Diet-induced Obesity Research Articles

Organ toxicities associated with diet-induced obesity in rats: Investigation of changes in activities selected enzymes.

Obesity stands out as one of the most significant health problems in the modern world. The prevalence of high-calorie diets (HCDs) globally exacerbates this condition. Throughout history, plants and plant-derived food products have been utilized for medicinal purposes, demonstrating their efficacy in the treatment and prevention of various diseases. Gundelia tournefortii (GT), a plant of interest, is known to possess beneficial properties. Hence, this study aimed to investigate the immunotoxic and neurotoxic effects of two different doses of GT plant extract on the liver, brain, and heart tissues of obese rats. For this purpose, Wistar male rats were divided into four groups: "CG," "HCDG," "HCDGUN1," and "HCDGUN2" At the conclusion of the study, adenosine deaminase (ADA) and myeloperoxidase (MPO) activities, as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) biomarkers, were evaluated in the liver, heart, and brain tissues. The study results revealed a statistically significant increase in ADA and MPO activities in the HCDG group compared to the CG group, alongside a significant decrease in the HCDGUN groups compared to the HCDG group. Regarding AChE and BChE activities, a statistically significant decrease was observed in the HCDG group compared to the CG group, whereas an increase was noted in the HCDGUN groups relative to the HCDG group, with the latter approaching values similar to those of the control group. In conclusion, the intake of GT plant extract exhibited positive effects on the immunotoxic and neurotoxic effects induced by HCD in rats with an experimental obesity model, as evidenced by tissue biomarker evaluations.

Maternal Dietary Improvement or Leptin Supplementation During Suckling Mitigates the Long-Term Impact of Maternal Obesogenic Conditions on Inflammatory and Oxidative Stress Biomarkers in the Offspring of Diet-Induced Obese Rats

This study investigates the impact of maternal nutrition during lactation on inflammation and oxidative stress in the offspring of diet-induced obese rats, along with the potential benefits of leptin supplementation during suckling. Dams were fed either a standard diet (SD), a western diet (WD) before and during gestation and lactation (WD-dams), or a WD switched to an SD during lactation (Rev-dams). Offspring were supplemented with leptin or vehicle during suckling and then fed an SD or WD until four months. Offspring of the Rev-dams exhibited improved metabolic indicators, including lower body weight, reduced plasma levels of TNF-alpha, a higher adiponectin/leptin (A/L) ratio, enhanced liver antioxidant defenses, and decreased inflammation markers in white adipose tissue (WAT) compared to WD-dams, with sex differences. Leptin supplementation further modulated these markers, reducing oxidative stress in liver and inflammation in WAT and liver (e.g., hepatic Tnfa expression decreased by 45% (males) and 41% (females) in the WD group on an SD), and improving the A/L ratio, with effects varying by maternal conditions and sex. In conclusion, this study underscores the importance of maternal nutrition and leptin intake during suckling in shaping long-term metabolic and inflammatory health in offspring, offering strategies to mitigate the adverse effects of maternal obesity on future generations.

Depot-specific differences and heterogeneity of adipose-derived stem cells in diet-induced obesity.

Obesity is a global health concern. Studying the heterogeneity of adipose-derived stem cells (ADSCs) plays a pivotal role in understanding metabolic disorders, such as obesity. Mass cytometry was used to determine the depot-specific differences and heterogeneity of ADSCs and their alterations at the single-cell level in a diet-induced-obesity (DIO) model in which mice were treated with liraglutide. We characterized the relationship among ADSC markers and found that CD26 and CD142 could identify the most representative heterogeneous ADSCs in subcutaneous adipose tissue and visceral adipose tissue. Specifically, CD26+CD142- and CD26+CD142+ ADSCs were exclusive to subcutaneous adipose tissue and visceral adipose tissue, respectively, whereas CD26-CD142+ ADSCs were present in both. RNA analysis explored the potential functions of these three subgroups. In the visceral adipose tissue of DIO mice, we observed a substantial downregulation of CD26+CD142+ ADSCs and upregulation of CD26-CD142+ ADSCs, both of which were mitigated by liraglutide treatment. Our study highlights the depot-specific differences and heterogeneity of ADSCs and their alterations under DIO conditions, which can potentially be reversed by liraglutide treatment. This study provides new insights into the identification of more specific ADSC subgroups to explore the etiology of metabolism-related diseases.

