Metabolic Decline Research Articles

Effect Of Electromyostimulation Training On Intramuscular Fat Accumulation And Blood Lipids In Older Adults

PURPOSE: Aging induces muscle atrophy, decline of muscular metabolism, and excessive intramuscular fat accumulation. Aerobic and anerobic training enhance glycolytic or oxidative enzymes, and improve muscle size in older adults. However, these trainings are assumed difficult for older adult with disfunction of lower leg. Electromyostimulation (EMS) is commonly used in clinical settings to improve the muscular functions in older adults. The purpose of this study was to examine the effects of EMS training on intramuscular fat content and blood lipids of quadriceps femoris muscles in older adults. METHODS: Nineteen physically active, non-obese older men and women (mean age 71.5 ± 5.4 years) were performed EMS training of the quadriceps femoris muscle for 12 weeks (3 times/week). Single EMS session consisted of 7 s contraction/relaxation cycle for 30 min. Intramuscular fat content was estimated by echo intensity of vastus lateralis using ultrasonography. Free fatty acids (FFA) were measured from blood samples. Echo intensity and FFA were measured before and after EMS training. To determine acute effect of single EMS session, FFA was measured before and after the EMS session. RESULTS: EMS training did not significant change echo intensity (pre 63.7 ± 11.1 a.u.; post 62.4 ± 9.0 a.u.) and FFA (pre 523.3 ± 187.0 μEq/L; post 503.5 ± 223.0 μEq/L). Regarding acute effect on blood lipid, single EMS session increased FFA (pre 523.3 ± 187.0 μEq/L; post 606.9 ± 185.2μEq/L, p < 0.01). CONCLUSIONS: Acute effect of EMS session on blood lipids was obtained, but EMS training intervention for 12 weeks did not improve intramuscular fat content of quadriceps femoris muscle and blood lipids. Supported by a Grant in Aid (KAKENHI 18 K17764).

Impact of Aging and Lifelong Exercise Training on Mitochondrial Function and Network Connectivity in Human Skeletal Muscle.

Aging is associated with metabolic decline in skeletal muscle, which can be delayed by physical activity. Moreover, both lifelong and short-term exercise training have been shown to prevent age-associated fragmentation of the mitochondrial network in mouse skeletal muscle. However, whether lifelong endurance exercise training exerts the same effects in human skeletal muscle is still not clear. Therefore, the aim of the present study was to examine the effect of volume-dependent lifelong endurance exercise training on mitochondrial function and network connectivity in older human skeletal muscle. Skeletal muscle complex I+II-linked mitochondrial respiration per tissue mass was higher, but intrinsic complex I+II-linked mitochondrial respiration was lower in highly trained older subjects than in young untrained, older untrained, and older moderately trained subjects. Mitochondrial volume and connectivity were higher in highly trained older subjects than in untrained and moderately trained older subjects. Furthermore, the protein content of the ADP/ATP exchangers ANT1 + 2 and VDAC was higher and of the mitophagic marker parkin lower in skeletal muscle from the highly trained older subjects than from untrained and moderately trained older subjects. In contrast, H2O2 emission in skeletal muscle was not affected by either age or exercise training, but SOD2 protein content was higher in highly trained older subjects than in untrained and moderately trained older subjects. This suggests that healthy aging does not induce oxidative stress or mitochondrial network fragmentation in human skeletal muscle, but high-volume exercise training increases mitochondrial volume and network connectivity, thereby increasing oxidative capacity in older human skeletal muscle.

The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging

The risk of chronic diseases caused by aging is reduced by caloric restriction (CR)-induced immunometabolic adaptation. Here, we found that the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), was inhibited by 2 years of 14% sustained CR in humans and elevated by obesity. SPARC converted anti-inflammatory macrophages into a pro-inflammatory phenotype with induction of interferon-stimulated gene (ISG) expression via the transcription factors IRF3/7. Mechanistically, SPARC-induced ISGs were dependent on toll-like receptor-4 (TLR4)-mediated TBK1, IRF3, IFN-β, and STAT1 signaling without engaging the Myd88 pathway. Metabolically, SPARC dampened mitochondrial respiration, and inhibition of glycolysis abrogated ISG induction by SPARC in macrophages. Furthermore, the N-terminal acidic domain of SPARC was required for ISG induction, while adipocyte-specific deletion of SPARC reduced inflammation and extended health span during aging. Collectively, SPARC, a CR-mimetic adipokine, is an immunometabolic checkpoint of inflammation and interferon response that may be targeted to delay age-related metabolic and functional decline.

