Mouse Model Of Obesity Research Articles

If You Give a Mouse a Cookie: Quantification of Metabolic and Neurologic Changes in Murine Model for Charcot Arthropathy

Category: Basic Sciences/Biologics; Diabetes Introduction/Purpose: Charcot arthropathy (Charcot) is a significant complication of diabetes mellitus thought to occur as a result of repetitive microtrauma to the insensate foot. We previously developed a murine model of diet-induced obese mice with peripheral neuropathy which underwent a high-intensity treadmill protocol designed to induce metabolic, neurologic, radiographic, and histopathologic features similar to Charcot in humans. Using this model, we aimed to further characterize the metabolic and sensory changes that occur in these diet-induced obese mice subjected to various high-intensity exercise protocols designed to induce repetitive microtrauma to the hind paws similar to Charcot. Methods: Forty-nine wild-type C57BL/6J mice were randomized to receive either a standard or high-fat diet and exposed to a high-intensity treadmill running protocol for various lengths of time as described in Figure 1A. Group 1 received a standard low-fat (10% kcal from fat) mouse diet and did not participate in the treadmill protocol. Groups 2, 3, 4, and 5 were fed a high-fat (60% kcal from fat) diet ad libidum to facilitate diet-induced obesity (DIO) and completed the treadmill protocol for various lengths of time. Initial body weights, DEXA scans, hind-paw Von-Frey filament sensory testing, and hot plate sensory testing following the previously published murine model were performed prior to the start of the running protocol and repeated at weeks 4, 8, 12, and 16. Plantar temperatures were measured initially and at 16 weeks. Paired-t-Test and one-way ANOVA were utilized to determine the significance of observed results. Results: Bodyweights are represented in Figure 1B. Plantar temperature was not significantly different between treadmill running groups at week 0 or 16 (Figure 1C). Hot plate testing demonstrated no significant difference in the number of responses between groups at week 0. By week 16, groups 3 and 5 demonstrated decreased hind-paw sensitivity to hot plate testing, suggestive of decreased sensation. Von Frey sensory testing also showed more force was required to induce a positive response, indicating decreased hind-paw sensation in high-fat diet groups (Figure 1D). By weeks 12 and 16, high-fat diet groups had significantly higher fasting blood glucose levels than group 1(Figure 1E). Additionally, high-fat diet groups demonstrated a significantly higher body fat percentage and lower bone mineral density (BMD) at weeks 0 and 16. Conclusion: Decreased sensitivity to hot plate and Von Frey testing demonstrate decreased sensation in the hind paws of DIO mice fed a high-fat diet. DIO mice also have significantly higher fasting blood glucose levels than mice fed a regular diet indicating impaired glucose tolerance. These metabolic and sensory changes suggest this is a reliable murine model of diabetic neuropathy. This model of diabetic neuropathy provides an avenue to study the radiographic and histologic changes that occur in these mice when exposed to repetitive exercise-induced microtrauma similar to Charcot arthropathy in humans.

Impact of Oral Administration of Lactiplantibacillus plantarum Strain CNCM I-4459 on Obesity Induced by High-Fat Diet in Mice.

Recent evidence suggests that some lactobacilli strains, particularly Lactiplantibacillus plantarum, have a beneficial effect on obesity-associated syndromes. Several studies have investigated probiotic challenges in models of high-fat diet (HFD)-induced obesity, specifically with respect to its impact on hepatic and/or adipocyte metabolism, gut inflammation and epithelial barrier integrity, and microbiota composition. However, only a few studies have combined these aspects to generate a global understanding of how probiotics exert their protective effects. Here, we used the probiotic strain L. plantarum CNCM I-4459 and explored its impact on a mouse model of HFD-induced obesity. Briefly, mice were administered 1 × 109 CFUs/day and fed HFD for 12 weeks. Treatment with this strain improved insulin sensitivity by lowering serum levels of fasting glucose and fructosamine. Administration of the probiotic also affected the transport and metabolism of glucose, resulting in the downregulation of the hepatic Glut-4 and G6pase genes. Additionally, L. plantarum CNCM I-4459 promoted a decreased concentration of LDL-c and modulated hepatic lipid metabolism (downregulation of Fasn, Plin, and Cpt1α genes). Probiotic treatment also restored HFD-disrupted intestinal microbial composition by increasing microbial diversity and lowering the ratio of Firmicutes to Bacteroidetes. In conclusion, this probiotic strain represents a potential approach for at least partial restoration of the glucose sensitivity and lipid disruption that is associated with obesity.