Transcription factor ETV4 plays a critical role in the development of non-alcoholic fatty liver disease.

The Angiopoietin-like 4 (ANGPTL4) and ETS Variant Transcription Factor 4 (ETV4) are involved in the metabolic transition and carcinogenesis in the liver. However, the role of ETV4 in the development of non-alcoholic fatty liver disease (NAFLD) is currently unknown. Our study reveals that ETV4 expression was upregulated in the diet-induced non-alcoholic fatty liver disease, and plays a critical role in the dysregulated lipid metabolism. We demonstrate a mechanism by which ANGPTL4 regulates lipid homeostasis via involving the AMPK/ETV4 axis. Transient knockdown of ETV4 abolished the ANGPTL4-induced expression of Srebp1c, Acc and Fasn. Insulin treatment potentially increased the physical association of ETV4 with SREBP1, and promotes nuclear translocation and transcriptional activity of SREBP1. In addition, we show that combined therapy with omega-3 fatty acids and diacylglycerol O-acyltransferase inhibitor 1 (DGAT1) inhibitor (A-922500) counteracted the ANGPTL4-ETV4 axis-induced lipogenesis in vitro, and in vivo in obese mice via activation of GPR120-βarrestin2-AMPK pathway. Finally, we demonstrate that targeted pharmacologic therapy using GalNac-ETV4 siRNA that specifically inhibits ETV4 gene expression in the liver protects against diet-induced NAFLD, obesity and dyslipidemia. Hence, our study reveal previously unrecognized role of ETV4 in the NAFLD, and provides rationale targeting ETV4 to treat NAFLD.

Dietary Lactate Intake and Physical Exercise Synergistically Reverse Brown Adipose Tissue Whitening to Ameliorate Diet-Induced Obesity.

Physical exercise represents an effective strategy for combating obesity via brown adipose tissue (BAT) activation, but the mechanism remains unclear. In this study, we demonstrated that the cooperation between lactate and adrenoceptor signaling regulated BAT activity during exercise. The lactate receptor GPR81 was highly expressed in the BAT of lean mice, whereas its expression was markedly decreased in obese mice. Notably, the level of GPR81 in BAT could be upregulated by exercise. The blockade of lactate production or GPR81 significantly impaired exercise-induced BAT activation. In addition, dietary lactate intake enhanced the efficacy of physical exercise in alleviating BAT whitening in obese mice, as evidenced by the improved mitochondrial ultrastructure, reduced lipid droplets, increased UCP1 expression, and elevated mitochondrial DNA content. Further data indicated that norepinephrine triggered UCP1 activation through both the cAMP/PKA and Ca2+/CaMK pathways during exercise, while lactate mediated this process via the GPR81-Ca2+/CaMK cascade. Our findings unveil a novel mechanism in the regulation of BAT function by physical exercise, providing a promising lifestyle intervention to improve metabolic health.

Maternal obesity induces sex-specific changes in the endocannabinoid system of the hypothalamus and dorsal hippocampus of offspring associated with anxiety-like behavior in adolescent female rats

