Search

Myoprotein degradation accelerates in obese individuals, resulting in a decline in muscular mass. Atg7 plays a crucial role in regulating protein stability and function through both autophagy-dependent and independent pathways. As obesity progresses, the expression of Atg7 gradually rises in muscle tissue. Nonetheless, the precise impact and mechanism of Atg7 in promoting muscle mass decline in obesity remain uncertain. The study aimed to elucidate the role and underly mechanism of Atg7 action in the context of obesity-induced muscle mass decline. In this study, we established a murine model of high-fat diet-induced obesity (DIO) and introduced adeno-associated virus delivery of short hairpin RNA to knock down Atg7 (sh Atg7) into the gastrocnemius muscle. We then examined the expressions of Atg7 and myoprotein degradation markers in the gastrocnemius tissues of obese patients and mice using immunofluorescence and western blotting techniques. To further investigate the effects of Atg7, we assessed skeletal muscle cell diameter and the myoprotein degradation pathway in C2C12 and HSkMC cells in the presence or absence of Atg7. Immunofluorescence staining for MyHC and western blotting were utilized for this purpose. To understand the transcriptional regulation of Atg7 in response to myoprotein degradation, we conducted luciferase reporter assays and chromatin immunoprecipitation experiments to examine whether FoxO3a enhances the transcription of Atg7. Moreover, we explored the role of Akt in Atg7-mediated regulation and its relevance to obesity-induced muscle mass decline. This was accomplished by Akt knockdown, treatment with MK2206, and GST pulldown assays to assess the interaction between Atg7 and Akt. After 20 weeks of being on a high-fat diet, obesity was induced, leading to a significant decrease in the gastrocnemius muscle area and a decline in muscle performance. This was accompanied by a notable increase in Atg7 protein expression (p < 0.01). Similarly, in gastrocnemius tissues of obese patients when compared to nonobese individuals, there was a significant increase in both Atg7 (p < 0.01) and TRIM63 (p < 0.01) levels. When palmitic acid was administered to C2C12 cells, it resulted in increased Atg7 (p < 0.01), LC3Ⅱ/Ⅰ (p < 0.01), and p62 levels (p < 0.01). Additionally, it promoted FoxO3a-mediated transcription of Atg7. The knockdown of Atg7 in the gastrocnemius partially reversed DIO-induced muscle mass decline. Furthermore, when Atg7 was knocked down in C2C12 and HSkMC cells, it mitigated palmitic acid-induced insulin resistance, increased the p-Akt/Akt ratio (p < 0.01), and reduced TRIM63 (p < 0.01). Muscular atrophy mediated by Atg7 was reversed by genetic knockdown of Akt and treatment with the p-Akt inhibitor MK2206. Palmitic acid administration increased the binding between Atg7 and Akt (p < 0.01) while weakening the binding of PDK1 (p < 0.01) and PDK2 (p < 0.01) to Akt. GST pulldown assays demonstrated that Atg7 directly interacted with the C-terminal domain of Akt. The consumption of a high-fat diet, along with lipid-induced effects, led to the inhibition of Akt signaling, which, in turn, promoted FoxO3a-mediated transcription, increasing Atg7 levels in muscle cells. The excess Atg7 inhibited the phosphorylation of Akt, leading to a cyclic activation of FoxO3a and exacerbating the decline in muscle mass regulated by obesity. Consequently, Atg7 serves as a regulatory point in determining the decline in muscle mass induced by obesity. [Display omitted] • Atg7 is a key regulatory node in promoting obesity-induced muscular mass decline. • Lipid-induced inhibition of Akt signaling promotes FoxO3a-mediated transcription of Atg7. • Atg7 directly interacts with the C-terminal domain of Akt, causing cyclic activation of FoxO3a. • Dysfunction of the Akt/FoxO3a/Atg7 regulatory loop exacerbates the obesity-triggered muscular mass decline. [ABSTRACT FROM AUTHOR]