Activation of AMPK ameliorates acute severe pancreatitis by suppressing pancreatic acinar cell necroptosis in obese mice models

Obese people with acute pancreatitis (AP) have an increased risk of developing severe acute pancreatitis (SAP), which prolongs the length of hospital stay and increases mortality. Thus, elucidation of the mechanisms through which SAP occurs in obese individuals will provide clues for possible treatment targets. Differences in early events in obese or lean patients with AP have not been conclusively reported. We selected C57BL/6 mice as lean mice models, ob/ob mice or diet induced obese (DIO) mice as obese mice models and then induced experimental AP in mice via injections of caerulein. There were suppressed p-AMPK expressions in the pancreas of obese mice, compared with same-age lean C57BL/6 mice, which were further reduced in AP mice models. Obese AP mice were treated using AICAR, a direct AMPK agonist, which prevented pancreatic damage and cell death, suppressed pancreatic enzyme levels in serum, reduced the areas of fat saponification in the peritoneal cavity, prevented injury in other organs and decreased mice mortality rate. Further assays showed that AICAR activates p-AMPK to stabilize pro-caspase-8. Pro-caspase-8 enhances RIPK3 degradation, inhibits pancreatic acinar cell necroptosis, and downregulates the release of pancreatic enzymes. Thus, activation of AMPK by AICAR alleviates pancreatic acinar cell necroptosis and converts SAP to mild acute pancreatitis in obese mice.

Gastrodia elata extract exerts anti-obesity effects on obese mice caused by a high-starch diet by suppressing SREBP-1 and ChREBP

ObjectiveGastrodia elata (GE), a natural treatment, is extensively used in traditional Korean medicine. The study's goal was to look into how GE affected obese mice that had been fed a high-starch diet (HSD). MethodsThe C57BL/6 J mice used in this investigation were given HSD to make them obese. Gastrodia elata extract (GEE) was administered orally to the mice throughout the course of the next five weeks in doses of 100, 200, and 500 mg/kg. When the experiment was over, we measured the animals body weight, liver and fat weight, blood biochemical parameters, and gene expression that is related to obesity. ResultsThe overall body weight of animals was dramatically lowered via GEE oral treatment. In comparison to the HSD group, the serum and liver TG levels were considerably lower in the GEE-treated group. Additionally, regional fatty tissues and liver weight markedly dropped in the GEE-treated batch in comparison to the HSD batch. We observed considerably lower levels of PPAR-γ, C/EBP-α, and ChREBP mRNA expression level in the GEE-treated group in addition to lower levels of SREBP-1, ACC, and FAS protein expression. ConclusionThe studies show that GEE has anti-obesity advantages in the mouse model of obesity caused by HSD. Despite the fact that we utilized mice as a model for the experiment rather than people, who have different biochemical pathways, the finding has significant implications for how GEE generally functions.

A Synthetic ERR Agonist Alleviates Metabolic Syndrome.

Physical exercise induces physiologic adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be effective in the treatment of a range of diseases including obesity and metabolic syndrome. Previously, we described the development of SLU-PP-332, an agonist for the estrogen-related receptor (ERR)α, β, and γ nuclear receptors that activates an acute aerobic exercise program. Here we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome. Diet-induced obese or ob/ob mice were administered SLU-PP-332, and the effects on a range of metabolic parameters were assessed. SLU-PP-332 administration mimics exercise-induced benefits on whole-body metabolism in mice including increased energy expenditure and fatty acid oxidation. These effects were accompanied by decreased fat mass accumulation. Additionally, the ERR agonist effectively reduced obesity and improved insulin sensitivity in models of metabolic syndrome. Pharmacological activation of ERR may be an effective method to treat metabolic syndrome and obesity. SIGNIFICANCE STATEMENT: An estrogen receptor-related orphan receptor agonist, SLU-PP-332, with exercise mimetic activity, holds promise as a therapeutic to treat metabolic diseases by decreasing fat mass in mouse models of obesity.

Global and local fat effects on bone mass and quality in obesity.

