Diet-induced Obesity Research Articles

Lack of PTEN in osteocytes increases Lipocalin-2 level and confers resistance to high-fat diet-induced obesity in mice.

Osteocytes have been shown to play critical roles in the regulation of a wide range of metabolic processes. However, their role in the regulation of glucose metabolism remains to be determined despite accumulating evidence of the integral role of osteoblasts in this regulation, in which osteoblast-derived Lipocalin-2 (LCN2) has been shown to regulate glucose metabolism. Additionally, Lcn2 expression is induced by AKT activation. These results led us to hypothesize that AKT activation in osteocytes regulates glucose metabolism by modulating Lcn2 expression. Therefore, in this study, the Pten gene was deleted in osteocytes to activate AKT signaling by crossing Pten-flox mice with Dmp1-Cre mice (PtenOcy-/- mice). Deleting Pten expression in osteocytes resulted in osteocytic AKT activation, which was associated with decreased adipose tissue mass and enhanced insulin sensitivity. Expression of Pparg2 and lipogenesis-associated genes were decreased in the adipose tissue of PtenOcy-/- mice. Mechanistically, the lack of PTEN in osteocytes increased Lcn2 expression in the femur, which was associated with increased serum and urine LCN2 levels. The urinary LCN2 level was negatively associated with white adipose tissue mass. Additionally, the treatment of primary white adipocytes with recombinant LCN2 reduced the expression of Pparg2 and lipogenesis-related genes. These results suggest that the absence of PTEN in osteocytes increases the expression of Lcn2, which acts in the adipose tissue to suppress lipogenesis, resulting in enhanced insulin sensitivity in these mice. This study provides novel insights into the critical role of AKT activation in osteocytes in regulating glucose metabolism by increasing Lcn2 expression.

Early-life gut mycobiome core species modulate metabolic health in mice

The gut microbiome causally contributes to obesity; however, the role of fungi remains understudied. We previously identified three core species of the infant gut mycobiome (Rhodotorula mucilaginosa, Malassezia restricta and Candida albicans) that correlated with body mass index, however their causal contributions to obesity development are unknown. Here we show the effects of early-life colonization by these fungal species on metabolic health in gnotobiotic mice fed standard (SD) or high-fat-high-sucrose (HFHS) diets. Each species resulted in bacterial microbiome compositional and functional differences. R. mucilaginosa and M. restricta increased adiposity in mice fed SD, while only R. mucilaginosa exacerbated metabolic disease. In contrast, C. albicans resulted in leanness and resistance to diet-induced obesity. Intestinal nutrient transporter expression was unaffected by the presence of fungi in jejunal enteroids, yet the immune landscape in white adipose tissue was distinctly impacted by each fungal species, suggesting that these phenotypes may be a result of fungal immune regulation. This work revealed that three common fungal colonizers have distinct causal influences on obesity and metabolic inflammation and justifies the consideration of fungi in microbiome research on host metabolism.

Diet-induced obesity alters the ovarian chemical biotransformation and oxidative stress response proteins both basally and in response to 7,12-dimethylbenz[a]anthracene exposure.

7,12-dimethylbenz[a]anthracene (DMBA) is a polycyclic aromatic hydrocarbon (PAH) that causes female infertility via DNA damage, and the ovary has the capacity to mitigate DMBA exposure via the action of proteins including the glutathione S-transferase (GST) family. Due to previous findings of DNA damage and a reduced ovarian chemical biotransformation response to DMBA exposure in hyperphagia-induced obese mice, this study investigated the hypothesis that diet-induced obesity would hamper the ovarian biotransformative response to DMBA exposure. Six-week-old C57BL6/J mice were fed either a normal rodent diet (L) or a high fat high sucrose diet (O) until the O group was ∼30% heavier than the L. Both L and O mice were exposed to either corn oil (C) or DMBA (1 mg/kg) for 7 d. Liver weight was increased (P < 0.05) in obese mice exposed to DMBA but no effect on spleen weight, uterine weight, ovary weight, estrous cyclicity, or circulating 17β-estradiol and progesterone were observed. Primordial and preantral follicle numbers were higher (P < 0.05) in the obese mice and there was a tendency (P = 0.055) for higher antral follicles in DMBA-exposed obese mice. The ovarian proteome was identified by LC-MS/MS analysis to be altered both by diet-induced obesity and by DMBA exposure with changes observed in levels of proteins involved in oocyte development and chemical biotransformation, including GST isoform pi. Fewer proteins were affected by the combined exposure of diet and DMBA than by a single treatment, indicating that physiological status impacts the response to DMBA exposure.