The characteristics of glucose metabolism and functional connectivity in posterior default network during nondemented aging: relationship with executive function performance.

Understanding the characteristics of intrinsic connectivity networks (ICNs) in terms of both glucose metabolism and functional connectivity (FC) is important for revealing cognitive aging and neurodegeneration, but the relationships between these two aspects during aging has not been well established in older adults. This study is to assess the relationship between age-related glucose metabolism and FC in key ICNs, and their direct or indirect effects on cognitive deficits in older adults. We estimated the individual-level standard uptake value ratio (SUVr) and FC of eleven ICNs in 59 cognitively unimpaired older adults, then analyzed the associations of SUVr and FC of each ICN and their relationships with cognitive performance. The results showed both the SUVr and FC in the posterior default mode network (pDMN) had a significant decline with age, and the association between them was also significant. Moreover, both decline of metabolism and FC in the pDMN were significantly correlated with executive function decline. Finally, mediation analysis revealed the glucose metabolism mediated the FC decline with age and FC mediated the executive function deficits. Our findings indicated that covariance between glucose metabolism and FC in the pDMN is one of the main routes that contributes to age-related executive function decline.

Ablation of Ghrelin Receptor Mitigates the Metabolic Decline of Aging Skeletal Muscle.

The orexigenic hormone ghrelin has multifaceted roles in health and disease. We have reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), protects against metabolic dysfunction of adipose tissues in aging. Our further observation interestingly revealed that GHS-R deficiency phenocopies the effects of myokine irisin. In this study, we aim to determine whether GHS-R affects the metabolic functions of aging skeletal muscle and whether GHS-R regulates the muscular functions via irisin. We first studied the expression of metabolic signature genes in gastrocnemius muscle of young, middle-aged and old mice. Then, old GHS-R knockout (Ghsr−/−) mice and their wild type counterparts were used to assess the impact of GHS-R ablation on the metabolic characteristics of gastrocnemius and soleus muscle. There was an increase of GHS-R expression in skeletal muscle during aging, inversely correlated with the decline of metabolic functions. Remarkedly the muscle of old GHS-R knockout (Ghsr−/−) mice exhibited a youthful metabolic profile and better maintenance of oxidative type 2 muscle fibers. Furthermore, old Ghsr−/− mice showed improved treadmill performance, supporting better functionality. Also intriguing to note was the fact that old GHS-R-ablated mice showed increased expression of the irisin precursor FNDC5 in the muscle and elevated plasma irisin levels in circulation, which supports a potential interrelationship between GHS-R and irisin. Overall, our work suggests that GHS-R has deleterious effects on the metabolism of aging muscle, which may be at least partially mediated by myokine irisin.

Hesperetin promotes longevity and delays aging via activation of Cisd2 in naturally aged mice

BackgroundThe human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging.MethodsHesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging.ResultsThree discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age.ConclusionsOur findings indicate that a Cisd2 activator, hesperetin, represents a promising and broadly effective translational approach to slowing down aging and promoting longevity via the activation of Cisd2.

Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer’s disease: additional results from the AMBAR study

PurposeThis study was designed to detect structural and functional brain changes in Alzheimer’s disease (AD) patients treated with therapeutic plasma exchange (PE) with albumin replacement, as part of the recent AMBAR phase 2b/3 clinical trial.MethodsMild-to-moderate AD patients were randomized into four arms: three arms receiving PE with albumin (one with low-dose albumin, and two with low/high doses of albumin alternated with IVIG), and a placebo (sham PE) arm. All arms underwent 6 weeks of weekly conventional PE followed by 12 months of monthly low-volume PE. Magnetic resonance imaging (MRI) volumetric analyses and regional and statistical parametric mapping (SPM) analysis on 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) were performed.ResultsMRI analyses (n = 198 patients) of selected subcortical structures showed fewer volume changes from baseline to final visit in the high albumin + IVIG treatment group (p < 0.05 in 3 structures vs. 4 to 9 in other groups). The high albumin + IVIG group showed no statistically significant reduction of right hippocampus. SPM 18FDG-PET analyses (n = 213 patients) showed a worsening of metabolic activity in the specific areas affected in AD (posterior cingulate, precuneus, and parieto-temporal regions). The high-albumin + IVIG treatment group showed the greatest metabolic stability over the course of the study, i.e., the smallest percent decline in metabolism (MaskAD), and least progression of defect compared to placebo.ConclusionsPE with albumin replacement was associated with fewer deleterious changes in subcortical structures and less metabolic decline compared to the typical of the progression of AD. This effect was more marked in the group treated with high albumin + IVIG.Trial registration(AMBAR trial registration: EudraCT#: 2011–001,598-25; ClinicalTrials.gov ID: NCT01561053).

