Diet-induced Obese Mice Research Articles

Effects of Partial Knockout of Skeletal Muscle Dynamin-Related Protein 1 on Skeletal Muscle Characteristics in Lean and Obese Mice

Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission and plays an essential role in maintaining skeletal muscle homeostasis. Recent studies reported muscle atrophy in mice when skeletal muscle Drp1 content was reduced. However, whether such atrophic phenotype also exists in diet-induced obese mice remains unknown. We recently reported that reducing skeletal muscle Drp1 resulted in improved whole-body glucose homeostasis and insulin sensitivity in diet-induced obese mice, but not lean healthy mice, suggesting Drp1 may exert divergent effects on physiological phenotypes under different conditions. OBJECTIVE: To determine the effects of partial knockout of skeletal muscle-specific heterozygous Drp1 (mDrp1+/−) on body composition, energy expenditure and skeletal muscle physiology in lean and obese mice. HYPOTHESIS: mDrp1+/− exhibits divergent alterations in physiological characteristics between lean healthy and obese mice. Methods: Tamoxifen-inducible mDrp1+/− mouse model was generated. Nine-week-old male and female mDrp1+/− and wildtype (WT) mice (n=6-8/group) were fed with either a high-fat diet (HFD) or low-fat diet (LFD) for four weeks, received tamoxifen injections, and remained on their respective diet for another four to six weeks. A DXA scan was conducted to measure body composition. Mice were housed in Promethion metabolic cages for 48 hours to measure energy expenditure. Isolated soleus (SOL) and extensor digitorum longus (EDL) muscles were used for assessing muscle cross sectional area (CSA) and contractility. Results: HFD-fed mice had significantly higher percentage of body fat ( p = 0.045) and lower respiratory exchange ratio ( p <0.0001) than LFD-fed mice, regardless of genotype. Regarding skeletal muscle characteristics, SOL from mDrp1+/− mice exhibited larger CSA ( p = 0.052) than WT mice, regardless of diet. However, there were no differences in muscle force or fatigue resistance in SOL between groups. In contrast, EDL muscle isolated from mDrp1+/− mice fed with HFD had greater muscle force than WT mice, but interestingly the force was lower in mDrp1+/−/LFD mice than WT/LFD mice (genotype x diet interaction effect, p = 0.001). Consistently, a significant interaction was found in both twitch and tetanic rate of force development and relaxation rates (genotype x diet interaction effect, p = 0.022, p = 0.033, p = 0.040, and p = 0.020, respectively). There was no difference in EDL muscle CSA between groups. CONCLUSION: Our data suggests that partial knockout of Drp1 in skeletal muscle induced divergent effects on CSA, force production and fatigability between diet induced obese and lean healthy mice. This study was supported by the National Institute of Health (R15DK131512). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Chronic UCN2 Administration Alters Muscle Mass, Exercise Metabolism, and Exercise Capacity in Lean Mice