Background Many studies have identified early-life risk factors for childhood overweight/obesity (OwOb), but few have evaluated how they combine to influence later cardiometabolic health. Objectives We aimed to examine the association of risk factors in the first 1000 d with adiposity and cardiometabolic risk in early adolescence. Methods We studied 1038 mother–child pairs in Project Viva. We chose 6 modifiable early-life risk factors previously associated with child adiposity or metabolic health in the cohort: smoking during pregnancy (yes compared with no); gestational weight gain (excessive compared with nonexcessive); sugar-sweetened beverage consumption during pregnancy (≥0.5 compared with <0.5 servings/d); breastfeeding duration (<12 compared with ≥12 mo); timing of complementary food introduction (<4 compared with ≥4 mo); and infant sleep duration (<12 compared with ≥12 h/d). We computed risk factor scores by calculating the cumulative number of risk factors for each child. In early adolescence (median: 13.1 y) we measured indicators of adiposity [BMI, fat mass index (FMI), trunk fat mass index (TFMI)]. We also calculated OwOb prevalence and metabolic syndrome (MetS) risk z score of adolescents. Results Among 1038 adolescents, 71% had >1 early-life risk factor. In covariate-adjusted models, we observed positive monotonic increases in BMI, FMI, TFMI, and MetS z scores with increasing risk factor score. Children with 5‒6 risk factors (compared with 0–1 risk factors) had the highest risk of OwOb [risk ratio (RR): 2.53; 95% CI: 1.63, 3.91] and being in the highest MetS quartile (RR: 2.46; 95% CI: 1.43, 4.21). The predicted probability of OwOb in adolescence varied from 9.4% (favorable levels for all factors) to 63.6% (adverse levels for all factors), and for being in the highest MetS quartile from 9.6% to 56.6%. Conclusions Early-life risk factors in the first 1000 d cumulatively predicted higher adiposity and cardiometabolic risk in early adolescence. Intervention strategies to prevent later obesity and cardiometabolic risk may be more effective if they concurrently target multiple modifiable factors. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (NDs) affect 15% of the world's population and are becoming an increasingly common cause of morbidity and mortality worldwide. Circadian rhythm disorders (CRDs) have been reported to be involved in the pathogenic regulation of various neurologic diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis. Proteomic technology is helpful to explore treatment targets for CRDs in patients with NDs. Here, we review the key differentially expressed (DE) proteins identified in previous proteomic studies investigating NDs, CRDs and associated models and the related pathways identified by enrichment analysis. Furthermore, we summarize the advantages and disadvantages of the above studies and propose new proteomic technologies for the precise study of circadian disorder-mediated regulation of ND pathology. This review provides a theoretical and technical reference for the precise study of circadian disorder-mediated regulation of ND pathology. [ABSTRACT FROM AUTHOR]

Exposure to fine particular matter (≤2.5 μM, PM 2.5) contributes to increased risk of obesity and type 2 diabetes. Hydroxytyrosol (HT), a simple polyphenol found in virgin olive oil, is considered to be beneficial for cardiovascular and metabolic disorders. The current study determined whether HT could improve PM 2.5 -induced adiposity and insulin resistance (IR), and explored the underlying mechanisms. Fifteen adult female C57BL/6j mice on a chow diet were randomly divided into three groups receiving (1) sterile PBS, (2) PM 2.5 suspended in sterile PBS (1 mg/mL) and (3) PM 2.5 +HT (50 mg/kg/day). PM 2.5 /PBS exposure was administered by oropharynx instillation every other day and HT supplementation was achieved by gavage every day. Four-week PM 2.5 exposure did not affect body weight, but significantly increased visceral fat mass. The abdominal adiposity coincided with adipocyte hypertrophy and proliferation in visceral white adipose tissue (WAT), as well as decreased metabolic activity in brown adipose tissue and subcutaneous WAT. PM 2.5 enhanced the oxidative stress by diminishing antioxidant enzyme activities in liver and serum, whereas contents of 4-hydroxynonenal (4-HNE), malondialdehyde (MDA) levels in liver and serum were elevated. These changes were accompanied by macrophage infiltration and activation of NF-κB pathway in the liver. Moreover, PM 2.5 exposure led to glucose intolerance and insulin insensitivity, impaired hepatic glycogenesis, and decreased insulin-stimulated Akt phosphorylation in peripheral tissues. Importantly, HT treatment prevented PM 2.5 -induced visceral adipogenesis, oxidative stress, hepatic