Calorie Restriction Rescues Mitochondrial Dysfunction in Adck2-Deficient Skeletal Muscle.

ADCK2 haploinsufficiency-mediated mitochondrial coenzyme Q deficiency in skeletal muscle causes mitochondrial myopathy associated with defects in beta-oxidation of fatty acids, aged-matched metabolic reprogramming, and defective physical performance. Calorie restriction has proven to increase lifespan and delay the onset of chronic diseases associated to aging. To study the possible treatment by food deprivation, heterozygous Adck2 knockout mice were fed under 40% calorie restriction (CR) and the phenotype was followed for 7 months. The overall glucose and fatty acids metabolism in muscle was restored in mutant mice to WT levels after CR. CR modulated the skeletal muscle metabolic profile of mutant mice, partially rescuing the profile of WT animals. The analysis of mitochondria isolated from skeletal muscle demonstrated that CR increased both CoQ levels and oxygen consumption rate (OCR) based on both glucose and fatty acids substrates, along with mitochondrial mass. The elevated aerobic metabolism fits with an increase of type IIa fibers, and a reduction of type IIx in mutant muscles, reaching WT levels. To further explore the effect of CR over muscle stem cells, satellite cells were isolated and induced to differentiate in culture media containing serum from animals in either ad libitum or CR diets for 72 h. Mutant cells showed slower differentiation alongside with decreased oxygen consumption. In vitro differentiation of mutant cells was increased under CR serum reaching levels of WT isolated cells, recovering respiration measured by OCR and partially beta-oxidation of fatty acids. The overall increase of skeletal muscle bioenergetics following CR intervention is paralleled with a physical activity improvement, with some increases in two and four limbs strength tests, and weights strength test. Running wheel activity was also partially improved in mutant mice under CR. These results demonstrate that CR intervention, which has been shown to improve age-associated physical and metabolic decline in WT mice, also recovers the defective aerobic metabolism and differentiation of skeletal muscle in mice caused by ADCK2 haploinsufficiency.

Simple Growth-Metabolism Relations Are Revealed by Conserved Patterns of Heat Flow from Cultured Microorganisms.

Quantitative analyses of cell replication address the connection between metabolism and growth. Various growth models approximate time-dependent cell numbers in culture media, but physiological implications of the parametrizations are vague. In contrast, isothermal microcalorimetry (IMC) measures with unprecedented sensitivity the heat (enthalpy) release via chemical turnover in metabolizing cells. Hence, the metabolic activity can be studied independently of modeling the time-dependence of cell numbers. Unexpectedly, IMC traces of various origins exhibit conserved patterns when expressed in the enthalpy domain rather than the time domain, as exemplified by cultures of Lactococcus lactis (prokaryote), Trypanosoma congolese (protozoan) and non-growing Brassica napus (plant) cells. The data comply extraordinarily well with a dynamic Langmuir adsorption reaction model of nutrient uptake and catalytic turnover generalized here to the non-constancy of catalytic capacity. Formal relations to Michaelis–Menten kinetics and common analytical growth models are briefly discussed. The proposed formalism reproduces the “life span” of cultured microorganisms from exponential growth to metabolic decline by a succession of distinct metabolic phases following remarkably simple nutrient–metabolism relations. The analysis enables the development of advanced enzyme network models of unbalanced growth and has fundamental consequences for the derivation of toxicity measures and the transferability of metabolic activity data between laboratories.