Obesity drives dysregulation in DC responses to viral infection

Abstract Introduction Obesity is a worldwide epidemic, with over 1 billion people worldwide living with obesity. It is associated with an increased risk of over 200 chronic co-morbidities, including an increased susceptibility to infection. Numerous studies have highlighted the dysfunction caused by obesity on a wide range of immune cell subsets, including dendritic cells (DCs). DCs are innate immune sentinels which bridge the innate and adaptive immune systems. DCs provide critical signals which instruct and shape the immune response. Our group has previously reported that DCs from people with obesity (PWO) display defective cytokine production, however the mechanisms underpinning these defects are unclear. Methods We investigated the functional responses of DCs using a murine-specific single-stranded RNA virus, Sendai virus (SeV), in mice on a standard diet and in a model of diet-induced obesity (DIO). Results Here, we demonstrate that GM-CSF cultured bone marrow-derived DCs (GM-DCs) from mice on a high fat diet (HFD) have reduced cytokine production following viral challenge. This was associated with a dysfunctional metabolism through reduced translation in the HFD GM-DCs. Conclusion We propose that obesity-mediated effects on DCs have downstream consequences on their ability to effectively mediate subsequent immune responses, especially during viral infection.

Linoleic acid metabolism is implicated in the anti-obesity effects of actein in C57BL/6 mice.

Natural products are known to be a rich source of potential compounds for metabolic diseases. In this study, we aim to identify the lead compounds with anti-adipogenic and anti-obesity effects in Cimicifuga foetida L. (CF). Five high-content chemicals from ethyl acetate-(EtOAc) extract of CF (ECF) were isolated to investigate their effects on adipogenesis in 3 T3-L1 preadipocytes. Actein is identified to possess substantial anti-adipogenic activity in 3 T3-L1 adipocytes, which exerts its anti-adipogenic effect throughout the entire adipocyte differentiation stages. Dietary actein ameliorates diet-induced obesity, improves the disturbed serum lipid levels, and enhances white fat browning in diet-induced obese mice. Metabolomic analysis using urine and serum samples from mice revealed that actein treatment reverses the dysregulation of γ-linolenic acid and lecithin in obese mice, thus ameliorating the disturbance of linoleic acid metabolism induced by high-fat diet, suggesting that actein can be used as a lead compound with the potential to develop new therapies for obesity and related metabolic disorders.

Acute and long-term transcriptomic responses of granulosa cells to obesogenic diet and concomitant effects on oocyte quality: insight from an outbred mouse model.

Diet-induced obesity can alter ovarian functions after long-term high-fat high-sugar (HFHS) diet feeding. However, the acute impact of obesogenic diets on the follicular cells, and how this impact evolves over time when intake is continued and obesity develops, is not known. Our aim was to determine the onset and progression of changes in the granulosa cell (GC) transcriptomic profile after starting a HFHS-diet feeding in mice. We also examined the changes in oocyte lipid droplet content (LDC) and mitochondrial ultrastructural abnormalities. Swiss (outbred) mice were sacrificed at 24h, 3days, and at 1, 4, 8, 12 and 16 wks of feeding HFHS and control diets. LDC significantly increased in the HFHS oocytes already after 24h compared to controls (P < 0.05). Oocyte mitochondrial abnormalities only increased starting from 8wks. Granulosa RNA-seq revealed altered transcriptomic gene-set enrichments (GO-terms and KEGG pathways, P adj < 0.05) already at 3d and 1wk indicating acute endoplasmic-reticulum unfolded-protein responses, with concomitant fluctuations in several cellular metabolic pathways and gene-sets related to mitochondrial bioenergetic functions, some of which persisted after 8wks. Interestingly the short- and long-term patterns of changes in cytochrome P450, steroid hormone biosynthesis, retinol metabolism, bile acid metabolism, fatty acid metabolism and Pi3K/Akt signaling pathways were most prominent and highly correlated; all being acutely upregulated, then chronically downregulated. These results show that the impact of obesogenic diet on the oocyte and granulosa cells is prompt, while the response depends on the duration of feeding and occurs in a multiphasic cascade together with a progressive deterioration in oocyte quality.