Urocortin 2 (UCN2) is a member of the corticotropin-releasing hormone (CRH) family and an agonist of the G protein-coupled receptor CRH receptor type 2 (CRHR2), which is highly expressed in skeletal muscle but absent from liver in both rodents and humans. UCN2 overexpression or chronic administration increases muscle mass in both lean and diet-induced obese (DIO) mice and is also believed to increase peripheral insulin sensitivity, reminiscent of the effect of acute exercise. However, how these effects of UCN2 may impact muscle function and exercise capacity remain incompletely understood. We hypothesized that treatment with a long term UCN2 treatment would increase lean and muscle mass and improve aerobic exercise capacity in lean, healthy mice. Lean 10-week-old male C57Bl/6J mice completed treadmill acclimatization and an incremental running test to exhaustion to determine maximal running distance and peak oxygen consumption (VO2). Mice were assigned to sedentary or maximal running groups and were treated with UCN2 for 18 days. After the final dose, body composition was assessed by qNMR. Vehicle- and UCN2-treated mice assigned to the maximal running group completed a second maximal test, and immediately upon completion of exercise, blood glucose was measured, and tissues were collected. Blood glucose and tissues were collected from sedentary vehicle- and UCN2-treated mice in the fed state. UCN2 treatment increased food intake, qNMR lean mass, and individual muscle weights. UCN2-treated mice had reduced maximal running distance, peak VO2, and blood glucose in response to exercise compared to vehicle mice. In addition, UCN2-treated mice had reduced hepatic glycogen in both the sedentary and post maximal exercise states. Gastrocnemius muscle from sedentary UCN2-treated mice had increased glycogen content and reduced phosphorylation of glycogen synthase. Following maximal exercise, UCN2-treated mice had higher gastrocnemius glycogen compared to vehicle mice. This indicated similar total glycogen utilization between treatment groups in response to maximal exercise, despite UCN2-treated mice performing less work. Follow-up studies in sedentary mice demonstrated UCN2 dosing increased phosphorylation of proteins involved in insulin-dependent and -independent glucose uptake in gastrocnemius muscle. These findings indicate that UCN2 affects whole-body and muscle substrate utilization and glucose regulation and signaling which results in increased muscle mass and altered exercise capacity. However, the unpredictability of the effects of UCN2 agonism on these parameters requires much further study. This research was funded by Eli Lilly and Company. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Heat-killed Lactiplantibacillus plantarum Shinshu N-07 exerts antiobesity effects in western diet-induced obese mice.

The aim of this study was to evaluate the antiobesity effects of heat-killed Lactiplantibacillus plantarum Shinshu N-07 (N-07) isolated from fermented Brassica rapa L. Male mice were divided into three groups (n=10/group); normal diet, western diet (WD), or WD+N-07 (N-07) group and administered each diet for 56 days. The N-07 group showed significant suppression of body weight gain and epididymal fat, perirenal fat, and liver weights compared with the WD group. Higher levels of fecal total cholesterol, triglyceride (TG), and free fatty acid (FFA) were observed in the N-07 group than in the WD group. The mRNA expression of the cholesterol transporter ATP-binding cassette transporter G5 (ABCG5) was significantly increased in the small intestine of N-07-fed mice compared with WD-fed mice. Moreover, N-07 supplementation significantly increased the mRNA expression of ABCG5 and ABCG8 in Caco-2 cells. Furthermore, the TG- and FFA-removal ability of N-07 was confirmed to evaluate its soybean oil- and oleic acid-binding capacities in in vitro experiments. The antiobesity effects of N-07 might be due to its ability to promote lipid excretion by regulating cholesterol transporter expression and lipid-binding ability.

Pre-Existing Metabolic Conditions Impair the Beneficial Effects of Estrogen on Memory and Cognition in Ovariectomized Mice

Loss of estrogen, as a result of menopause, has been associated with cognitive decline and memory loss. Intriguingly, studies conducted with postmenopausal healthy women suggest that hormone replacement therapy improves cognitive functions. In contrast, clinical data involving subjects with a wide range of health conditions indicate that the effect of estrogen treatment varies. In addition to the cognitive decline, postmenopausal women have an increased risk of developing metabolic disorders including obesity, insulin resistance, and diabetes. In this study, we tested the hypothesis that pre-existing metabolic conditions reduce the beneficial effects of estradiol treatment and are responsible for the conflicting findings in cognitive functions after menopause. Female, seven-month-old C57BL/6J mice were fed with either a high-fat diet (HFD, BioServ #F3282) or a control diet (LFD, BioServ #F4031) for 10 to 14 weeks, then ovariectomized (OVX). In a randomized manner, mice received a silastic tube implant containing either 17β-estradiol (E2) or vehicle (VEH, cholesterol) and stayed on their respective diets. Body composition and metabolic parameters were measured in the four groups (HFD+VEH, HFD+E2, LFD+VEH, LFD+E2) to assess metabolic status, and novel object recognition test was performed to assess memory and cognition. Before OVX, HFD fed mice had significantly increased body weight, fat mass, basal blood glucose and insulin levels compared to mice fed with LFD. After OVX, LFD-VEH mice developed obesity and had elevated blood glucose and insulin levels, whereas E2 treatment prevented the metabolic changes. Interestingly, HFD-VEH mice had a reduction in fat mass after OVX, which was further decreased with E2 treatment. Overall, mice treated with E2 had lower body weight, fat mass, blood glucose and insulin levels compared to VEH treated mice regardless of their diet, and HFD fed mice had a higher body weight than mice fed the LFD, irrespective of their treatment. The novel object recognition test revealed that LFD-E2 mice spent significantly more time exploring the novel object than LFD-VEH mice. In contrast, there was no difference in exploration time between HFD-VEH and HFD-E2 treated mice. These preliminary results suggest that 1) E2 treatment may be beneficial to prevent the development of metabolic changes and improve cognitive function in LFD fed mice; 2) OVX alone did not worsen the metabolic status of diet-induced obese mice; 3) E2 treatment partially improved the metabolic status of HFD fed mice by decreasing fat mass, blood glucose and insulin levels; and 4) E2 treatment did not improve memory and cognition of HFD fed mice. Source of funding: P01AG071746 8456. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Evaluate and compare the anti-obesity effects of two probiotic preparations in high-fat diet-induced obese mice

