Obese Model Research Articles

Altered hippocampal effective connectivity predicts BMI and food approach behavior in children with obesity.

The vicious circle model of obesity proposes that the hippocampus plays a crucial role in food reward processing and obesity. However, few studies focused on whether and how pediatric obesity influences the potential direction of information exchange between the hippocampus and key regions, as well as whether these alterations in neural interaction could predict future BMI and eating behaviors. In this longitudinal study, a total of 39 children with excess weight (overweight/obesity) and 51 children with normal weight, aged 8 to 12, underwent resting-state fMRI. One year later, we conducted follow-up assessments of eating behaviors and BMI. Resting-state functional connectivity and spectral dynamic casual modeling (spDCM) technique were used to examine altered functional and effective connectivity (EC) of the hippocampus in children with overweight/obesity. Linear support vector regression, a machine learning method, was employed to further investigate whether these sensitive hippocampal connections at baseline could predict future BMI and eating behaviors. Compared to controls, children with excess weight displayed abnormal bidirectional inhibitory effects between the right hippocampus and left postcentral gyrus (PoCG), that is, stronger inhibitory hippocampus→PoCG EC but weaker inhibitory PoCG→hippocampus EC, which further predicted BMI and food approach behavior one year later. These findings point to a particularly important role of abnormal information exchange between the hippocampus and somatosensory cortex in pediatric obesity and future food approach behavior, which provide novel insights into the neural hierarchical mechanisms underlying childhood obesity and further expand the spDCM model of adult obesity by identifying the directionality of abnormal influences between crucial circuits associated with appetitive regulation.

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.

NFAT5 exacerbates β-cell ferroptosis by suppressing the transcription of PRDX2 in obese type 2 diabetes mellitus

Pancreatic β-cell damage is a critical pathological mechanism in the progression of obese type 2 diabetes mellitus (T2DM). However, the exact underlying mechanism remains unclear. We established an obese T2DM mouse model via high-fat diet feeding. The protein expression profiles of pancreatic tissues from normal and obese T2DM mice were analyzed, revealing that nuclear factor of activated T cells 5 (NFAT5) and ferroptosis are potential mediators and mechanisms of β-cell damage in obese T2DM mice. In vitro, high glucose and palmitate treatment resulted in increased NFAT5 expression and nuclear translocation in MIN6 cells. Inhibition of NFAT5 expression by shRNA significantly reduced ferroptosis and improved the reduction in insulin secretion in palmitic acid and high glucose (PG)-treated MIN6 cells. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays confirmed the ability of NFAT5 to bind to the peroxiredoxin 2 (PRDX2) promoter, leading to the downregulation of PRDX2 transcription. Subsequent rescue experiments confirmed that NFAT5 is involved in PG-induced ferroptosis in MIN6 cells by inhibiting the expression of PRDX2. Finally, we demonstrated that the use of the AAV8-RIP2-miR30-shNFAT5 vector to specifically inhibit the expression of NFAT5 in β-cells significantly diminishes ferroptosis in obese T2DM mice, thereby increasing insulin secretion and improving abnormal glucose tolerance. These findings collectively highlight the therapeutic potential of targeting NFAT5 in β cells to counteract obesity-induced T2DM.

Discovery of 1,4-Disubstituted Cyclohexene Analogues as Selective GPR119 Agonists for the Treatment of Type 2 Diabetes.

GPR119 has emerged as a promising target for treating type 2 diabetes and associated obesity, as its stimulation induces the secretion of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide in the intestinal tract as well as the glucose-dependent release of insulin in pancreatic β-cells. We describe the design and synthesis of novel GPR119 agonists containing a 1,4-disubstituted cyclohexene scaffold. Compound 21b displayed nanomolar potency (EC50 = 3.8 nM) for hGPR119 activation and demonstrated a hypoglycemic efficacy of 17.0% in an oral glucose tolerance test. The hypoglycemic effect of compound 21b, compared to sitagliptin, a DPP-4 inhibitor, showed the relatively higher efficacy in both FATZO and db/db mice. Additionally, compound 21b exhibited a significant reduction in body weight in a female diet-induced obese rat model, comparable to that of metformin. Furthermore, in vivo pharmacokinetic experiments revealed that compound 21b is a potential candidate for the treatment of type 2 diabetes and obesity.