Maternal obesity during perinatal period increases the risk of metabolic and behavioral deleterious outcomes in the offspring, since it is critical for brain development, maturation, and reorganization. These processes are highly modulated by the endocannabinoid system (ECS), which comprises the main lipid ligands anandamide and 2-arachidonoylglycerol, cannabinoid receptors 1 and 2 (CB1R and CB2R), and several metabolizing enzymes. The ECS is overactivated in obesity and it contributes to the physiological activity of the hypothalamus-pituitary-adrenal (HPA) axis, promoting stress relief. We have previously demonstrated that maternal high-fat diet during gestation and lactation programmed the food preference for fat in adolescent male offspring and adult male and female offspring. In the present study, we hypothesized that maternal diet-induced obesity would induce sex-specific changes of the ECS in the hypothalamus and dorsal hippocampus of rat offspring associated with dysregulation of the HPA axis and stress-related behavior in adolescence. Rat dams were fed a control (C) or an obesogenic high-fat high-sugar diet (OD) for nine weeks prior to mating and throughout gestation and lactation. Maternal obesity differentially altered the CB1R in the hypothalamus of neonate offspring, with significant increase in male but not in female pups, associated with decreased CB2R prior to obesity development. In adolescence, maternal obesity induced anxiety-like behavior only in adolescent females which was associated with increased content of CB1R in the dorsal hippocampus. Our findings suggest that the early origins of anxiety disorders induced by maternal exposome is associated with dysregulation of the brain ECS, with females being more susceptible.

Increased neutrophil extracellular traps caused by diet-induced obesity delay fracture healing.

Obesity, recognized as a risk factor for nonunion, detrimentally impacts bone health, with significant physical and economic repercussions for affected individuals. Nevertheless, the precise pathomechanisms by which obesity impairs fracture healing remain insufficiently understood. Multiple studies have identified neutrophil granulocytes as key players in the systemic immune response, being the predominant immune cells in early fracture hematomas. This study identified a previously unreported critical period for neutrophil infiltration into the callus. Invivo experiments demonstrated that diet-induced obesity (DIO) mice showed earlier neutrophil infiltration, along with increased formation of neutrophil extracellular traps (NETs), compared to control mice during the endochondral phase of fracture repair. Furthermore, Padi4 knockout was found to reduce NET formation and mitigate the fracture healing delays caused by high-fat diets. Mechanistically, invitro analyses revealed that NETs, by activating NLRP3 inflammasomes, inhibited the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and concurrently promoted M1-like macrophage polarization. These findings establish a connection between NET formation during the endochondral phase and delayed fracture healing, suggesting that targeting NETs could serve as a promising therapeutic approach for addressing obesity-induced delays in fracture recovery.

Semaglutide normalizes increased cardiomyocyte calcium transients in a rat model of high fat diet-induced obesity.

Obesity increases the risk of heart failure with preserved (HFpEF), but not reduced ejection fraction (HFrEF). The glucagon-like peptide-1 receptor agonist (GLP-1-RA) semaglutide improves outcome of patients with obesity with or without HFpEF, while GLP-1-RAs were associated with adverse outcome in patients with HFrEF. Here, we investigate the effect of in vivo treatment with semaglutide on excitation-contraction coupling in a rat model of obesity. Rats received high-fat/high-fructose diet for 8weeks and were then randomized to semaglutide (HFD/Sema) or vehicle (HFD/Veh) for another 8weeks, during which they could choose between HFD and a low-fat/high-fructose diet (LFD). Control rats received either standard chow (CON), HFD or LFD only, without treatment. After 16weeks, sarcomere shortening and cytosolic Ca2+ concentrations ([Ca2+]c) were determined in isolated cardiomyocytes. Compared with CON, HFD/Veh increased the amplitude of [Ca2+]c transients and systolic sarcomere shortening in absence or presence of β-adrenergic stimulation, which was reversed by HFD/Sema. Caffeine-induced sarcoplasmic reticulum (SR) Ca2+ release and L-type Ca2+ channel (LTCC) currents were reduced by HFD/Sema versus HFD/Veh, while SR Ca2+ ATPase activity remained unaffected. Compared with HFD, LFD increased [Ca2+]c transients and sarcomere shortening further despite similar effects on body weight. While HFD increased cardiomyocyte [Ca2+]c transients and systolic sarcomere shortening, semaglutide normalized these alterations, mediated by reduced SR Ca2+ load and LTCC currents. Because increased LTCC currents were previously traced to cardiac hypertrophy, these effects may explain why GLP-1-RAs provide benefits for patients with obesity with or without HFpEF, but rather adverse outcome in HFrEF.