This study screened two probiotic preparations and comprehensively evaluated for anti-obesity efficacy in high-fat diet-induced obese mice. Obese mice were orally administered with low, medium, and high doses of AB-Kefir (ABK) or Lactiplantibacillus plantarum TWK10 (TWK), respectively. After 8 weeks of administration, medium doses and above of ABK and TWK significantly reduced body weight, white adipose tissue weight, serum glucose, and lipid levels and attenuated hepatic steatosis and adipocyte hypertrophy in obese mice without affecting appetite. ABK and TWK also decreased serum adipokine levels and increased the adiponectin/leptin ratio to ameliorate obesity-induced adipose tissue dysfunction and chronic inflammation. Moreover, ABK and TWK reduced adipogenesis/lipogenesis-related transcription factors and enzymes in adipose tissue and improved energy metabolism by activating the AMPK pathway. In particular, TWK showed superior anti-obesity activity compared to ABK. The outcomes of this study will help explore potential anti-obesity probiotic functional foods.

ZnPP-laden nanoparticles improve glucose homeostasis and chronic inflammation during obesity.

Chronic inflammation plays a pivotal role in the development of Type 2 diabetes mellitus (T2DM). Previous studies have shown that haem oxygenase-1 (HO-1) plays a proinflammatory role during metabolic stress, suggesting that HO-1 inhibition could be an effective strategy to treat T2DM. However, the application of HO-1 inhibitors is restricted due to solubility-limited bioavailability. In this study, we encapsulated the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), within nanoparticles and investigated their role in regulating glucose homeostasis and chronic inflammation during obesity. We delivered DMSO-dissolved ZnPP (DMSO-ZnPP) and ZnPP-laden nanoparticles (Nano-ZnPP) to diet-induced obese male mice for 6weeks. Glucose and insulin tolerance tests were carried out, liver and adipose tissue gene expression profiles analysed, and systemic inflammation analysed using flow cytometry. Nanoparticles significantly increased the delivery efficiency of ZnPP in both cells and mice. In mice with diet-induced obesity, inhibition of HO-1 by Nano-ZnPP significantly decreased adiposity, increased insulin sensitivity, and improved glucose tolerance. Moreover, Nano-ZnPP treatment attenuated both local and systemic inflammatory levels during obesity. Mechanistically, Nano-ZnPP significantly attenuated glucagon, TNF, and fatty acid synthesis signalling pathways in the liver. In white adipose tissue, the oxidative phosphorylation signalling pathway was enhanced and the inflammation signalling pathway diminished by Nano-ZnPP. Our results show that Nano-ZnPP has better effects on the improvement of glucose homeostasis and attenuation of chronic inflammation, than those of DMSO-dissolved ZnPP. These findings indicate that ZnPP-laden nanoparticles are potential therapeutic agents for treating T2DM.