The aim of this study was to investigate the global and local impact of fat on bone in obesity by using the diet-induced obese (DIO) mouse model. In this study, we generated a diet-induced mouse model of obesity to conduct lipidomic and 3D imaging assessments of bone marrow fat, and evaluated the correlated bone adaptation indices and bone mechanical properties. Our results indicated that bone mass was reduced and bone mechanical properties were impaired in DIO mice. Lipidomic sequencing and bioinformatic analysis identified 373 differential lipids, 176 of which were upregulated and 197 downregulated. Functional enrichment analysis revealed a significant downregulation of the pathways: fat digestion and absorption (ko04975) and lipolysis regulation in adipocytes (ko04923) in DIO mice, leading to local fat accumulation. The use of 3D imaging confirmed the increase in fat accumulation within the bone marrow cavity of obese mice. Our study sheds light on the intricate interplay between fat and bone, and provides a non-toxic and non-invasive method for measuring marrow adipose tissue.

Metformin targets intestinal immune system signaling pathways in a high-fat diet-induced mouse model of obesity and insulin resistance.

Research findings of the past decade have highlighted the gut as the main site of action of the oral antihyperglycemic agent metformin despite its pharmacological role in the liver. Extensive evidence supports metformin's modulatory effect on the composition and function of gut microbiota, nevertheless, the underlying mechanisms of the host responses remain elusive. Our study aimed to evaluate metformin-induced alterations in the intestinal transcriptome profiles at different metabolic states. The high-fat diet-induced mouse model of obesity and insulin resistance of both sexes was developed in a randomized block experiment and bulk RNA-Seq of the ileum tissue was the method of choice for comparative transcriptional profiling after metformin intervention for ten weeks. We found a prominent transcriptional effect of the diet itself with comparatively fewer genes responding to metformin intervention. The overrepresentation of immune-related genes was observed, including pronounced metformin-induced upregulation of immunoglobulin heavy-chain variable region coding Ighv1-7 gene in both high-fat diet and control diet-fed animals. Moreover, we provide evidence of the downregulation NF-kappa B signaling pathway in the small intestine of both obese and insulin-resistant animals as well as control animals after metformin treatment. Finally, our data pinpoint the gut microbiota as a crucial component in the metformin-mediated downregulation of NF-kappa B signaling evidenced by a positive correlation between the Rel and Rela gene expression levels and abundances of Parabacteroides distasonis, Bacteroides spp., and Lactobacillus spp. in the gut microbiota of the same animals. Our study supports the immunomodulatory effect of metformin in the ileum of obese and insulin-resistant C57BL/6N mice contributed by intestinal immunoglobulin responses, with a prominent emphasis on the downregulation of NF-kappa B signaling pathway, associated with alterations in the composition of the gut microbiome.

Obesity amplifies influenza virus-driven disease severity in male and female mice

Influenza virus-induced respiratory pneumonia remains a major public health concern. Obesity, metabolic diseases, and female sex are viewed as independent risk factors for worsened influenza virus-induced lung disease severity. However, lack of experimental models of severe obesity in female mice limits discovery-based studies. Here, via utility of thermoneutral housing (30°C) and high-fat diet (HFD) feeding, we induced severe obesity and metabolic disease in female C57BL/6 mice and compared their responses to severely obese male C57BL/6 counterparts during influenza virus infection. We show that lean male and female mice have similar lung edema, inflammation, and immune cell infiltration during influenza virus infection. At standard housing conditions, HFD-fed male, but not female, mice exhibit severe obesity, metabolic disease, and exacerbated influenza disease severity. However, combining thermoneutral housing and HFD feeding in female mice induces severe obesity and metabolic disease, which is sufficient to amplify influenza virus-driven disease severity to a level comparable to severely obese male counterparts. Lastly, increased total body weights of male and female mice at time of infection correlated with worsened influenza virus-driven disease severity metrics. Together, our findings confirm the impact of obesity and metabolic disease as key risk factors to influenza disease severity and present a novel mouse experimental model suitable for future mechanistic interrogation of sex, obesity, and metabolic disease traits in influenza virus-driven disease severity.