Malícia honey (Mimosa quadrivalvis L.) produced by the jandaíra bee (Melipona subnitida D.) shows antioxidant activity via phenolic compound action in obese rats

Background and aimsObesity is a disease associated with increased oxidative stress in humans and animals, and consumption of antioxidant compounds such as polyphenols can minimise it. These compounds are abundant in malícia (Mimosa quadrivalvis L.) honey produced by stingless bees. This study aimed to evaluate whether administration of Mimosa quadrivalvis L. honey to obese rats could reduce oxidative stress in vital organs through phenolic compound action.MethodsWistar rats (228 ± 14.69 g) were randomly divided into two groups: a healthy group (HG, n = 20) fed a control diet and an obese group (OG, n = 20) fed a cafeteria diet for the initial 8 weeks. After this period, these groups were again randomised into four subgroups: healthy (HG, n = 10), obese (OG, n = 10), healthy with malícia honey administration (1,000 mg/kg; HGH, n = 10), and obese with malícia honey administration (1,000 mg/kg; OGH, n = 10) for the final 8 weeks fed the previously mentioned diets. The rats were euthanised at the end of the experiment to collect brain, gut, kidney, and liver tissues to evaluate parameters related to oxidative stress and phenolic profile.ResultsThe administration of malícia honey reduced energy intake and weight gain in the OGH in comparison to the OG. Total antioxidant capacity increased in the brain, liver, and gut in both groups treated with honey compared to respective controls. Lipid peroxidation decreased in the brain, gut, and kidney of the OGH. Both treated groups showed elevated phenolic compound deposition, including catechin, procyanidins, and flavonoids, across all organs. Specifically, the brain in the OGH showed greater procyanidin B2 and gallic acid deposition; the liver showed increased procyanidin B1 and B2, epicatechin, and myricetin concentrations; the gut showed higher procyanidin B2 and kaempferol 3-glucoside concentrations; and the kidneys had increased catechin, procyanidin B1 and B2, and gallic acid deposition compared to the OG.ConclusionHistologically, the OGH displayed reduced neuronal damage and prevention of hepatic steatosis induced by the cafeteria diet. Malícia honey effectively reduced oxidative stress via modulation of phenolic compounds in the brain, gut, kidney, and liver of cafeteria diet-induced obese rats.

Machine learning prediction of obesity-associated gut microbiota: identifying Bifidobacterium pseudocatenulatum as a potential therapeutic target

BackgroundThe rising prevalence of obesity and related metabolic disorders highlights the urgent need for innovative research approaches. Utilizing machine learning (ML) algorithms to predict obesity-associated gut microbiota and validating their efficacy with specific bacterial strains could significantly enhance obesity management strategies.MethodsWe leveraged gut microbiome data from 1,563 healthy individuals and 2,043 overweight patients sourced from the GMrepo database. We assessed the anti-obesity effects of Bifidobacterium pseudocatenulatum through experimentation with Caenorhabditis elegans and C3H10T1/2 cells.ResultsOur analysis revealed a significant correlation between gut bacterial composition and body weight. The top 40 bacterial species were utilized to develop ML models, with XGBoost demonstrating the highest predictive accuracy. SHAP analysis indicated a negative association between the relative abundance of six bacterial species, including B. pseudocatenulatum, and body mass index (BMI). Furthermore, B. pseudocatenulatum was shown to reduce lipid accumulation in C. elegans and inhibit lipid differentiation in C3H10T1/2 cells.ConclusionBifidobacterium pseudocatenulatum holds potential as a therapeutic agent for managing diet-induced obesity, underscoring its relevance in microbiome-based obesity research and intervention.

Leptin receptor downregulation in the carotid body treats obesity-induced hypertension.