Age- and Sex-Associated Glucose Metabolism Decline in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by a high etiological and clinical heterogeneity, which has obscured the diagnostic and treatment efficacy, as well as limited the development of potential drugs. Sex differences are among the risk factors that contribute to the variability of disease manifestation. Unlike men, women are at greater risk of developing AD and suffer from higher cognitive deterioration, together with important changes in pathological features. Alterations in glucose metabolism are emerging as a key player in the pathogenesis of AD, which appear even decades before the presence of clinical symptoms. We aimed to study whether AD-related sex differences influence glucose metabolism. We used male and female APPswe/PS1dE9 (APP/PS1) transgenic mice of different ages to examine glucose metabolism effects on AD development. Our analysis suggests an age-dependent decline of metabolic responses, cognitive functions, and brain energy homeostasis, together with an increase of Aβ levels in both males and females APP/PS1 mice. The administration of Andrographolide (Andro), an anti-inflammatory and anti-diabetic compound, was able to restore several metabolic disturbances, including the glycolytic and the pentose phosphate pathway fluxes, ATP levels, AMPKα activity, and Glut3 expression in 8-month-old mice, independent of the sex, while rescuing these abnormalities only in older females. Similarly, Andro also prevented Aβ accumulation and cognitive decline in all but old males. Our study provides insight into the heterogeneity of the disease and supports the use of Andro as a potential drug to promote personalized medicine in AD.

Compositional changes in human gut microbiota reveal a putative role of intestinal mycobiota in metabolic and biological decline during aging

BACKGROUND: Age-related alterations in the composition and function of gut microbiota may influence human health and disease mechanisms. However, connections between compositional changes in gut bacterial and fungal communities, and their role in the aging process, remain poorly understood. OBJECTIVE: Compare the gut microbiota and mycobiota composition in different age groups and evaluate the functionality. METHODS: In this study, we performed 16S rRNA and ITS2 gene-based microbial profiling analysis and shotgun metagenomics using the NextSeq platform. RESULTS: We observed a shift in compositional changes of human gut microbiota with age. Older individuals revealed a significantly different gut microbiota profile compared to younger individuals. For example, gut microbiota composition of the older individuals showed increase in genera Bacteroides, Blautia, Ruminococcaceae, and Escherichia coli. Additionally, older individuals had significant reduction in fungi belonging to saccharomyces cerevisiae and candida albicans in comparison to their younger counterparts. Moreover, metagenomics functional profiling analysis using shotgun metagenomics sequencing data showed substantial differences in the enrichment of 48 pathways between the young and older age groups. Metabolic pathways such as amino acid biosynthesis, carbohydrate metabolism, cell structure biosynthesis and vitamin biosynthesis were declined in the older age group, in comparison with the younger individuals. CONCLUSIONS: The identified differences provide a new insight to enrich our understanding of age-related changes in gut microbiota, their metabolic capabilities, and potential impact on health and disease conditions.

Assessing Nordihydroguaiaretic Acid Therapeutic Effect for Glioblastoma Multiforme.

In this study, we demonstrate that Raman microscopy combined with computational analysis is a useful approach to discriminating accurately between brain tumor bio-specimens and to identifying structural changes in glioblastoma (GBM) bio-signatures after nordihydroguaiaretic acid (NDGA) administration. NDGA phenolic lignan was selected as a potential therapeutic agent because of its reported beneficial effects in alleviating and inhibiting the formation of multi-organ malignant tumors. The current analysis of NDGA’s impact on GBM human cells demonstrates a reduction in the quantity of altered protein content and of reactive oxygen species (ROS)-damaged phenylalanine; results that correlate with the ROS scavenger and anti-oxidant properties of NDGA. A novel outcome presented here is the use of phenylalanine as a biomarker for differentiating between samples and assessing drug efficacy. Treatment with a low NDGA dose shows a decline in abnormal lipid-protein metabolism, which is inferred by the formation of lipid droplets and a decrease in altered protein content. A very high dose results in cell structural and membrane damage that favors transformed protein overexpression. The information gained through this work is of substantial value for understanding NDGA’s beneficial as well as detrimental bio-effects as a potential therapeutic drug for brain cancer.