Comparison of Lean, Obese, and Weight Loss Models Reveals TREM2 Deficiency Attenuates Breast Cancer Growth Uniquely in Lean Mice and Alters Clonal T Cell Populations.

Obesity is an established risk factor for breast cancer development and poor prognosis. The adipose environment surrounding breast tumors, which is inflamed in obesity, has been implicated in tumor progression, and TREM2, a transmembrane receptor expressed on macrophages in adipose tissue and tumors, is an emerging therapeutic target for cancer. A better understanding of the mechanisms for the obesity-breast cancer association and the potential benefits of weight loss could help inform treatment strategies. Here, we utilized lean, obese, and weight loss mouse models to examine the impacts of TREM2 deficiency (Trem2+/+ and Trem2-/-) on postmenopausal breast cancer depending on weight history conditions. Trem2 deficiency constrained tumor growth in lean, but not obese or weight loss, mice. Single-cell RNA sequencing, in conjunction with VDJ sequencing of tumor and tumor-adjacent mammary adipose tissue (mATTum-adj) immune cells, revealed differences in the immune landscapes across the different models. Tumors of lean Trem2-/- mice exhibited a shift in clonal CD8+ T cells from an exhausted to an effector memory state, accompanied increased clonality of CD4+ Th1 cells, that was not observed in any other diet-genotype group. Notably, identical T cell clonotypes were identified in the tumor and mATTum-adj of the same mouse. Finally, anti-PD-1 therapy restricted tumor growth in lean and weight loss, but not obese, mice. These findings indicate that weight history could impact the efficacy of TREM2 inhibition in postmenopausal breast cancer. The reported immunological interactions between tumors and the surrounding adipose tissue highlight significant differences under obese and weight loss conditions.

Obesity increases DNA damage in the breast epithelium

Obesity is a modifiable risk factor for breast cancer. Yet, how obesity contributes to cancer initiation is not fully understood. The goal of this study was to determine if the body mass index (BMI) and metabolic hallmarks of obesity are related to DNA damage in normal breast tissue. In a mouse model of diet-induced obesity, weight gain was associated with elevated levels of DNA double-strand breaks in the mammary gland. We also found a positive correlation between BMI and DNA breaks in the breast epithelium of premenopausal women (but not postmenopausal women). High BMI was associated with elevated systemic and tissue-level oxidative DNA damage across the lifespan, and we propose that the breast epithelium undergoing menstruous proliferation waves is particularly prone to the generation of DNA breaks from oxidative lesions. Ancestry was an important modulator of the obesity-DNA break connection. Compared to non-Hispanic Whites, women identifying as African Americans had higher levels of DNA breaks, as well as elevated leptin and IGF-1. In 3D cultures of breast acini, both leptin and IGF-1 caused an accumulation of DNA damage. The results highlight a connection between premalignant genomic alterations in the breast epithelium and metabolic health modulated by obesity and ancestry. They call for attention on biological determinants of breast cancer risk disparities.

Targeting IGF1 to alleviate obesity through regulating energy expenditure and fat deposition.

Insulin-like growth factor 1 (IGF1) is a regulator of both cellular hypertrophy and lipogenesis, which are two key processes for pathogenesis of obesity. However, the in vivo role of IGF1 in the development of obesity remains unclear. Here, we show that IGF1 expression is increased in adipose tissue in obese human patients and animal models. Elevation of IGF1 is associated with increased lipogenic gene expression and decreased energy expenditure. Genetic down-regulation of IGF1 normalizes lipogenic gene expression, restores aberrant energy metabolism and alleviates obese phenotype of a genetic mouse model with IGF1-hypersecretion. Importantly, genetic down-regulation of IGF1 exerts similar effects on development of diet-induced obesity. Furthermore, berberine that is an AMP-activated protein kinase (AMPK) activator in medicinal herbs inhibits IGF1 secretion, decreases lipogenic gene expression and alleviates diet-induced adiposity. Collectively, our findings demonstrate that hypersecretion of IGF1 is a critical factor for the development of obesity and can be targeted using AMPK activators to alleviate obesity.