Obesity and co-morbid sleep disordered breathing lead to high cardiovascular morbidity and mortality via multiple mechanisms including hypertension. Obesity also leads to high levels of leptin, which is produced in adipocytes. Increased leptin levels have also been implicated in increased sympathetic activity and the pathogenesis of hypertension in obesity. However, mechanisms for the effects of leptin on blood pressure are unclear. The carotid bodies (CB) express leptin receptor (Leprb), and diet-induced obesity (DIO) increases Leprb expression levels, but the mechanisms and consequences of leptin action in CB are poorly understood. We hypothesize that leptin signaling in CB in obesity leads to hypertension, which can be treated by Leprb knockdown specifically in CB. DIO male and female mice and lean male C57BL/6J mice were implanted with telemetry in the left femoral artery for continuous blood pressure monitoring. The adenoviral vectors carrying anti-sense RNA, Ad-LepR shRNA or Ad-scrambled control shRNA, were administered locally to the CB region. Blood pressure measurements were performed at baseline and 9-11 days after CB infection with the adenoviral vector. DIO male mice showed increased blood pressure compared to lean males and DIO females. Ad-LepR shRNA induced a 2-fold decrease in Leprb mRNA level in CB and abolished obesity-induced hypertension. Leprb knockdown was particularly effective during the light phase, when animals were predominantly asleep, decreasing mean arterial pressure by 8.5 mmHg. Control shRNA had no effect on DIO-induced hypertension. We conclude that inhibition of Leprb in the carotid bodies abolished obesity-induced hypertension.

Gut Bacteria-Derived Tryptamine Ameliorates Diet-Induced Obesity and Insulin Resistance in Mice

Tryptophan is an essential amino acid that is metabolized in the intestine by gut bacteria into indole derivatives, including tryptamine. However, little is known about which bacterial tryptophan metabolites directly influence obesity. In this study, we identified tryptamine as a bacterial metabolite that significantly reduced fat mass following the intraperitoneal injection of five bacterial tryptophan end-products in a diet-induced obese mouse model. Interestingly, tryptamine, a serotonin analog, inhibited both lipogenesis and lipolysis in adipose tissue, which was further confirmed in a 3T3-L1 adipocyte cell culture study. Moreover, oral tryptamine supplementation markedly reduced fat mass and improved insulin sensitivity in a long-term, high-fat-diet, pair-feeding model. These studies demonstrate the therapeutic potential of tryptamine, a bacterial tryptophan metabolite, in ameliorating obesity and insulin resistance by directly regulating lipogenesis and lipolysis in white adipose tissue.

Effects of celastrol on the heart and liver galaninergic system expression in a mouse model of Western-type diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis

BackgroundThe complexity of the galaninergic system is still not fully understood, especially under specific pre-existing comorbidities related to metabolic dysfunction. A plant-derived triterpenoid celastrol was demonstrated to exert a complex effect on the galaninergic system and to have hepatoprotective and anti-obesity properties. However, the exact molecular mechanisms responsible for these effects remain unclear. Specifically, there are no data on the impact of celastrol on the heart and liver galaninergic system. Therefore, this study aimed to investigate the effects of celastrol on the galaninergic system expression in the heart and liver of mice suffering from diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH).MethodsThe male mice C57BL/6J were fed a Western-type high-fat diet for 16 and 20 weeks to induce obesity and MASLD/MASH. Celastrol was administered along with a specific diet for the last 4 weeks to evaluate its impact on the progression of these conditions. Moreover, the inhibitor of sterol regulatory element-binding protein 1/2 (SREBP1/2), fatostatin, was also tested to compare its influence on the galaninergic system with celastrol.ResultsThe study demonstrates that celastrol treatment was safe and led to a reduction in food and energy intake, body fat and liver weights, and MASLD-to-MASH progression and improved glucose tolerance, serum biochemistry markers, and hepatic lipid peroxidation in mice. Quantitative gene expression originally showed significant regulation of galanin and all three of its receptors (GalR1/2/3) in the heart ventricles and only GalR2 in the liver of obese mice. Celastrol influenced the gene expression of galanin receptors: it downregulated Galr1 in the heart and upregulated Galr2 in the liver and Galr3 in the heart ventricles, potentially affecting energy metabolism, oxidative stress, and inflammation. Fatostatin suppressed gene expression of all the detected members of the galaninergic system in the heart ventricles, depicting the role of SREBP in this process.ConclusionThese findings suggest that celastrol may beneficially modulate the galaninergic system under obesity and MASLD-to-MASH progression, indicating its potential as a therapeutic agent for disorders associated with metabolic dysfunction.

Hypothalamic Estrogen Receptor α Is Essential for Female Marmoset Sexual Behavior Without Protecting From Obesity.