Single cell tracing of Pomc neurons reveals recruitment of ‘Ghost’ subtypes with atypical identity in a mouse model of obesity

The hypothalamus contains a remarkable diversity of neurons that orchestrate behavioural and metabolic outputs in a highly plastic manner. Neuronal diversity is key to enabling hypothalamic functions and, according to the neuroscience dogma, it is predetermined during embryonic life. Here, by combining lineage tracing of hypothalamic pro-opiomelanocortin (Pomc) neurons with single-cell profiling approaches in adult male mice, we uncovered subpopulations of ‘Ghost’ neurons endowed with atypical molecular and functional identity. Compared to ‘classical’ Pomc neurons, Ghost neurons exhibit negligible Pomc expression and are ‘invisible’ to available neuroanatomical approaches and promoter-based reporter mice for studying Pomc biology. Ghost neuron numbers augment in diet-induced obese mice, independent of neurogenesis or cell death, but weight loss can reverse this shift. Our work challenges the notion of fixed, developmentally programmed neuronal identities in the mature hypothalamus and highlight the ability of specialised neurons to reversibly adapt their functional identity to adult-onset obesogenic stimuli.

TAT38 and TAT38 mimics potently inhibit adipogenesis by repressing C/EBPα, PPARγ, Pi-PPARγ, and SREBP1 expression

Antiretroviral therapy-naive people living with HIV possess less fat than people without HIV. Previously, we found that HIV-1 transactivator of transcription (TAT) decreases fat in ob/ob mice. The TAT38 (a.a. 20–57) is important in the inhibition of adipogenesis and contains three functional domains: Cys-ZF domain (a.a. 20–35 TACTNCYCAKCCFQVC), core-domain (a.a. 36–46, FITKALGISYG), and protein transduction domain (PTD)(a.a. 47–57, RAKRRQRRR). Interestingly, the TAT38 region interacts with the Cyclin T1 of the P-TEFb complex, of which expression increases during adipogenesis. The X-ray crystallographic structure of the complex showed that the Cys-ZF and the core domain bind to the Cyclin T1 via hydrophobic interactions. To prepare TAT38 mimics with structural and functional similarities to TAT38, we replaced the core domain with a hydrophobic aliphatic amino acid (from carbon numbers 5 to 8). The TAT38 mimics with 6-hexanoic amino acid (TAT38 Ahx (C6)) and 7-heptanoic amino acid (TAT38 Ahp (C7)) inhibited adipogenesis of 3T3-L1 potently, reduced cellular triglyceride content, and decreased body weight of diet-induced obese (DIO) mice by 10.4–11 % in two weeks. The TAT38 and the TAT38 mimics potently repressed the adipogenic transcription factors genes, C/EBPα, PPARγ, and SREBP1. Also, they inhibit the phosphorylation of PPARγ. The TAT peptides may be promising candidates for development into a drug against obesity or diabetes.

Resistant starch-enriched brown rice exhibits prebiotic properties and enhances gut health in obese mice

Resistant starch serves as a prebiotic in the large intestine, aiding in the maintenance of a healthy intestinal environment and mitigating associated chronic illnesses. This study aimed to investigate the impact of resistant starch-enriched brown rice (RBR) on intestinal health and functionality. We assessed changes in resistant starch concentration, structural alterations, and branch chain length distribution throughout the digestion process using an in vitro model. The efficacy of RBR in the intestinal environment was evaluated through analyses of its prebiotic potential, effects on intestinal microbiota, and intestinal function-related proteins in obese animals fed a high-fat diet. RBR exhibited a higher yield of insoluble fraction in both the small and large intestines compared to white and brown rice. The total digestible starch content decreased, while the resistant starch content significantly increased during in vitro digestion. Furthermore, RBR notably enhanced the growth of four probiotic strains compared to white and brown rice, displaying higher proliferation activity than the positive control, FOS. Notably, consumption of RBR by high-fat diet-induced obese mice suppressed colon shortening, increased Bifidobacteria growth, and improved intestinal permeability. These findings underscore the potential prebiotic and gut health-promoting attributes of RBR, offering insights for the development of functional foods aimed at preventing gastrointestinal diseases.