Tacrolimus and diabetic rodent models.

Tacrolimus (TAC) is an immunosuppressant widely utilized in organ transplantation. One of its primary adverse effects is glucose metabolism disorder, which significantly increases the risk of diabetes. Investigating the molecular mechanisms underlying TAC-induced diabetes is essential for developing effective prevention and treatment strategies for these adverse effects. In addition, TAC can induce cost-effective, non-obese animal models of diabetes, where the metabolic parameter changes closely resemble those observed during the onset and progression of type 2 diabetes (T2DM), post-transplantation diabetes mellitus (PTDM), and associated complications. This review, based on articles indexed in PubMed up to August 19, 2024, identified 48 studies focusing on TAC-induced diabetic rodent models and 22 studies exploring the effects of TAC on diabetic or obese rodent models. These studies were systematically summarized based on TAC dosage, route of administration, duration of administration, and glucose metabolism indices used for evaluation. Additionally, the impact of TAC dose reduction or discontinuation on glucose metabolism was assessed, along with pharmacological agents that modulate TAC-induced diabetes, including anti-diabetic medications, anti-inflammatory and antioxidant compounds, biologics, and antibiotics. Key signaling pathways implicated in TAC-induced diabetes include CaN/NFAT, PI3K/AKT/mTOR, and TGF-β/Smad, all of which impair islet β-cell function, thereby contributing to diabetes development. This review provides a concise summary of the characteristics of relevant murine models, offering valuable guidance for selecting appropriate and economical animal models for future research.

Isocaloric high-fat diet decreases motivation in the absence of obesity.

Obesogenic diets induce persistent changes in physical activity and motivation. It remains unclear whether these behavioral changes are driven by weight gain or exposure to obesogenic diets themselves. We investigated how exposure to a high-fat diet (HFD) in the absence of obesity affected physical activity, food motivation, and circadian patterns in mice. C57Bl6/J mice were given ~80% of their daily calories in an HFD, known as isocaloric feeding, along with ad libitum access to laboratory chow. Weekly weights, physical activity levels, circadian patterns, operant behavior, and peripheral blood metabolic markers were measured to determine how an isocaloric HFD affected behavior and physiology. Following this period, the same cohort was exposed to an ad libitum HFD to monitor changes in weight gain and physical activity. An isocaloric HFD did not significantly increase weight or change physical activity levels. An isocaloric HFD decreased motivation for sucrose pellets but did not alter weight gain with ad libitum HFD exposure. An isocaloric HFD was associated with decreased motivation for sucrose, as observed in reports of rodent models of obesity. These findings suggest that exposure to an obesogenic diet, even in the absence of significant weight gain, can induce behavioral changes associated with obesity.

Impact of protein intake from a caloric-restricted diet on liver lipid metabolism in overweight and obese rats of different sexes