Estrogen receptor α (ERα) in the ventromedial (VMN) and arcuate (ARC) nuclei of female rodent mediobasal hypothalami (MBHs) provides a crucial molecular gateway facilitating estradiol (E2) regulation of sexual behavior, reproductive neuroendocrinology, and metabolic function. In female nonhuman primates (NHPs) and women, however, its hypothalamic counterpart remains unknown. We hypothesized that knockdown (KD) of ERα expression in the hypothalamic VMN and ARC of female marmosets would diminish sexual receptivity, while simultaneously disrupting gonadotropic and metabolic homeostasis. We ovariectomized (OVX) adult female marmosets of comparable age and weight, immediately replaced E2 at midcycle levels, and approximately 1 month later assigned monkeys to diet-induced obesity (DIO) within group (1) control, receiving scrambled short hairpin RNA (shRNA), or (2) ERαKD, receiving selective ERα gene silencing shRNA. Magnetic resonance imaging-guided neural surgery enabled hypothalamic infusion of viral vector shRNA and subsequent brain immunohistochemistry enabled observer-validated, NIS-elements computer software quantification of ERα knockdown. ERα expression was significantly diminished in the VMN and ARC, but not the preoptic area (POA), of ERαKD females coincident with elimination of timely female sexual responses, more than 80% loss of female receptivity, modestly elevated gonadotropin levels, hyperglycemia, and diminished calorie consumption. Density and intensity of ERα-expressing cells in the VMN correlated positively with female sexual receptivity and calorie consumption, negatively with timeliness of female sexual responses, and in the ARC, correlated negatively with calorie consumption. ERα activation in the female NHP MBH is critically important for female sexual behavior and modestly contributes to gonadotropic and metabolic control.

Alternate-day fasting enhanced weight loss and metabolic benefits over pair-fed calorie restriction in obese mice.

Both alternate-day fasting (ADF) and calorie restriction (CR) are effective weight loss strategies. However, most individuals find it difficult to adhere to CR. Furthermore, CR can induce an excessive loss of not only fat but also muscle mass. This study aimed to compare the effects of ADF and pair-feeding (PF) CR on metabolic pathways underlying obesity in mice with high-fat diet (HFD)-induced obesity. Male C57BL/6N Tac mice (n = 10 per group) were fed an HFD for 8 weeks to establish a diet-induced obesity model. Mice were then continued on the HFD with either alternate-day access to food or PF for the next 8 weeks. We measured body weight, adiposity, plasma biomarkers, and molecular mechanisms involving lipolysis and autophagy. Both ADF and PF resulted in comparable weight and fat loss. Compared with PF, ADF showed a significant reduction in liver weight and hepatic triglyceride levels. ADF significantly increased plasma ketone body levels and white adipose tissue lipolysis. Compared with PF, ADF tended to activate autophagy elongation and autophagosome formation, which were insignificant. These findings indicated that ADF is a promising intervention for metabolic diseases, potentially due to its superior efficacy in promoting ketogenesis and lipolysis compared with PF.

Evaluating Anti-Diabetic Effect of Courmarin Derivative Aesculetin in Rats with Diet-Induced Obesity.

Obesity, modifiable and an avertable medical condition, has become a global threat due to rapid modernization and industrialization. Swift growth in modernization not only eases the day-to-day life, it also mandates sedentary lifestyle, which leads to various noncommunicable diseases. At present one in eight people in global population are obese, and these booming obese individuals are prone to various other micro- and macrovascular diseases such hyperglycemia, myocardial infraction, hypertension, stroke, and so forth. Ample research had unveiled an intricate association perceived between obesity and Type 2 diabetes mellitus pathogenesis. Although the intake of anti-obesity drugs along with anti-diabetic drugs had effectively regulated the hyperglycemic conditions in diabetic patients, it causes various side effects on long-term usage. Coumarins are phytochemicals that have demonstrated pharmacological properties including anti-inflammatory, antioxidant, anti-tumor, and so forth. In this analysis, we assessed anti-obesity and anti-diabetic potency of aesculetin, a courmarin derivative. The rats were induced obesity with high-fat diet and subjected to streptozotocin infusion to induce hyperglycemia. Obese diabetic induced rats were treated with aesculetin and assessed for its anti-diabetic effect. BMI were assessed in the rats to analyze the anti-obesity effect of aesculetin. Diabetic profile test and lipid profile test were performed to evaluate the anti-diabetic effect of aesculetin. Ameliorative effect of aesculetin in obese rats during hyperglycemic conditions was assessed with renal profile test, hepatic function biomarkers, and by histopathological analysis of cardiac tissue. The anti-inflammatory and antioxidant property were also assessed to determine the mechanism of action of aesculetin. To confirm the anti-obesity potency of aesculetin, adipokines levels were estimated. Aesculetin eminently decreased the BMI, HbA1c, cholesterol levels, and intensified secretion of insulin in obese diabetic rats. It also regulated the renal, hepatic functional markers and prevented cardiac tissue injury in obese diabetic rats. It regulated the adipokines, increased antioxidants, and decreased level of proinflammatory cytokines, thereby prevented obesity-induced hyperglycemic effects in rats. To conclude, our findings had confirmed the supplementary intake of aesculetin prevents obesity-induced hyperglycemic disorder in rats.

