribution to inflammation through cytokine production indicate declining metabolic health, that is, insulin resistance and T2D. While some Th subset alterations are consistent between mice and humans with obesity, some changes mainly characterize male mice, whereas female mice often resist obesity and inflammation. However, protection from obesity and inflammation is not observed in human females, who can develop obesity-related T-cell inflammation akin to males. The decline in female sex hormones after menopause is also implicated in promoting obesity and inflammation. Age is a second underappreciated factor for defining and regulating obesity-associated inflammation toward translating basic science findings to the clinic. Weight loss in mice and humans, in parallel with these other factors, does not resolve obesity-associated inflammation. Instead, inflammation persists amid modest changes in CD4+ T cell frequencies, highlighting the need for further research into resolving changes in T-cell function after weight loss. How lingering inflammation after weight loss affecting the common struggle to maintain lower weight is unknown. Semaglutide, a newly popular pharmaceutical used for treating T2D and reversing obesity, holds promise for alleviating obesity-associated health complications, yet its impact on T-cell-mediated inflammation remains unexplored. Further work in this area could significantly contribute to the scientific understanding of the impacts of weight loss and sex/hormones in obesity and obesity-associated metabolic decline.

Genome-wide analysis of hepatic DNA methylation reveals impact of epigenetic aging on xenobiotic metabolism and transport genes in an aged mouse model

Hepatic xenobiotic metabolism and transport decline with age, while intact xenobiotic metabolism is associated with longevity. However, few studies have examined the genome-wide impact of epigenetic aging on these processes. We used reduced representation bisulfite sequencing (RRBS) to map DNA methylation changes in liver DNA from mice ages 4 and 24 months. We identified several thousand age-associated differentially methylated sites (a-DMS), many of which overlapped genes encoding Phase I and Phase II drug metabolizing enzymes, in addition to ABC and SLC classes of transporters. Notable genes harboring a-DMS were Cyp1a2, Cyp2d9, and Abcc2 that encode orthologs of the human drug metabolizing enzymes CYP1A2 and CYP2D6, and the multidrug resistance protein 2 (MRP2) transporter. Cyp2d9 hypermethylation with age was significantly associated with reduced gene expression, while Abcc2 expression was unchanged with age. Cyp1a2 lost methylation with age while, counterintuitively, its expression also reduced with age. We hypothesized that age-related dysregulation of the hepatic transcriptional machinery caused down-regulation of genes despite age-related hypomethylation. Bioinformatic analysis of hypomethylated a-DMS in our sample found them to be highly enriched for hepatic nuclear factor 4 alpha (HNF4α) binding sites. HNF4α promotes Cyp1a2 expression and is downregulated with age, which could explain the reduction in Cyp1a2 expression. Overall, our study supports the broad impact of epigenetic aging on xenobiotic metabolism and transport. Future work should evaluate the interplay between hepatic nuclear receptor function and epigenetic aging. These results may have implications for studies of longevity and healthy aging.

Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies

BackgroundAccumulation of tau leads to neuroinflammation and neuronal cell death in tauopathies, including Alzheimer’s disease. As the disease progresses, there is a decline in brain energy metabolism. However, the role of tau protein in regulating lipid metabolism remains less characterized and poorly understood.MethodsWe used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N- and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation.ResultsWe showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. We also found that this process depended on the amount of extracellular tau. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism.ConclusionOur results revealed that lipid metabolism is significantly affected during different stages of tau pathology. Thus, our results demonstrate that the dysregulation of lipid composition by pathological tau disrupts the microenvironment, further contributing to the propagation of pathology.