In addition to being linked to an excess of lipid accumulation in the liver, being overweight or obese can also result in disorders of lipid metabolism. There is limited understanding regarding whether different levels of protein intake within an energy-restricted diet affect liver lipid metabolism in overweight and obese rats and whether these effects differ by gender, despite the fact that both high protein intake and calorie restriction can improve intrahepatic lipid. The purpose of this study is to explore the effects and mechanisms of different protein intakes within a calorie-restricted diet on liver lipid metabolism, and to investigate whether these effects exhibit gender differences. The Sprague-Dawley rats, which were half female and half male, were used to construct a rat model of overweight and obesity attributed to a high-fat diet. They were then split up into five groups: the normal control (NC) group, the model control (MC) group, the calorie-restricted low protein (LP) group, the calorie-restricted normal protein (NP) group, and the calorie-restricted high protein (HP) group. Body weight was measured weekly. Samples of plasma and liver were obtained after eight weeks and analyzed for glucose, triglycerides, cholesterol, and hormones in the plasma as well as the liver fat and factors involved in the liver’s synthesis and degradation. For the male rats, compared to the HP group, the weight of liver fat in the LP and NP group was significantly higher (P < 0.05). However, for the female rats, there was no significant variation among the three calorie-restricted groups (P > 0.05). There was no significant variation in the concentration of total cholesterol (TC), very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) among the three male calorie-restricted groups (P > 0.05), while the TC and VLDL concentrations in the female LP and NP group were significantly higher compared to those in the HP group (P < 0.05). Moreover, the trend of expression in the signaling pathways of adiponectin/phosphorylated AMP-activated protein kinase (p-AMPK) and adiponectin/peroxisome proliferators-activated receptor alpha (PPARα) in the liver was consistent with that of the liver fat content, and leptin acted in the same way as adiponectin. Compared with the three calorie-restricted groups, the expressions of nuclear sterol-regulatory element-binding protein-2 (nSREBP-2) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) involved in cholesterol synthesis and low-density lipoprotein receptor (LDLR) and cholesterol 7-alpha hydroxylase (CYP7A1) involved in cholesterol clearance in the MC group were significantly lower (P < 0.05). A 40% energy restriction can significantly reduce the body weight, body fat, liver fat, and the blood concentration of TG in both male and female overweight and obese rats, but it can significantly increase the blood concentration of TC in overweight and obese male rats. At the same time of 40% calorie restriction, increasing dietary protein intake to twice the normal protein intake has a stronger effect on promoting hepatic triglyceride oxidation and reducing liver fat content in the male overweight and obese rats by increasing the levels of adiponectin and leptin in the blood, and can also significantly reduce the plasma cholesterol concentration in the female overweight and obese rats through inhibiting cholesterol synthesis most likely by increasing glucagon level in the blood.

In vivo Differential Effects of Extractable and Non-Extractable Phenolic Compounds from Grape Pomace on the Regulation of Obesity and Associated Metabolic Alterations.

Grape pomace (GP) is a by-product rich in phytochemicals, including extractable polyphenols (EPPs) and non-extractable polyphenols (NEPPs), which have distinct metabolic fates that may affect their biological activities. The benefits of GP have been reported in relation to obesity and its comorbidities, particularly when administered preventively focusing on EPPs. Therefore, the aim of this study was to investigate the effects of EPPs and NEPPs from GP as a treatment for obesity and its associated metabolic alterations. A previous comprehensive characterization of the selected GP revealed the most relevant individual compounds in the EPPs fraction (malvidin hexoside, (-)-epicatechin, quercetin, and procyanidin dimer B2 isomer II), as well as in the NEPPs fraction (hydroxybenzoic acid isomers I-II). The experiment was performed in obese rats with insulin resistance, treated for 8 weeks with EPPs or NEPPs grape pomace fractions (100mg/kg). After the intervention, the HFFD + EPP group showed a significantly lower weight gain (9.6%) and body mass index (9.7%) compared to the HFFD group. While liver triglyceride levels were only significantly reduced in the HFFD + NEPP group (47%) compared to the HFFD group. Neither treatment resulted in a reduction of insulin resistance. Therefore, the supplementation with grape pomace phenolic fractions to an animal model of obesity exerted differential beneficial effects on body weight and liver lipid accumulation, overall contributing to an amelioration of some the metabolic alterations present in obesity, although not to aspects such as glycemic homeostasis.

LGR4 is a key regulator of hepatic gluconeogenesis.