48 Metformin Rescues the Aging-induced Failure of Post-burn White Adipose Browning

IntroductionSevere burns are responsible for an estimated 300,000 deaths per year worldwide. While modern burn care has markedly improved survival for pediatric and adult patients, this is sadly not the case for one population: the elderly. Despite being the fastest-growing demographic in North America, burn patients over the age of 60 years have the highest mortality and morbidity rates. Recent evidence suggests that progressive aging induces several structural and functional alterations which impair the capacity of older trauma patients to adequately respond to stress. Indeed, it was discovered that reduced survival in elderly burn patients is associated with the failure to initiate the browning of white adipose tissue (WAT) —a hallmark of the systemic response to injury commonly observed in adults. Interestingly, the widely used hypoglycemic drug metformin has been found to protect against aging-induced metabolic decline in various pathological conditions. Thus, we investigated the anti-aging effects of metformin on the metabolic deterioration of post-burn WAT responses in elderly patients and mice after injury.MethodsHuman WAT was obtained from elderly patients admitted to our burn center. Elderly (75-week) mice received a full-thickness scald burn and/or daily intraperitoneal injections of metformin (100 mg/kg) for 7 days. The inguinal WAT was harvested for histological analyses. Mitochondrial respiration was measured via Seahorse XF96. Gene and protein expression was assessed via RT-PCR and western blot, respectively.ResultsPost-burn metformin treatment restores the thermogenic activation of WAT in elderly patients and mice, reflected by the increased expression of key browning markers, UCP-1 and PGC-1α (p< 0.05). This was accompanied by higher mitochondrial respiration, improved lipolysis (p< 0.05) and increased fat wasting (p< 0.01) relative to control counterparts. The anti-aging effects of metformin appeared to be mediated by AMPK, which consequently increased [NAD+] (p< 0.01), thereby promoting activation of the longevity-specific enzyme Sirt-1 (p< 0.05).ConclusionsHere, we show that post-burn metformin treatment effectively rejuvenates adaptive metabolic responses in elderly WAT by targeting key longevity pathways which rescue the age-dependent loss of being back to youthful levels. Our findings support the potential of anti-aging modalities to improve care and outcomes in elderly burned patients.

High-Throughput Metabolomics Platform for the Rapid Data-Driven Development of Novel Additive Solutions for Blood Storage.

Red blood cell transfusion is a life-saving intervention, and storage is a logistic necessity to make ~110 million units available for transfusion every year worldwide. However, storage in the blood bank is associated with a progressive metabolic decline, which correlates with the accumulation of morphological lesions, increased intra- and extra-vascular hemolysis upon transfusion, and altered oxygen binding/off-loading kinetics. Prior to storage, red blood cells are suspended in nutrient formulations known as additive solutions to prolong cellular viability. Despite a thorough expansion of knowledge regarding red blood cell biology over the past few decades, only a single new additive solution has been approved by the Food and Drug Administration this century, owing in part to the limited capacity for development of novel formulations. As a proof of principle, we leveraged a novel high-throughput metabolomics technology as a platform for rapid data-driven development and screening of novel additive solutions for blood storage under both normoxic and hypoxic conditions. To this end, we obtained leukocyte-filtered red blood cells (RBCs) and stored them under normoxic or hypoxic conditions in 96 well plates (containing polyvinylchloride plasticized with diethylhexylphthalate to concentrations comparable to full size storage units) in the presence of an additive solution supplemented with six different compounds. To inform this data-driven strategy, we relied on previously identified metabolic markers of the RBC storage lesion that associates with measures of hemolysis and post-transfusion recovery, which are the FDA gold standards to predict stored blood quality, as well as and metabolic predictors of oxygen binding/off-loading parameters. Direct quantitation of these predictors of RBC storage quality were used here—along with detailed pathway analysis of central energy and redox metabolism—as a decision-making tool to screen novel additive formulations in a multiplexed fashion. Candidate supplements are shown here that boost-specific pathways. These metabolic effects are only in part dependent on the SO2 storage conditions. Through this platform, we anticipate testing thousands of novel additives and combinations thereof in the upcoming months.

Iron Supplementation Delays Aging and Extends Cellular Lifespan through Potentiation of Mitochondrial Function.

Aging is the greatest challenge to humankind worldwide. Aging is associated with a progressive loss of physiological integrity due to a decline in cellular metabolism and functions. Such metabolic changes lead to age-related diseases, thereby compromising human health for the remaining life. Thus, there is an urgent need to identify geroprotectors that regulate metabolic functions to target the aging biological processes. Nutrients are the major regulator of metabolic activities to coordinate cell growth and development. Iron is an important nutrient involved in several biological functions, including metabolism. In this study using yeast as an aging model organism, we show that iron supplementation delays aging and increases the cellular lifespan. To determine how iron supplementation increases lifespan, we performed a gene expression analysis of mitochondria, the main cellular hub of iron utilization. Quantitative analysis of gene expression data reveals that iron supplementation upregulates the expression of the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain (ETC) genes. Furthermore, in agreement with the expression profiles of mitochondrial genes, ATP level is elevated by iron supplementation, which is required for increasing the cellular lifespan. To confirm, we tested the role of iron supplementation in the AMPK knockout mutant. AMPK is a highly conserved controller of mitochondrial metabolism and energy homeostasis. Remarkably, iron supplementation rescued the short lifespan of the AMPK knockout mutant and confirmed its anti-aging role through the enhancement of mitochondrial functions. Thus, our results suggest a potential therapeutic use of iron supplementation to delay aging and prolong healthspan.