Diet-induced Obesity: Pathophysiology, Consequences and Target Specific Therapeutic Strategies.

Diet has emerged as a pivotal factor in the current time for diet-induced obesity (DIO). A diet overloaded with fats and carbohydrates and unhealthy dietary habits contribute to the development of DIO through several mechanisms. The prominent ones include the transition of normal gut microbiota to obese microbiota, under-expression of AMPK, and abnormally high levels of adipogenesis. DIO is the root of many diseases. The present review deals with various aspects of DIO and its target proteins that can be specifically used for its treatment. Also, the currently available treatment strategies have been explored. It was found that the expression of five proteins, namely, PPARγ, FTO, CDK4, 14-3-3 ζ protein, and Galectin-1, is upregulated in DIO. They can be used as potential targets for drug-designing studies. Thus, with these targets, the treatment strategy for DIO using natural bioactive compounds can be a safer alternative to medications and bariatric surgeries.

IGF1 enhances memory function in obese mice and stabilizes the neural structure under insulin resistance via AKT-GSK3β-BDNF signaling.

Obesity is a prevalent metabolic disorder linked to insulin resistance, hyperglycemia, increased adiposity, chronic inflammation, and cognitive dysfunction. Recent research has focused on developing therapeutic strategies to mitigate cognitive impairment associated with obesity. Insulin growth factor-1 (IGF1) deficiency is linked to insulin resistance, glucose intolerance, and the progression of obesity-related central nervous system (CNS) disorders. In this study, we investigated the neuroprotective effects of IGF1 in two obesity models: diet-induced obesity (high-fat diet mice) and genetic obesity (ob/ob mice which is genetically deficient in leptin), and in vitro Neuro2A neuronal cells and primary cortical neurons under insulin resistance conditions. We performed RNA sequencing analysis using the cortex of high-fat diet mice injected with IGF1. Also, we detected cytokine levels in blood of high-fat diet mice injected with IGF1. In addition, we conducted the Barnes maze test as a spatial memory function test and open field test as an anxiety behavior test in ob/ob mice. We measured the levels of proteins and mRNAs related to insulin signaling, including synaptic density proteins in brain cortex of ob/ob mice. Our results showed that IGF1 injection enhanced spatial memory function and synaptic plasticity in obese mice. Furthermore, in vitro data demonstrated that IGF1 treated neurons revealed enhanced neural complexity and improved neurite outgrowth under insulin resistance condition through the AKT-GSK3β-BDNF pathway related to antidepressant, cognitive function and anti-apoptotic mechanisms. Therefore, our results provided that IGF1 have potential to alleviate cognitive impairment by promoting synaptic plasticity and neural complexity in the obese brain.

Abstract TMP109: Remote Ischemic Conditioning Treatment: A Study Report on Animal Stroke Model in Different Species, Sex, Age and Comorbidities from the Stroke Preclinical Assessment Network (SPAN)