Emerging evidence underscored the significance of leucine-rich repeat-containing G protein-coupled receptor (LGR) 4 in endocrine and metabolic disorders. Despite this, its role in LGR4 in hepatic glucose metabolism remains poorly understood. In this study we set out to test whether LGR4 regulates glucose production in liver through a specific signaling pathway. Hepatic glucose production and gluconeogenic gene expressions were detected after silence of LGR4 in three obese mice models. Then, whole-body LGR4-deficient (LGR4 KO) mice, liver-specific LGR4 knockout (LGR4LKO) mice, and liver-specific LGR4 overexpression (LGR4LOV) mice were generated, in which we analyzed the effects of LGR4 on hepatic glucose metabolism upon HFD feeding, among which live imaging and quantitative analysis of hepatic phosphoenolpyruvate carboxykinase (PEPCK)-luciferase activity were conducted. LGR4 expression was significantly upregulated in the liver of three obese mouse models, and presented dynamic expression patterns in response to nutritional fluxes. We utilized global and liver-specific LGR4 knockouts (LGR4LKO), along with adenoviral-mediated LGR4 knockdown in mice, to show improved glucose tolerance and decreased hepatic gluconeogenesis. Specifically, the expression of rate-limiting gluconeogenic enzymes, PEPCK was significantly downregulated. Conversely, mouse model with adenovirus-mediated LGR4 overexpression (LGR4LOV) exhibited elevated gluconeogenesis and PEPCK expression and reversed the suppression observed in LGR4 knockout models. Notably, neither RANKL nor PKA signaling pathways, which were reported to take part in LGR4's function, were involved in the process of LGR4 regulating PEPCK. Instead, TopFlash reporter system and inhibitors application suggested that LGR4's influence on hepatic gluconeogenesis operates through the canonical Wnt/β-catenin/TCF7L2 signaling pathway. Overall, these findings underscore a novel mechanism by which LGR4 regulates hepatic gluconeogenesis, presenting a potential therapeutic target for diabetes management.

Sex-specific response of intramuscular fat to diet-induced obesity in rats

Metabolic abnormalities associated with excess adiposity in obesity contribute to many noncommunicable diseases, including sarcopenic obesity. Sarcopenic obesity is the loss of muscle mass coupled with excess fat mass and fatty infiltrations in muscle tissue called myosteatosis. A diet-induced obesity model was developed to study fat infiltration in muscle tissue. Only male rats have been considered in these investigations neglecting that female rats might respond differently. The objective of this study was to determine if the response to diet-induced obesity can be generalized to both sexes, or whether sex affects the response to the HFS diet, as indicated by markers of metabolic syndrome and changed in muscle integrity. Using a combination of histological staining techniques, quantitative proteomics, and measures of metabolic syndrome and inflammation, it was determined that the diet-induced obesity model in female Sprague-Dawley rats is a viable model with pronounced effects on the musculoskeletal system. We found sex-dependent and muscle-specific differences in intramuscular fat infiltration between male and female rats receiving the obesogenic diet. Including females in research may allow for identifying distinct causes of the mechanistic relationship between diet, obesity, metabolic syndrome, and the sex-dependent differential effects of these factors on adaptation and degeneration of musculoskeletal tissues.

Systematical identification of regulatory GPCRs by single-cell trajectory inference reveals the role of ADGRD1 and GPR39 in adipogenesis.

Adipogenesis is the healthy expansion of white adipose tissue (WAT), serving as a compensatory response to maintain metabolic homeostasis in the presence of excess energy in the body. Therefore, the identification of novel regulatory molecules in adipogenesis, specifically membrane receptors such as G protein-coupled receptors (GPCRs), holds significant clinical promise. These receptors can serve as viable targets for pharmaceuticals, offering potential for restoring metabolic homeostasis in individuals with obesity. We utilized trajectory inference methods to analyze three distinct single-nucleus sequencing (sNuc-seq) datasets of adipose tissue and systematically identified GPCRs with the potential to regulate adipogenesis. Through verification in primary adipose progenitor cells (APCs) of mice, we discovered that ADGRD1 promoted the differentiation of APCs, while GPR39 inhibits this process. In the obese mouse model induced by a high-fat diet (HFD), both gain-of-function and loss-of-function studies validated that ADGRD1 promoted adipogenesis, thereby improving metabolic homeostasis, while GPR39 inhibited adipogenesis, leading to metabolic dysfunction. Additionally, through the analysis of 2,400 ChIP-seq data and 1,204 bulk RNA-seq data, we found that the transcription factors (TFs) MEF2D and TCF12 regulated the expression of ADGRD1 and GPR39, respectively. Our study revealed the regulatory role of GPCRs in adipogenesis, providing novel targets for clinical intervention of metabolic dysfunction in obese patients.