Caffeic acid combined with arabinoxylan or β-glucan attenuates diet-induced obesity in mice via modulation of gut microbiota and metabolites

Polyphenols and dietary fibers in whole grains are important bioactive compounds to reduce risks for obesity. However, whether the combination of the two components exhibits a stronger anti-obesity effect remains unclear. Caffeic acid is a major phenolic acid in cereals, and arabinoxylan and β-glucan are biological macromolecules with numerous health benefits. Here, we investigated the effect of caffeic acid combined with arabinoxylan or β-glucan on glucose and lipid metabolism, gut microbiota, and metabolites in mice fed a high-fat diet (HFD). Caffeic acid combined with arabinoxylan or β-glucan significantly reduced the body weight, blood glucose, and serum free fatty acid concentrations. Caffeic acid combined with β-glucan effectively decreased serum total cholesterol levels and hepatic lipid accumulation, modulated oxidative and inflammatory stress, and improved gut barrier function. Compared with arabinoxylan, β-glucan, and caffeic acid alone, caffeic acid combined with arabinoxylan or β-glucan exhibited a better capacity to modulate gut microbiota, including increased microbial diversity, reduced Firmicutes/Bacteroidetes ratio, and increased abundance of beneficial bacteria such as Bifidobacterium. Furthermore, caffeic acid combined with β-glucan reversed HFD-induced changes in microbiota-derived metabolites involving tryptophan, purine, and bile acid metabolism. Thus, caffeic acid and β-glucan had a synergistic anti-obesity effect by regulating specific gut microbiota and metabolites.

Adipocyte-targeted delivery of rosiglitazone with localized photothermal therapy for the treatment of diet-induced obesity in mice

Obesity represents a growing public health concern and is closely associated with metabolic complications such as diabetes and fatty liver disease. Anti-obesity medications currently available have limited efficacy in weight loss and are often accompanied by adverse effects. This study proposes a localized photothermal therapy (PTT) combined with adipocyte-targeted delivery of rosiglitazone (RSG) to address obesity. Specifically, cationic albumin nanoparticles (cNPs) were synthesized to deliver RSG precisely to white adipocytes, stimulating the browning process. An IR780-loaded thermosensitive hydrogel was injected and allowed to gel in situ to afford a subcutaneous reservoir that enables localized PTT and controlled release of RSG cNPs. Notably, cNPs significantly enhanced the internalization efficiency in adipocytes in vitro and prolonged the therapeutic retention in the adipose tissue in vivo. Co-administration of RSG cNPs and PTT substantially reduced fat content, induced browning in white adipose tissue in diet-induced obese mice, and mitigated complications such as insulin resistance, fatty liver, and hyperlipidemia. The increased expression of uncoupling protein 1 contributes to enhancing energy expenditure and facilitating adipose metabolism, thereby effectively combating obesity. This therapeutic approach integrates localized PTT with adipocyte-targeted delivery to combat the global obesity epidemic thus offering a promising solution with reduced systemic toxicity and enhanced efficacy. Statement of significanceCationic albumin nanoparticles are capable of efficient internalization in adipocytes, which may enhance drug targeting to adipose tissue.The combination of rosiglitazone-loaded cationic albumin nanoparticles and local hyperthermia effectively reduces lipid accumulation in adipocytes and induces an upregulated expression of uncoupling protein 1.The combination therapy effectively inhibits fat accumulation, induces adipocyte browning, and regulates systemic metabolism in diet-induced obese mice.

Fructooligosaccharides Intake during Pregnancy Improves Metabolic Phenotype of Offspring in High Fat Diet-Induced Obese Mice.