Influence of Mitochondrial NAD(P) + Transhydrogenase (NNT) on Hypothalamic Inflammation and Metabolic Dysfunction Induced by a High-Fat Diet in Mice.

The mitochondrial protein NAD(P)+ transhydrogenase (NNT) has been implicated in the metabolic derangements observed in obesity. Mice with the C57BL/6J genetic background bear a spontaneous mutation in the Nnt gene and are known to exhibit increased susceptibility to diet-induced metabolic disorders. Most of the studies on NNT in the context of diet-induced obesity have compared C57BL/6J mice with other mouse strains, where differences in genetic background can serve as confounding factors. Moreover, these studies have predominantly employed a high-fat diet (HFD) consisting of approximately 60% of calories from fat, which may not accurately mimic real-world fat-rich diets. In this study, we sought to examine the role of NNT in diet-induced hypothalamic inflammation and metabolic syndrome by using a congenic mice model lacking NNT, along with a HFD providing approximately 45% of calories from fat. Our findings indicate that mice lacking NNT were more protected from HFD-induced weight gain but presented a worse performance on glucose tolerance test, albeit not in insulin tolerance test. Interestingly, the brown adipose tissue of HFD-fed Nnt +/+ mice presented a greater mass and a higher whole-tissue ex-vivo oxygen consumption rate. Also, HFD increased the expression of the inflammatory markers Il1β, Tlr4 and Iba1 in the hypothalamus of Nnt -/- mice. In conclusion, our study highlights the importance of NNT in the context of diet-induced obesity and metabolic syndrome, indicating its contribution to mitigate hypothalamic inflammation and suggesting its role in the brown adipose tissue increased mass.

Natural Honey Proteins Prevent Diet-Induced Obesity and Metabolic Disorders in Rats.

Previous studies have shown that oral whole honey reduces weight gain in rats on a normal diet (ND) or high-fat diet (HFD) and suppresses inflammation by modulating immunological cytokines in human neutrophils and macrophages. We hypothesize that the honey proteins (HP) are responsible for the reduced weight gain in rats on ND and HFD and that HP would alleviate obesity parameters. To test this, proteins were isolated from acacia honey through the salting-out method. Wistar rats (N = 24) were randomized to get ND or HFD for 4 weeks, then further randomized to four groups and treated with HP or saline for another 4 weeks. Energy intake (EI), body weight gain, EI per gram body weight gain, serum glucose, and lipids were measured. Expression of adipose tissue genes fatty acid binding protein (FABP), lipase C (LIPC), and apolipoprotein A-1 (APOA1) was evaluated through the quantitative polymerase chain reaction. HFD increased the body weight versus ND in weeks 1-4. HP for the next 4 weeks reduced weight gain in ND-HP and HFD-HP groups versus saline controls (P < .01). EI was not significantly different among groups. However, EI per gram body weight gain among groups was markedly different (P < .01), demonstrating reduced weight gain efficiency by HP (P < .01). HP reduced glucose in ND but not in HFD groups. Triglycerides were lower in both HP groups. The expressions of FABP, LIPC, and APOA1 genes were significantly increased (P < .05) in HP-treated HFD rats. Collectively, weight gain efficiency was remarkably reduced without altering EI in rats following the HP treatment, suggesting HP increased metabolic rate or substrate partitioning. Studies of HP are suggested in humans.

Host Genetics Background Affects Intestinal Cancer Development Associated with High-Fat Diet-Induced Obesity and Type 2 Diabetes