Chemerin loss-of-function attenuates glucagon-like peptide-1 secretion in exercised obese mice.

To investigate the role of chemerin reduction in mediating exercise-induced Glucagon-like peptide-1 (GLP-1) secretion and the amelioration of pancreatic β-cell function in obesity. Obesity models were established using wild-type and chemerin systemic knockout mice, followed by 8 weeks of moderate-intensity continuous aerobic exercise training. Serum chemerin levels, GLP-1 synthesis, glucose tolerance, pancreatic β-cell function, structure, and apoptosis were assessed. In vitro experiments were conducted on STC-1 cells, derived from murine intestinal endocrine cells, to evaluate GLP-1 secretion following exogenous chemerin treatment. Additionally, colonic tissue inflammation and apoptosis were analyzed using qPCR and TUNEL staining. In obese wild-type mice, moderate-intensity aerobic exercise significantly reduced serum chemerin levels, enhanced GLP-1 secretion, and improved glucose tolerance, pancreatic β-cell structure, function, and apoptosis. These effects were absent in obese chemerin knockout mice. Exogenous chemerin treatment reduced GLP-1 secretion in STC-1 cells. Furthermore, the beneficial effects of exercise on colonic inflammation and apoptosis observed in wild-type mice were abolished in chemerin knockout mice. Reduction of chemerin is crucial for the beneficial effects of aerobic exercise on GLP-1 secretion and pancreatic β-cell function in obesity. The mechanisms behind these effects may involve improvements in colonic inflammation and apoptosis. These findings offer new insights into the molecular mechanisms through which exercise improves obesity-related metabolic dysfunction.

MMPC-live: Accessible resources for phenotyping of live mouse models of diabetes and obesity

MMPC-live: Accessible resources for phenotyping of live mouse models of diabetes and obesity

Olivetol's Effects on Metabolic State and Gut Microbiota Functionality in Mouse Models of Alimentary Obesity, Diabetes Mellitus Type 1 and 2, and Hypercholesterolemia.

Disorders of glucose and lipid metabolism, such as obesity, diabetes mellitus, or hypercholesterolemia, can cause serious complications, reduce quality of life, and lead to increased premature mortality. Olivetol, a natural compound, could be proposed as a promising therapeutic agent for preventing, treating, or alleviating metabolic complications of such pathological conditions. In this study, the researchers conducted a broad parallel investigation of olivetol's effects on metabolic state and gut microbiota functionality in mouse models of alimentary obesity, diabetes mellitus type 1 and 2, and hypercholesterolemia. According to the results of the study, olivetol caused a lowering of body weight in C57Bl6 mice fed a high-fat diet and in ldlr(-/-) mice, decreased serum glucose levels in db/db mice, improved lipid metabolism in ldlr(-/-) mice, and prevented inflammatory infiltration of the pancreas and loss of insulin secretion in NOD mice. In addition, olivetol affected the composition and functional activity of gut microbiota communities, inducing an expansion of probiotic species such as Akkermansia muciniphila and Bacteroides acidifaciens and depleting the representation of pathobionts such as Prevotella, although olivetol supplementation did not influence the diversity or richness of the communities. These results suggest that olivetol is a promising therapeutic agent for preventing, treating, or alleviating the metabolic complications of obesity, diabetes mellitus type 1 and 2, and hypercholesterolemia; however, more investigations are required in order to attain a full understanding of its physiological effects.

Evaluation of Anti-Obesity Potential of Isolated Bioactive Fractions from Justicia Adhatoda Leaves: An In Vitro, In Vivo, and 3T3-L1 cell line Approach Using HPTLC-MS-MSn for Compound Identification.