Obesity and metabolic diseases are closely associated, and individuals who become obese are also prone to type 2 diabetes and cardiovascular disorders. Gut microbiota is mediated by diet and can influence host metabolism and the incidence of metabolic disorders. Recent studies have suggested that improving gut microbiota through a fructooligosaccharide (FOS)-supplemented diet may ameliorate obesity and other metabolic disorders. Although accumulating evidence supports the notion of the developmental origins of health and disease, the underlying mechanisms remain obscure. ICR mice are fed AIN-93G formula-based cellulose -, FOS-, acetate-, or propionate-supplemented diets during pregnancy. Offspring are reared by conventional ICR foster mothers for 4 weeks; weaned mice are fed high fat diet for 12 weeks and housed individually. The FOS and propionate offspring contribute to suppressing obesity and improving glucose intolerance. Gut microbial compositions in FOS-fed mothers and their offspring are markedly changed. However, the beneficial effect of FOS diet on the offspring is abolished when antibiotics are administered to pregnant mice. The findings highlight the link between the maternal gut environment and the developmental origin of metabolic syndrome in offspring. These results open novel research avenues into preemptive therapies for metabolic disorders by targeting the maternal gut microbiota.

Diet switch pre-vaccination improves immune response and metabolic status in formerly obese mice.

Metabolic disease is epidemiologically linked to severe complications upon influenza virus infection, thus vaccination is a priority in this high-risk population. Yet, vaccine responses are less effective in these same hosts. Here we examined how the timing of diet switching from a high-fat diet to a control diet affected influenza vaccine efficacy in diet-induced obese mice. Our results demonstrate that the systemic meta-inflammation generated by high-fat diet exposure limited T cell maturation to the memory compartment at the time of vaccination, impacting the recall of effector memory T cells upon viral challenge. This was not improved with a diet switch post-vaccination. However, the metabolic dysfunction of T cells was reversed if weight loss occurred 4 weeks before vaccination, restoring a functional recall response. This corresponded with changes in the systemic obesity-related biomarkers leptin and adiponectin, highlighting the systemic and specific effects of diet on influenza vaccine immunogenicity.

Identification of phenolic compounds from fermented Moringa oleifera Lam. leaf supplemented with Fuzhuan brick tea and their volatile composition and anti-obesity activity.

As a nutritious plant with valuable potential, the Moringa oleifera Lam. (MOL) leaf addition on Fuzhuan brick tea (FBT) for the co-fermentation (MOL-FBT) was an industry innovation and a new route to make full use of MOL leaf. After optimization of the extraction conditions, the best conditions for the polyphenols extraction method from MOL-FBT (MFP) were 60°C for 40min (1:80, V/W) using response surface methodology. A total of 30 phenolics were identified and quantified. Most of the polyphenols were increased after adding MOL leaf for co-fermentation compared to FBT polyphenols. In particular, caffeic acids were found only in MFP. Moreover, the MFP received high value in taste, aroma, and color. In total, 62 volatile flavor compounds, consisting of 3 acids, 5 alcohols, 15 aldehydes, 4 esters, 20 hydrocarbons, 10 ketones, and 5 others, were identified in MFP. In addition, MFP inhibited 3T3-L1 preadipocyte differentiation in a dose-dependent manner and decreased lipid accumulation via the peroxisome proliferator-activated receptor gamma (PPARγ)/CCAAT/enhancer binding protein alpha (CEBPα)/cluster of differentiation 36 (CD36) axis and induced a brown adipocyte-like phenotype. In vivo experiments were further conducted to confirm the in vitro results. MFP regulated lipid accumulation, glucose/insulin tolerance, improved liver and kidney function, and inhibited the secretion of pro-inflammatory factors by the PPARγ/CEBPα/CD36 axis and alleviated inflammation in high fat and high fructose diet-induced obese mice. In summary, MFP possesses high-quality properties and anti-obesity effects, as well as the great potential to be used as a novel functional food product.

Anti-obesity potentiality of Lactiplantibacillus plantarum E2_MCCKT isolated from a fermented beverage, haria: a high fat diet-induced obese mice model study.