inflammation and NF-κB activation, systemic and peripheral IR. In vitro, after HepG2 cells were incubated with PM 2.5 (0, 5, 25, 50, 100 and 200 μg/mL), reduced glutathione depletion and 4-HNE, 8-hydroxy-2'-deoxyguanosine, MDA increment in a dose-dependent manner were observed; likewise, insulin-stimulated glucose uptake decreased in a dose-dependent manner. Further, with antioxidant NAC and NF-κB inhibitor PDTC, we confirmed that HT attenuated PM 2.5 -induced IR through restraining NF-κB activation evoked by oxidative stress. In addition, HT could expand gut microbiota richness, reduce pathogenic bacteria and accommodate the microbial architecture in PM 2.5 -exposed mice, which were correlated with parameters of adiposity, oxidative stress and glycometabolism. HT could effectively correct imbalanced oxidative stress triggered by PM 2.5 , in turn ameliorated NF-κB pathway and insulin signaling. Gut microbiota may mediate the actions of HT. A schematic illustration of how HT interfered with PM 2.5 -induced oxidative stress and metabolic disorders in vivo and in vitro. vWAT, visceral white adipose tissue; scWAT, subcutaneous WAT; BAT, brown adipose tissue; PPARγ, peroxisome proliferator-activated receptor gamma; C/EBPα, CCAAT/enhancer-binding protein alpha; UCP1, uncoupling protein 1; COX2, cyclooxygenase 2; IL-1β, interleukin 1beta; TNFα, tumor necrosis factor alpha; GSK3β, glycogen synthase kinase 3β; GS, glycogen synthase; ↑indicates increase, ↓indicates decrease. Image 1 • Hydroxytyrosol alleviates PM 2.5 -induced visceral adiposity, oxidative stress, insulin resistance (IR), and gut dysbiosis. • Hydroxytyrosol mitigates hepatic IR through inhibiting NF-κB activation derived from oxidative stress induced by PM 2.5. • Modulation of gut microbiota may mediate the pharmacologic actions of orally administrated Hydroxytyrosol. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) is a principal organelle responsible for energy and nutrient management. Its dysfunction has been viewed in the context of obesity and related glucolipid metabolic disorders. However, therapeutic approaches to improve ER adaptation and systemic energy balance in obesity are limited. Thus, we examined whether hydroxytyrosol (HT), an important polyphenolic compound found in virgin olive oil, could correct the metabolic impairments in diet-induced obesity (DIO) mice. Here, we found that HT gavage for 10 weeks significantly ameliorated glucose homeostasis and chronic inflammation and decreased hepatic steatosis in DIO mice. At the molecular level, ER stress indicators, inflammatory and insulin signaling markers demonstrated that high-fat diet (HFD)-induced ER stress and insulin resistance (IR) in insulin sensitive tissue were corrected by HT. In vitro studies confirmed that HT supplementation (100 μM) attenuated palmitate-evoked ER stress, thus rescuing the downstream JNK/IRS pathway. As a result from suppression of ER stress in the liver, HT further decreased hepatic sterol regulatory element-binding protein-1 expression (SREBP1). Additionally, aberrant expression of genes involved in hepatic lipogenesis (SREBP1, ACC, FAS, SCD1) caused by HFD was restored by HT. These findings suggested that HT ameliorated chronic inflammation and IR and decreased hepatic steatosis in obesity by beneficial modulation of ER stress. [ABSTRACT FROM AUTHOR]

Aims Exercise is beneficial in obesity, however, the debate about the value of high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MICT) has been long lasting. Therefore, here we have compared the possible beneficial effects of two different exercise training regimes in a mouse model of diet-induced obesity (DIO). Materials and methods Following 7 wk. on high fat diet (HFD), ten-week-old male ICR mice ( n = 30) were assigned to HIIT, distance-matched MICT or remained sedentary for the next 8 constitutive weeks while maintaining the dietary treatments. Age-matched sedentary mice with standard diet were used as a control ( n = 10). Exercise was performed on a motorized treadmill for 5 days a week. Key findings Both modes of exercise ameliorated adiposity and related metabolic dysfunction induced by HFD and sedentary lifestyle, while mice following HIIT exhibited significantly lower body weight, percentage of fat mass and smaller adipocyte size. HIIT was more favorable in preventing liver lipid accumulation by restoring mRNA levels of genes involved in hepatic lipogenesis ( SREBP1 , ACC1 , FAS ) and β-oxidation ( PPARα , CPT1a , HAD ). In addition, HIIT was more efficient in mitigating adipose tissue inflammation and insulin insensitivity, partly dependent on abrogating phosphorylation of JNK/IRS1 (Ser307) pathway. Moreover, only HIIT led to pronounced beige adipocyte recruitment in inguinal subcutaneous adipose tissue. Significance We conclude that HIIT contribute a more favorable regulation of metabolic dysfunctions in DIO mice compared with MICT. [ABSTRACT FROM AUTHOR]