Background: The Stroke Preclinical Assessment Network (SPAN), a multi-center network consisting of a coordinating center and testing laboratories, was created to enhance the rigor of preclinical research, including testing of potential therapies in animals of different species, sex, age, and co-morbidities, with blinding and randomization. SPAN evaluated six potential therapies with the goal of identifying one or more efficacious agents to advance toward a clinical trial. Remote ischemic post-conditioning (RIC) was selected as a candidate therapy for testing. Methods: In Stage I, young, healthy mixed-sex mice were randomized into treatment groups by the coordinating center. In Stage II, aged mice, mice with high-fat diet-induced obesity, and spontaneously hypertensive rats were utilized. Each stage included 25% of the study population and efficacy/futility was determined after each stage. RIC was bilaterally administered as the first session occurred immediately after reperfusion, and the second session occurred as close as possible to 12 ± 2 hours at post-MCAo, using an automated blood pressure cuff that delivered 200-mmHg to the hindlimbs for 4 cycles x 5 minutes/cycle and then once per day x 5 days under anesthesia. Sham-conditioned animals were treated with a cuff that did not inflate. The primary outcome measure was a modified corner test on days 7 and 30 post-stroke. MRI was performed at 48 hours and 30 days. Probabilistic index models, which adjusted for covariates of interest, were fit to estimate the probability of a lower corner test index (better outcome) between sham and RIC. Results: A total of 266 mice (132 sham, 134 RIC) were enrolled in the study, with 50 sham and 51 RIC-treated mice dying within 5 days of stroke. Analysis of all data revealed no significant differences in day 30 alternative corner test index between sham and RIC-treated mice after stroke in young, healthy mice (p=0.449), aged mice (p=0.079), mice with diet-induced obesity (p=0.135), or in spontaneously hypertensive rats (p=0.807). The secondary analysis found that RIC improved day 30 tissue infarction volume by MRI in young, healthy mice (p=0.024 vs. sham) but not in other co-morbid conditions. Conclusions: After advancing through Stages I and II, RIC was deemed futile at the end of Stage II, as determined by the modified corner test on day 30. The requirement for repeated daily general anesthesia during RIC administration may have been a complicated factor.

Nicotinamide Phosphoribosyltransferase Acetylation Mediating Muscle Dysfunction Contributes to Sleep Apnoea in Obesity.

Obstructive sleep apnoea (OSA) occurs frequently among individuals with obesity, which is attributed to upper airway muscle dysfunction. Muscle function is regulated by the dynamic balance of the nicotinamide adenine dinucleotide (NAD+) and its reduced form (NADH), which is controlled by the enzyme nicotinamide phosphoribosyltransferase (NAMPT). Elevated NAMPT levels have been found in individuals with obesity. However, the role of NAMPT in obesity-induced muscle impairment has not been fully clarified. A total of 110 participants (70 moderate-to-severe OSA vs. 40 mild or no OSA) underwent electrical impedance mammography and polysomnography. C57BL/6J mice with high-fat diet-induced obesity (DIO) and control group were utilized for their characterizations, which included forced running wheel tests, glucose tolerance tests, haematoxylin and eosin staining, immunostaining, magnetic resonance imaging, whole-body plethysmography, electromyographic techniques, western blot, NAMPT enzymatic activity assays and NAD+/NADH ratio measurements. Patients with moderate-severe OSA have a significant decrease in lean mass percentage of upper airway muscles compared with those in controls (p < 0.01). Invivo, a high-fat diet reduced the levels of NAD-dependent deacetylase sirtuin-1 (SIRT1) (p < 0.01), which plays a crucial role in the deacetylation of NAMPT. The reduction in SIRT1-mediated NAMPT deacetylation (p < 0.001) resulted in decreased NAMPT activity (p < 0.01), leading to a decrease in NAD+/NADH ratio (p < 0.05) and decreased the myosin heavy chain isoform (MyHC) I level (p < 0.05), thereby affecting the effectiveness of upper airway muscle and ultimately leading to upper airway collapse (101.0 vs. 81.7 pixels, p = 0.02). The introduction of estradiol mitigated high-fat diet-induced muscle dysfunction by enhancing expression of SIRT1 and inhibiting the acetylation of NAMPT, reducing upper airway collapse (81.7 vs. 96.7 pixels, p = 0.06). These findings highlight the crucial role of SIRT1-mediated NAMPT deacetylation on obesity-induced muscle dysfunction, suggesting targeting NAMPT has the potential to reverse the obesity induced muscle dysfunction and provide effective treatment options for OSA.

Investigation of calonysterone and 20-hydroxyecdysone effects in high-fat, high-sugar diet-induced obesity rat model

Investigation of calonysterone and 20-hydroxyecdysone effects in high-fat, high-sugar diet-induced obesity rat model

Faecalibacterium longum alleviates high-fat diet-induced obesity and protects the intestinal epithelial barrier in mice

<i>Faecalibacterium longum</i> alleviates high-fat diet-induced obesity and protects the intestinal epithelial barrier in mice