Obesity is a growing epidemic worldwide. Several pharmacologic drugs are being used to treat obesity but these medicines exhibit side effects. To find out the alternatives of these drugs, we aimed to assess the probiotic properties and anti-obesity potentiality of a lactic acid bacterium E2_MCCKT, isolated from a traditional fermented rice beverage, haria. Based on the 16S rRNA sequencing, the bacterium was identified as Lactiplantibacillus plantarum E2_MCCKT. The bacterium exhibited in vitro probiotic activity in terms of high survivability in an acidic environment and 2% bile salt, moderate auto-aggregation, and hydrophobicity. Later, E2_MCCKT was applied to obese mice to prove its anti-obesity potentiality. Adult male mice (15.39 ± 0.19g) were randomly divided into three groups (n = 5) according to the type of diet: normal diet (ND), high-fat diet (HFD), and HFD supplemented with E2_MCCKT (HFT). After four weeks of bacterial treatment on the obese mice, a significant reduction of body weight, triglyceride, and cholesterol levels, whereas, improvements in serum glucose levels were observed. The bacterial therapy led to mRNA up-regulation of lipolytic transcription factors such as peroxisome proliferator-activated receptor-α which may increase the expression of fatty acid oxidation-related genes such as acyl-CoA oxidase and carnitine palmitoyl-transferase-1. Concomitantly, both adipocytogenesis and fatty acid synthesis were arrested as reflected by the down-regulation of sterol-regulatory element-binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase genes. In protein expression study, E2_MCCKT significantly increased IL-10 expression while decreasing pro-inflammatory cytokine (IL-1Ra and TNF-α) expression. In conclusion, the probiotic Lp. plantarum E2_MCCKT might have significant anti-obesity effects on mice.

Orally Ingested Self-Powered Stimulators for Targeted Gut-Brain Axis Electrostimulation to Treat Obesity and Metabolic Disorders.

Obesity is a significant health concern that often leads to metabolic dysfunction and chronic diseases. This study introduces a novel approach to combat obesity using orally ingested self-powered electrostimulators. These electrostimulators consist of piezoelectric BaTiO3 (BTO) particles conjugated with capsaicin (Cap) and aim to activate the vagus nerve. Upon ingestion by diet-induced obese (DIO) mice, the BTO@Cap particles specifically target and bind to Cap-sensitive sensory nerve endings in the gastric mucosa. In response to stomach peristalsis, these particles generate electrical signals. The signals travel via the gut-brain axis, ultimately influencing the hypothalamus. By enhancing satiety signals in the brain, this neuromodulatory intervention reduces food intake, promotes energy metabolism, and demonstrates minimal toxicity. Over a 3-week period of daily treatments, DIO mice treated with BTO@Cap particles show a significant reduction in body weight compared to control mice, while maintaining their general locomotor activity. Furthermore, this BTO@Cap particle-based treatment mitigates various metabolic alterations associated with obesity. Importantly, this noninvasive and easy-to-administer intervention holds potential for addressing other intracerebral neurological diseases.

Conditioned overconsumption is dependent on reinforcer type in lean, but not obese, mice.

Associative learning can drive many different types of behaviors, including food consumption. Previous studies have shown that cues paired with food delivery while mice are hungry will lead to increased consumption in the presence of those cues at later times. We previously showed that overconsumption can be driven in male mice by contextual cues, using chow pellets. Here we extended our findings by examining other parameters that may influence the outcome of context-conditioned overconsumption training. We found that the task worked equally well in males and females, and that palatable substances such as high-fat diet and Ensure chocolate milkshake supported learning and induced overconsumption. Surprisingly, mice did not overconsume when sucrose was used as the reinforcer during training, suggesting that nutritional content is a critical factor. Interestingly, we also observed that diet-induced obese mice did not learn the task. Overall, we find that context-conditioned overconsumption can be studied in lean male and female mice, and with multiple reinforcer types.