The adverse effects of bisphenol A (BPA) on learning and memory may be related with oxidative stress, but the mechanisms are unclear. This study aimed to investigate the mechanism of damaged learning and memory caused by BPA through inducing oxidative stress, as well as to explore whether alpha-lipoic acid (ALA) show a protective action. Female mice were exposed to 0.1 μg/mL BPA, 0.2 μg/mL BPA, 0.6 mg/mL ALA, and 0.2 BPA + ALA through drinking water for 8 weeks. The results showed that ALA protected against the impairment of spatial, recognition, and avoidance memory caused by BPA. ALA replenished the reduce of hippocampus coefficient, serum estradiol (E2) level, and hippocampal neurotransmitters levels induced by BPA. ALA alleviated BPA-induced oxidative stress and hippocampal histological changes. BPA exposure reduced the levels of synaptic structural proteins and PKC/ERK/CREB pathway proteins, and ALA improved these reductions. ALA altered the protein levels of nNOS and keap1/Nrf2 pathway affected by BPA. Our results suggested that impairments of learning and memory caused by BPA was related to the damage of hippocampal synapses mediated by oxidative stress, and ALA protected learning and memory by reducing the oxidative stress induced by BPA through regulating the nNOS and keap1/Nrf2 pathway. [Display omitted] • Exposure to BPA impaired learning and memory ability by causing synaptic damages. • The damages was due to oxidative stress mediated by nNOS and keap1/Nrf2 pathway. • ALA alleviated the impairments of BPA by protecting synapses from oxidative damage. • The protection of ALA was related to regulation of nNOS and keap1/Nrf2 pathway. [ABSTRACT FROM AUTHOR]

Cannabinoid receptor 2 (CB2R) is an important regulator of immunoinflammatory responses. Interestingly, studies have demonstrated that CB2R was expressed in metabolically active tissue, so we speculated that CB2R might have a crucial impact on energy balance. We thus examined the anti-inflammatory activities of CB2R and a CB2R agonist, JWH-133, in diet-induced obese in mice as well as in cultured macrophages. We evaluated the in vivo effect of JWH-133 on diet-induced adipose tissue inflammation. We also assessed the in vitro effects of JWH-133 on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages, with a focus on the nuclear factor E2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway. We found that JWH-133 reduced body weight gain, relieved glucose tolerance, and enhanced insulin sensitivity in a mouse model. It also down-regulated the expression of M1 macrophage biomarkers (tumor necrosis factor-α, interleukin (IL)-6, inducible nitric oxide synthase (iNOS), IL-1β, C C motif chemokine ligand 2, and C-X-C motif chemokine 10) in vivo and in vitro, but up-regulated levels of M2 macrophage biomarkers (IL-10 and arginase-1) in both mice and cultured macrophages. Furthermore, the underlying mechanisms were studied in an LPS-treated RAW264.7 cell line. We found a role for JWH-133 in controlling M1 macrophage polarization by activating the Nrf2/HO-1 pathway, while the effect of JWH-133 was diminished by a HO-1 inhibitor, Sn(IV) protoporphyrin IX dichloride. JWH-133 showed anti-obesity effects that ameliorated pro-inflammatory M1 macrophage polarization through the Nrf2/HO-1 pathway. Therefore, our results provide a new proof for the potential use of the CB2R agonist, JWH-133, in the treatment of obesity. • The present study revealed beneficial effects of JWH-133 on weight gain, glucose tolerance and insulin insensitivity; • JWH-133 orchestrate anti-inflammatory activities by regulating macrophage M1/M2 polarization via the Nrf2/HO-1 pathway; • CB2R may play a therapeutic role in obesity and associated metabolic disorders. [ABSTRACT FROM AUTHOR]