Interrelation of striatal dopamine, brain metabolism and cognition in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB), the second most common neurodegenerative dementia, is characterized by cognitive decline, fluctuation of cognition and alertness, visual hallucinations, rapid eye movement sleep behaviour disorder and parkinsonism. Imaging biomarkers are of great importance in diagnosing patients with DLB and associated with characteristic clinical features including cognitive decline. In this study, we investigate interrelation between nigrostriatal dopamine depletion, brain metabolism and cognition in DLB. We enrolled 55 patients with probable DLB (15 with prodromal DLB and 40 with DLB) and 13 healthy controls. All subjects underwent N-(3-[18F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane PET/CT, 18F-fluorodeoxyglucose PET/CT, 18F-florbetaben PET/CT and detailed neuropsychological testing. The relationship between striatal dopamine transporter availability and regional brain metabolism was assessed using general linear models, and the effect of striatal dopamine transporter availability and brain metabolism on specific cognitive function was evaluated by multivariate linear regression analysis. Path analyses were used to evaluate the relationship between striatal dopamine transporter availability, fluorodeoxyglucose uptake and cognitive function scores. Additionally, a linear mixed model was used to investigate the association between baseline dopamine transporter availability or brain metabolism and longitudinal cognitive decline. Independent of amyloid deposition, caudate and putamen dopamine transporter availabilities were positively correlated with brain metabolism in the DLB-specific hypometabolic regions, most prominently in the occipital and lateral parietal cortices. Both reduced caudate dopamine and brain hypometabolism were associated with low z-scores of Rey-Osterrieth Complex Figure Test copy, Seoul Verbal Learning Test immediate recall and Controlled Oral Word Association Test (COWAT)-animal. Path analyses showed that the effect of reduced caudate dopamine on the Rey-Osterrieth Complex Figure Test copy z-score was completely mediated by brain hypometabolism, whereas it affected the Seoul Verbal Learning Test immediate recall z-score both directly and via the mediation of brain hypometabolism. Caudate dopamine depletion was directly associated with the COWAT-animal z-score, not mediated by brain hypometabolism. Both baseline caudate dopamine transporter availability and brain hypometabolism were associated with longitudinal cognitive decline, with brain hypometabolism being more relevant. Our findings suggest that in DLB, striatal dopaminergic depletion and brain hypometabolism are closely related, and they differentially affect cognitive dysfunction in an item-specific manner. Additionally, brain hypometabolism would be more relevant to longitudinal cognitive outcomes than striatal dopaminergic degeneration.

Weighing in on Adipogenesis.

Obesity is a growing health concern worldwide because of its contribution to metabolic syndrome, type II diabetes, insulin resistance (IR), and numerous cancers. In obesity, white adipose tissue (WAT) expands through two mechanisms: increase in adipocyte cell number by precursor cell differentiation through the process of adipogenesis (hyperplasia) and increase in existing mature adipocyte cell size (hypertrophy). While hypertrophy is associated with the negative effects of obesity on metabolic health, such as inflammation and lipotoxicity, adipogenesis prevents obesity-mediated metabolic decline. Moreover, in metabolically healthy obesity adipogenesis is increased. Thus, it is vital to understand the mechanistic basis for adipose expansion to inform novel therapeutic approaches to mitigate the dysfunction of this tissue and associated diseases. In this mini-review, we summarize recent studies on the regulation of adipogenesis and provide a perspective on targeting adipogenesis as a potential therapeutic avenue for metabolic disorders.