Mechanistic insights into the role of USP14 in adipose tissue macrophage recruitment and insulin resistance in obesity

Diet-induced obesity can cause metabolic syndromes. The critical link in disease progression is adipose tissue macrophage (ATM) recruitment, which drives low-level inflammation, triggering adipocyte dysfunction. It is unclear whether ubiquitin-specific proteinase 14 (USP14) affects metabolic disorders by mediating adipose tissue inflammation. In the present study, we showed that USP14 is highly expressed in ATMs of obese human patients and diet-induced obese mice. Mouse USP14 overexpression aggravated obesity-related insulin resistance by increasing the levels of pro-inflammatory ATMs, leading to adipose tissue inflammation, excessive lipid accumulation, and hepatic steatosis. In contrast, USP14 knockdown in adipose tissues alleviated the phenotypes induced by a high-fat diet. Co-culture experiments showed that USP14 deficiency in macrophages led to decreased adipocyte lipid deposition and enhanced insulin sensitivity, suggesting that USP14 plays an important role in ATMs. Mechanistically, USP14 interacted with TNF receptor-associated 6, preventing K48-linked ubiquitination as well as proteasome degradation, leading to increased pro-inflammatory polarization of macrophages. In contrast, the pharmacological inhibition of USP14 significantly ameliorated diet-induced hyperlipidemia and insulin resistance in mice. Our results demonstrated that macrophage USP14 restriction constitutes a key constraint on the pro-inflammatory M1 phenotype, thereby inhibiting obesity-related metabolic diseases.

Enhanced Metabolic Effects of Fish Oil When Combined with Vitamin D in Diet-Induced Obese Male Mice.

Vitamin D (vit D) and fish oil (FO) both offer unique health benefits, however, their combined effects have not been evaluated in obesity and nonalcoholic fatty liver disease (NAFLD). Hence, we hypothesized that vit D and FO supplementation would have additive effects in reducing obesity-associated inflammation and NAFLD. Male C57BL6 mice were split into four groups and fed a high fat (HF) diet supplemented with a low (HF; +200 IU vit D) or high dose of vitamin D (HF + D; +1000 IU vit D); combination of vit D and FO (HF-FO; +1000 IU vit D); or only FO (HF-FO; +200 IU vit D) for 12 weeks. We measured body weight, food intake, glucose tolerance, and harvested epididymal fat pad and liver for gene expression analyses. Adiposity was reduced in groups supplemented with both FO and vit D. Glucose clearance was higher in FO-supplemented groups compared to mice fed HF. In adipose tissue, markers of fatty acid synthesis and oxidation were comparable in groups that received vit D and FO individually in comparison to HF. However, the vit D and FO group had significantly lower fatty acid synthesis and higher oxidation compared to the other groups. Vit D and FO also significantly improved fatty acid oxidation, despite similar fatty acid synthesis among the four groups in liver. Even though we did not find additive effects of vit D and FO, our data provide evidence that FO reduces markers of obesity in the presence of adequate levels of vit D.

Systemic investigation of di-isobutyl phthalate (DIBP) exposure in the risk of cardiovascular via influencing the gut microbiota arachidonic acid metabolism in obese mice model

Phthalate esters (PE), a significant class of organic compounds used in industry, can contaminate humans and animals by entering water and food chains. Recent studies demonstrate the influence of PE on the development and progression of heart diseases, particularly in obese people. Di-isobutyl phthalate (DIBP) was administered orally to normal and diet-induced obese mice in this research to assess cardiovascular risk. The modifications in the microbial composition and metabolites were examined using RNA sequencing and mass spectrometry analysis. Based on the findings, lean group rodents were less susceptible to DIBP exposure than fat mice because of their cardiovascular systems. Histopathology examinations of mice fed a high-fat diet revealed lesions and plagues that suggested a cardiovascular risk. In the chronic DIBP microbial remodeling metagenomics Faecalibaculum rodentium was the predominant genera in obese mice. According to metabolomics data, arachidonic acid (AA) metabolism changes caused by DIBP were linked to unfavorable cardiovascular events. Our research offers new understandings of the cardiovascular damage caused by DIBP exposure in obese people and raises the possibility that arachidonic acid metabolism could be used as a regulator of the gut microbiota to avert related diseases.