This study was conducted to investigate the anti-obesity effects of bioactive fractions JAF2 and JAF3 from Justicia adhatoda (JA) in vitro using enzymatic assays, 3T3-L1 cells and in vivo using a monosodium glutamate-high-fat diet (MSG-HFD) model. High-Performance Thin Layer Chromatography coupled with Mass Spectrometry (HPTLC-MS-MSn) was finally utilized to analyze bioactive fractions for the compounds responsible for the activity. In vitro, the anti-obesity effects of JAF2 and JAF3 were assessed in 3T3-L1 adipocytes, revealing that JAF2 significantly reduced lipid and triglyceride levels. In the in vivo MSG-HFD-induced obesity model, JAF2 improved hepatic profiles, countered oxidative stress, enhanced lipid profiles, and reduced pro-inflammatory cytokines. Overall, the assessment revealed a significant reduction in adipose tissue content in the treated groups, keeping other organ profiles safe. As per future perspectives, these cocktail fractions can be used in the context of genetically predisposed obesity in modern days.

Metabolome and RNA-seq reveal discrepant metabolism and secretory metabolism profile in skeletal muscle between obese and lean pigs at different ages.

Metabolites and metabolism-related gene expression profiles in skeletal muscle change dramatically under obesity, aging and metabolic disease. Since obese and lean pigs are ideal models for metabolic research. Here, we compared metabolome and transcriptome of Longissimus dorsi (LD) muscle between Taoyuan black (TB, obese) and Duroc (lean) pigs at different ages. We defined the "window phase" of intramuscular fat (IMF) deposition in TB pig, which has significantly higher IMF than Duroc pig. Our results displayed discrepant lipid composition and different expression genes (DEGs) enriched in lipid metabolism, and both metabolome and transcriptome analyses revealed stronger energy expenditure and more active amino acid and protein metabolism in Duroc pig. 10 up- and 51 down-regulated biomarker metabolites with age- and breed-specificity were identified. Potential secretory metabolites, including organic acid (fumaric acid, succinate, malic acid, and gamma-aminobutyric acid), amino acid (L-lysine, and L-glutamic acid), lipid (2-hydroxyisovaleric acid, and L-carnitine) were demonstrated a significant correlation with IMF deposition. Our research highlights the huge difference of metabolic spectrum in skeletal muscle between obese and lean model and muscle-derived secretory metabolites might act as an ambassador of intercellular communication to regulate systematic metabolism.

Pathophysiological Role of Neutrophil Extracellular Traps in Diet-Induced Obesity and Metabolic Syndrome in Animal Models.

The global pandemic of obesity poses a serious health, social, and economic burden. Patients living with obesity are at an increased risk of developing noncommunicable diseases or to die prematurely. Obesity is a state of chronic low-grade inflammation. Neutrophils are first to be recruited to sites of inflammation, where they contribute to host defense via phagocytosis, degranulation, and extrusion of neutrophil extracellular traps (NETs). NETs are web-like DNA structures of nuclear or mitochondrial DNA associated with cytosolic antimicrobial proteins. The primary function of NETosis is preventing the dissemination of pathogens. However, neutrophils may occasionally misidentify host molecules as danger-associated molecular patterns, triggering NET formation. This can lead to further recruitment of neutrophils, resulting in propagation and a vicious cycle of persistent systemic inflammation. This scenario may occur when neutrophils infiltrate expanded obese adipose tissue. Thus, NETosis is implicated in the pathophysiology of autoimmune and metabolic disorders, including obesity. This review explores the role of NETosis in obesity and two obesity-associated conditions-hypertension and liver steatosis. With the rising prevalence of obesity driving research into its pathophysiology, particularly through diet-induced obesity models in rodents, we discuss insights gained from both human and animal studies. Additionally, we highlight the potential offered by rodent models and the opportunities presented by genetically modified mouse strains for advancing our understanding of obesity-related inflammation.