Differential Effects of 2-Deoxyglucose and Glucose Deprivation on 4-Hydroxynonenal Dependent Mitochondrial Dysfunction in Primary Neurons

Mitochondrial dysfunction and metabolic decline are prevalent features of aging and age-related disorders, including neurodegeneration. Neurodegenerative diseases are associated with a progressive loss of metabolic homeostasis. This pathogenic decline in metabolism is the result of several factors, including decreased mitochondrial function, increased oxidative stress, inhibited autophagic flux, and altered metabolic substrate availability. One critical metabolite for maintaining neuronal function is glucose, which is utilized by the brain more than any other organ to meet its substantial metabolic demand. Enzymatic conversion of glucose into its downstream metabolites is critical for maintaining neuronal cell growth and overall metabolic homeostasis. Perturbation of glycolysis could significantly hinder neuronal metabolism by affecting key metabolic pathways. Here, we demonstrate that the glucose analogue 2-deoxyglucose (2DG) decreases cell viability, as well as both basal and maximal mitochondrial oxygen consumption in response to the neurotoxic lipid 4-hydroxynonenal (HNE), whereas glucose deprivation has a minimal effect. Furthermore, using a cell permeabilization assay we found that 2DG has a more pronounced effect on HNE-dependent inhibition of mitochondrial complex I and II than glucose deprivation. Importantly, these findings indicate that altered glucose utilization plays a critical role in dictating neuronal survival by regulating the mitochondrial response to electrophilic stress.

Anti-Obesity Effects of Polymethoxyflavone-Rich Fraction from Jinkyool (Citrus sunki Hort. ex Tanaka) Leaf on Obese Mice Induced by High-Fat Diet.

Polymethoxyflavones (PMFs) are flavonoids exclusively found in certain citrus fruits and have been reported to be beneficial to human health. Most studies have been conducted with PMFs isolated from citrus peels, while there is no study on PMFs isolated from leaves. In this study, we prepared a PMF-rich fraction (PRF) from the leaves of Citrus sunki Hort ex. Tanaka (Jinkyool) and investigated whether the PRF could improve metabolic decline in obese mice induced by a high-fat diet (HFD) for 5 weeks. The HFD-induced obese mice were assigned into HFD, OR (HFD + orlistat at 15.6 mg/kg of body weight/day), and PRF (HFD + 50, 100, and 200 mg/kg of body weight/day) groups. Orlistat and PRF were orally administered for 5 weeks. At the end of the experiment, the serum biochemical parameters, histology, and gene expression profiles in the tissues of each group were analyzed. The body weight gain of the obese mice was significantly reduced after orlistat and PRF administration for 5 weeks. PRF effectively improved HFD-induced insulin resistance and dyslipidemia. Histological analysis in the liver demonstrated that PRF decreased adipocyte size and potentially improved the liver function, as it inhibited the incidence of fatty liver. PRF activated AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), and hormone-sensitive lipase (HSL) in HFD-induced obese mice. Moreover, liver transcriptome analysis revealed that PRF administration enriched genes mainly related to fatty-acid metabolism and immune responses. Overall, these results suggest that the PRF exerted an anti-obesity effect via the modulation of lipid metabolism.

SGLT2 inhibitor dapagliflozin prevents atherosclerotic and cardiac complications in experimental type 1 diabetes.

IntroductionCardiovascular disease (CVD) is two to five times more prevalent in diabetic patients and is the leading cause of death. Therefore, identification of novel therapeutic strategies that reduce the risk of CVD is a research priority. Clinical trials showed that reduction in the relative risk of heart failure by sodium-glucose cotransporter 2 inhibitors (SGLT2i) are partly beyond their glucose lowering effects, however, the molecular mechanisms are still elusive. Here we investigated the role of SGLT2i dapagliflozin (DAPA) in the prevention of diabetes-induced cardiovascular complications.MethodsType 1 diabetes was induced with streptozotocin (65 mg/bwkg, ip.) in adult, male Wistar rats. Following the onset of diabetes rats were treated for six weeks with DAPA (1 mg/bwkg/day, po.).ResultsDAPA decreased blood glucose levels (D: 37±2.7 vs. D+DAPA: 18±5.6 mmol/L; p<0.05) and prevented metabolic decline. Aortic intima-media thickening was mitigated by DAPA. DAPA abolished cardiac hypertrophy, and myocardial damage. Cardiac inflammation and fibrosis were also moderated after DAPA treatment.ConclusionsThese data support the preventive and protective role of SGLT2i in diabetes-associated cardiovascular disease. SGLT2i may provide novel therapeutic strategy to hinder the development of cardiovascular diseases in type 1 diabetes, thereby improve the outcomes.