Background: Obesity and type 2 diabetes (T2D) promote inflammation, increasing the risk of colorectal cancer (CRC). High-fat diet (HFD)-induced obesity is key to these diseases through biological mechanisms. This study examined the impact of genetic background on the multimorbidity of intestinal cancer, T2D, and inflammation due to HFD-induced obesity. Methods: A cohort of 357 Collaborative Cross (CC) mice from 15 lines was fed either a control chow diet (CHD) or HFD for 12 weeks. Body weight was tracked biweekly, and blood glucose was assessed at weeks 6 and 12 via intraperitoneal glucose tolerance tests (IPGTT). At the study’s endpoint, intestinal polyps were counted, and cytokine profiles were analyzed to evaluate the inflammatory response. Results: HFD significantly increased blood glucose levels and body weight, with males showing higher susceptibility to T2D and obesity. Genetic variation across CC lines influenced glucose metabolism, body weight, and polyp development. Mice on HFD developed more intestinal polyps, with males showing higher counts than females. Cytokine analysis revealed diet-induced variations in pro-inflammatory markers like IL-6, IL-17A, and TNF-α, differing by genetic background and sex. Conclusions: Host genetics plays a crucial role in susceptibility to HFD-induced obesity, T2D, CRC, and inflammation. Genetic differences across CC lines contributed to variability in disease outcomes, providing insight into the genetic underpinnings of multimorbidity. This study supports gene-mapping efforts to develop personalized prevention and treatment strategies for these diseases.

Hypoxia-inducible factor-1α-deficient adipose-tissue macrophages produce the heat to mediate lipolysis of white adipose tissue through uncoupling protein-1

BackgroundUncoupling protein 1 (UCP1) is a proton uncoupler located across the mitochondrial membrane generally involved in thermogenesis of brown adipose tissues. Although UCP1 is known to be strongly expressed in brown adipocytes, recent evidence suggest that white adipocytes can also express UCP1 under certain circumstances such as cold- or β-adrenergic receptor-stimulation, allowing them to acquire brown adipocyte-like features thereby becoming 'beige’ adipocytes.ResultsIn this study, we report that UCP1 can be expressed in adipose-tissue macrophages (ATM) lacking functional hypoxia-inducible factor-1 (HIF-1) and this does not require cold- nor β-adrenergic receptor activation. By using myeloid-specific Hif-1α knockout (KO) mice, we observed that these mice were protected from diet-induced obesity and exhibited an improved thermogenic tolerance upon cold challenge. ATM isolated from white adipose tissues (WAT) of these mice fed with high fat diet exhibited significantly higher M2-polarization, decreased glycolysis, increased mitochondrial functions and acetyl-CoA levels, along with increased expression of Ucp1, peroxisome proliferator activated receptor-gamma co-activator-1a, and others involved in histone acetylation. Consistent with the increased Ucp1 gene expression, these ATM produced a significant amount of heat mediating lipolysis of co-cultured adipocytes liberating free fatty acid. Treating ATM with acetate, a substrate for acetyl-CoA synthesis was able to boost the heat production in wild-type or Hif-1α-deficient but not UCP1-deficient macrophages, indicating that UCP1 was necessary for the heat production in macrophages. Lastly, we observed a significant inverse correlation between the number of UCP1-expressing ATM in WAT and the body mass index of human individuals.ConclusionsUCP1-expressing ATM produce the heat to mediate lipolysis of adipocytes, indicating that this can be a novel strategy to treat and prevent diet-induced obesity.

Nitric oxide donors rescue metabolic and mitochondrial dysfunction in obese Alzheimer’s model

Reduced nitric oxide (NO) bioavailability is a pathological link between obesity and Alzheimer’s disease (AD). Obesity-associated metabolic and mitochondrial bioenergetic dysfunction are key drivers of AD pathology. The hypothalamus is a critical brain region during the development of obesity and dysfunction is an area implicated in the development of AD. NO is an essential mediator of blood flow and mitochondrial bioenergetic function, but the role of NO in obesity-AD is not entirely clear. We investigated diet-induced obesity in female APPswe/PS1dE9 (APP) mouse model of AD, which we treated with two different NO donors (sodium nitrite or L-citrulline). After 26 weeks of a high-fat diet, female APP mice had higher adiposity, insulin resistance, and mitochondrial dysfunction (hypothalamus) than non-transgenic littermate (wild type) controls. Treatment with either sodium nitrite or L-citrulline did not reduce adiposity but improved whole-body energy expenditure, substrate oxidation, and insulin sensitivity. Notably, both NO donors restored hypothalamic mitochondrial respiration in APP mice. Our findings suggest that NO is an essential mediator of whole-body metabolism and hypothalamic mitochondrial function, which are severely impacted by the dual insults of obesity and AD pathology.

Targeted Deletion of Fibroblast Growth Factor 23 Rescues Metabolic Dysregulation of Diet-induced Obesity in Female Mice.

Fibroblast growth factor 23 (FGF23) is a bone-secreted protein widely recognized as a critical regulator of skeletal and mineral metabolism. However, little is known about the nonskeletal production of FGF23 and its role in tissues other than bone. Growing evidence indicates that circulating FGF23 levels rise with a high-fat diet (HFD) and they are positively correlated with body mass index (BMI) in humans. In the present study, we show for the first time that increased circulating FGF23 levels in obese humans correlate with increased expression of adipose Fgf23 and both positively correlate with BMI. To understand the role of adipose-derived Fgf23, we generated adipocyte-specific Fgf23 knockout mice (AdipoqFgf23Δfl/Δfl) using the adiponectin-Cre driver, which targets mature white, beige, and brown adipocytes. Our data show that targeted ablation of Fgf23 in adipocytes prevents HFD-fed female mice from gaining body weight and fat mass while preserving lean mass but has no effect on male mice, indicating the presence of sexual dimorphism. These effects are observed in the absence of changes in food and energy intake. Adipose Fgf23 inactivation also prevents dyslipidemia, hyperglycemia, and hepatic steatosis in female mice. Moreover, these changes are associated with decreased respiratory exchange ratio and increased brown fat Ucp1 expression in knockout mice compared to HFD-fed control mice (Fgf23fl/fl). In conclusion, this is the first study highlighting that targeted inactivation of Fgf23 is a promising therapeutic strategy for weight loss and lean mass preservation in humans.

Eubacterium siraeum suppresses fat deposition via decreasing the tyrosine-mediated PI3K/AKT signaling pathway in high-fat diet-induced obesity.

Obesity in humans can lead to chronic diseases such as diabetes and cardiovascular disease. Similarly, subcutaneous fat (SCF) in pigs affects feed utilization, and excessive SCF can reduce the feed efficiency of pigs. Therefore, identifying factors that suppress fat deposition is particularly important. Numerous studies have implicated the gut microbiome in pigs' fat deposition, but research into its suppression remains scarce. The Lulai black pig (LL) is a hybrid breed derived from the Laiwu pig (LW) and the Yorkshire pig, with lower levels of SCF compared to the LW. In this study, we focused on these breeds to identify microbiota that regulate fat deposition. The key questions were: Which microbial populations reduce fat in LL pigs compared to LW pigs, and what is the underlying regulatory mechanism? In this study, we identified four different microbial strains, Eubacterium siraeum, Treponema bryantii, Clostridium sp. CAG:413, and Jeotgalibaca dankookensis, prevalent in both LW and LL pigs. Blood metabolome analysis revealed 49 differential metabolites, including tanshinone IIA and royal jelly acid, known for their anti-adipogenic properties. E. siraeum was strongly correlated with these metabolites, and its genes and metabolites were enriched in pathways linked to fatty acid degradation, glycerophospholipid, and glycerolipid metabolism. In vivo mouse experiments confirmed that E. siraeum metabolites curb weight gain, reduce SCF adipocyte size, increase the number of brown adipocytes, and regulate leptin, IL-6, and insulin secretion. Finally, we found that one important pathway through which E. siraeum inhibits fat deposition is by suppressing the phosphorylation of key proteins in the PI3K/AKT signaling pathway through the reduction of tyrosine. We compared LW and LL pigs using fecal metagenomics, metabolomics, and blood metabolomics, identifying E. siraeum as a strain linked to fat deposition. Oral administration experiments in mice demonstrated that E. siraeum effectively inhibits fat accumulation, primarily through the suppression of the PI3K/AKT signaling pathway, a critical regulator of lipid metabolism. These findings provide a valuable theoretical basis for improving pork quality and offer insights relevant to the study of human obesity and related chronic metabolic diseases. Video Abstract.

Single-cell transcriptomic analysis reveals dynamic activation of cellular signaling pathways regulating beige adipogenesis.

PDGFRA+ cells have been identified as adipocyte stem cells (ASCs) that differentiate into beige adipocytes in white adipose tissue (WAT) following thermogenic stimuli. To elucidate the molecular heterogeneity of ASCs, we conducted single-cell transcriptomic profiling of PDGFRA+ cells isolated from the inguinal WAT (iWAT) of mice treated with the beta3 adrenergic receptor agonist CL316243. Single-cell RNA-seq revealed nine major clusters, which were categorized into four groups: resting, proliferating, differentiating, and adipogenic factor-expressing cells (AFECs). Trajectory analysis revealed sequential activation of molecular pathways, including the Hedgehog and Notch signaling pathways, during beige adipogenesis. AFECs expressed Dpp4 and did not differentiate into adipocytes in culture or after transplantation. Furthermore, genetic lineage tracing studies indicated that DPP4+ cells did not differentiate into adipocytes in iWAT during CL316243-induced beige adipogenesis. However, high-fat diet feeding led to the recruitment of adipocytes from DPP4+ cells in iWAT. Overall, this study improved our understanding of the dynamic molecular basis of beige adipogenesis and the potential contribution of DPP4+ adipocyte lineages to the pathological expansion of WAT during diet-induced obesity.

Significance of LIF/LIFR Signaling in the Progression of Obesity-Driven Triple-Negative Breast Cancer

American women with obesity have an increased incidence of triple-negative breast cancer (TNBC). The impact of obesity conditions on the tumor microenvironment is suspected to accelerate TNBC progression; however, the specific mechanism(s) remains elusive. This study explores the hypothesis that obesity upregulates leukemia inhibitory factor receptor (LIFR) oncogenic signaling in TNBC and assesses the efficacy of LIFR inhibition with EC359 in blocking TNBC progression. TNBC cell lines were co-cultured with human primary adipocytes, or adipocyte-conditioned medium, and treated with EC359. The effects of adiposity were measured using cell viability, colony formation, and invasion assays. Mechanistic studies utilized RNA-Seq, Western blotting, RT-qPCR, and reporter gene assays. The therapeutic potential of EC359 was tested using xenograft and patient-derived organoid (PDO) models. The results showed that adipose conditions increased TNBC cell proliferation and invasion, and these effects correlated with enhanced LIFR signaling. Accordingly, EC359 treatment reduced cell viability, colony formation, and invasion under adipose conditions and blocked adipose-mediated organoid growth and TNBC xenograft tumor growth. RNA-Seq analysis identified critical pathways modulated by LIF/LIFR signaling in diet-induced obesity mouse models. These findings suggest that adiposity contributes to TNBC progression via the activation of the LIF/LIFR pathway, and LIFR inhibition with EC359 represents a promising therapeutic approach for obesity-associated TNBC.

Modulatory L-Alliin Effect on Acute Inflammatory Cytokines in Diet-Induced Obesity Mice

Background/Objectives: The inflammatory response has evolved as a protective mechanism against pathogens and tissue damage. However, chronic inflammation can occur, potentially leading to severe disease. Low-grade chronic inflammation is associated with obesity, and the Th1 cytokine profile plays an important role in this proinflammatory environment. Diet-induced obesity (DIO) can lead to persistent dysbiosis and maintain high concentrations of circulating lipopolysaccharides (LPSs) over prolonged periods of time, resulting in metabolic endotoxemia. In this context, the study of natural immunomodulators has recently increased. Objective: The aim of this study is improve scientific evidence for the immunomodulatory role of L-Alliin in obesity and inflammation. Methods: In the present work, we describe the effect of L-Alliin on serum levels of cytokines in DIO mice after an acute inflammatory challenge. L-Alliin is the main organosulfurized molecule of garlic that has been studied for its numerous beneficial physiological effects in health and disease and is beginning to be considered a nutraceutical. Two situations are simulated in this experimental model, health and chronic, low-grade inflammation that occurs in obesity, both of which are confronted with an acute, inflammation-inducing challenge. Results: Based on our findings, L-Alliin seems to somehow stimulate the cellular chemotaxis by eliciting the release of key molecules, including IL-2, IFN-γ, TNF-α, MCP-1, IL-6, IL-9, and G-CSF. However, the molecular mechanism involved remains unknown. This, in turn, mitigates the risk of severe inflammatory symptoms by preventing the release of IL-1β and its downstream molecules such as IL-1α, GM-CSF, and RANTES. Conclusions: Taken together, these results indicate that L-Alliin can boost immunity in healthy organisms and act as an immunomodulator in low-grade inflammation.

Wheat bran oil ameliorates high-fat diet-induced obesity in rats with alterations in gut microbiota and liver metabolite profile

BackgroundObesity is one of the public health issues that seriously threatens human health. This study aimed to investigate the effects of wheat bran oil (WBO) on body weight and fat/lipid accumulation in high-fat diet (HFD)-induced obese rats and further explore the possible mechanisms by microbiome and metabolome analyses.MethodsFifty Sprague-Dawley (SD) rats were fed either a normal chow diet (B group, n = 10) or HFD (n = 40) for 14 weeks to establish an obesity model. The HFD-induced obese rats were further divided into four groups and given WBO at 0 mL/kg (M group), 1.25 mL/kg (WBO-L group), 2.5 mL/kg (WBO-M group), and 5 mL/kg (WBO-H group) by oral gavage for 9 weeks. The body weight of rats was weighed weekly. The gut microbiota structure was analyzed using 16 S rDNA high-throughput sequencing. The liver metabolite profile was determined using UHPLC-QE-MS non-target metabolomics technology.ResultsIn this study, WBO treatment reduced body weight gain, fat and lipid accumulation, and ameliorated hepatic steatosis and inflammation. WBO treatment increased the relative abundance of Romboutsia and Allobaculum and decreased that of Candidatus_Saccharimonas, Alloprevotella, Rikenellaceae_RC9_gut_group, Alistipes, Parabacteroides, UCG-005, Helicobacter, Colidextribacter, and Parasutterella compared with the M group. A total of 22 liver metabolites were significantly altered by WBO treatment, which were mainly involved in taurine and hypotaurine metabolism, nicotinate and nicotunamide metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, and ether lipid metabolism.ConclusionsWBO alleviated body weight gain and fat/lipid accumulation in HFD-induced obese rats, which may be related to altered gut microbiota and liver metabolites.

Novel Phenoxyalkanoic Acid Derivatives as Free Fatty Acid Receptor 4 Agonists for Treating Type 2 Diabetes Mellitus

Diabetes mellitus (DM) is a common metabolic disease that poses a severe threat to human health. Despite a range of therapeutic approaches, there remains a lack of effective and safe therapies with the existing drugs. Therefore, there is an urgent need to develop novel, effective, and safe therapeutic strategies for DM. Free fatty acid receptor 4 (FFAR4), also known as GPR120, is a member of the G protein-coupled receptor family, which has received considerable attention as an attractive new therapeutic target for treating DM. In the present study, based on the structure of TUG-891, which has excellent activity and selectivity, a series of novel FFAR4 agonists was designed by replacing the phenylpropanoic acid β position carbon atom with an oxygen atom, while replacing the linking oxymethylene with an amide-linking group. The target compounds were evaluated for FFAR4 agonistic activity, and the preferred compounds were evaluated for selectivity, oral glucose tolerance in normal ICR mice, antidiabetic activity in diet-induced obese (DIO) mice, pharmacokinetic properties in ICR mice and molecular modeling studies. The results showed that compound 10f possessed excellent FFAR4 agonistic activity and selectivity, significantly improved glucose tolerance in normal ICR mice, lowered blood glucose and promoted insulin secretion in a dose-dependent manner in DIO mice, and showed favorable pharmacokinetic properties. These results indicate that compound 10f may be a promising compound that deserves further structure–activity relationship and pharmacological studies for the development of antidiabetic drugs.