Hepatic FASN deficiency differentially affects nonalcoholic fatty liver disease and diabetes in mouse obesity models.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown. Here, we show that hepatic FASN deficiency differentially affects NAFLD and diabetes depending on the etiology of obesity. Hepatocyte-specific ablation of FASN ameliorated NAFLD and diabetes in melanocortin 4 receptor-deficient mice but not in mice with diet-induced obesity. In leptin-deficient mice, FASN ablation alleviated hepatic steatosis and improved glucose tolerance but exacerbated fed hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with suppression of DNL and attenuation of gluconeogenesis and fatty acid oxidation, respectively. The exacerbation of fed hyperglycemia by FASN ablation in leptin-deficient mice appeared attributable to impairment of hepatic glucose uptake triggered by glycogen accumulation and citrate-mediated inhibition of glycolysis. Further investigation of the therapeutic potential of hepatic FASN inhibition for NAFLD and diabetes in humans should thus consider the etiology of obesity.

High-fat diet aggravates the severity of the in vitro posttraumatic osteoarthritis model through macrophagic FBW7.

Osteoarthritis (OA) is a prevalent and distressing chronic degenerative joint disorder characterized by damaged articular cartilage and inflamed joints. Among risk factors, obesity has emerged as the second-leading contributor to OA after age. Obesity is believed to play a key role in the development and progression of OA. This study aimed to investigate the role and underlying mechanisms of high-fat diet (HFD)-induced obesity in the development of OA. Our findings revealed that HFD could aggravate the destabilization of the medial meniscus (DMM)-induced damage in the mouse model of obesity. Similar results were observed when macrophages obtained from HFD-fed mice were cocultured with cartilage and subsequently stimulated with interleukin-1β (IL-1β). Mechanistically, we observed a decrease in the expression of intraarticular macrophagic FBW7, which was implicated in the aggravation of OA in the HFD-fed animal. Furthermore, by modulating the immune status of macrophages, we found that reversing the macrophagic expression of FBW7 in these cells can alleviate the chondrocyte damage. In conclusion, this study provides novel insights into the pathological mechanisms underlying HFD-related OA development by identifying the role of FBW7 in synovial macrophages. These findings open up new avenues for research and therapeutic interventions targeting HFD-related OA.

Abstract 041: Adipocyte (Pro)Renin Receptor Via SPRR Regulates Renal Sodium-glucose Cotransporter-2 Expression And Glomerular Filtration Rate In Mice

Evidence is available to suggest a potential role of adipocyte-derived factors to control renal function but the nature of these endocrine factors largely remains elusive. Sodium-glucose cotransporter 2 (SGLT2) controls Na + delivery to the macula densa thereby determining tubuloglomerular feedback and thus glomerular filtration rate (GFR), providing the molecular basis for attenuation of glomerular hyperfiltration and diabetic kidney disease by SGLT2 inhibitors. Furthermore, we previously reported that soluble (pro)renin receptor (sPRR) inhibits obesity-induced renal SGLT2 expression, thus reducing GFR and albuminuria in a mouse model of diet-induced obesity. In the present study, we examined adipocytes as a potential source of sPRR that acts in an endocrine manner to regulate renal function, particularly GFR, through regulation of renal SGLT2 expression. PRR floxed mice was crossed with Adipoq-CreERT2 mice and gene inactivation was induced by tamoxifen in adulthood (termed as Adipo PRR KO). Under basal condition, male 4-month old Adipo PRR KO mice exhibited a 33.65% increase in GFR as assessed by transdermal measurement of GFR as compared with floxed controls (1318.26± 38.35 in KO group vs . 986.33± 14.31 ul/min/100g b.w. in floxed group, n = 6, p < 0.01). Dapagliflozin-sensitive SGLT2 activity as assessed by 6-h urinary glucose excretion was increased by 1.93 folds in Adipo PRR KO mice (SGLT2 activity: 13.19± 1.64 in KO group vs. 6.83± 1.20 mg/6h in floxed group, n=7-10, p < 0.05). Immunoblotting analysis detected a more than 10-fold increase in renal protein abundance of SGLT2 in the null mice (12.38± 1.51 in KO group vs.1.00± 0.26 in floxed group, n=6, p < 0.01) whereas the increase in renal SGLT2 mRNA was quite modest (1.25± 0.08 in KO group vs . 1.00± 0.06 in floxed group; n = 6, p < 0.05). As compared with floxed mice, Adipo PRR KO mice showed a 44.62% fall in plasma sPRR concentration as assessed by ELISA (1.18± 0.09 in KO group vs . 2.12± 0.10 ng/ml in floxed group, n = 6, p < 0.01). Taken together, the present study, for the first time, provides evidence for an endocrine action of adipocyte PRR to regulate renal SGLT2 expression and GFR likely through sPRR.

Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA.

The lateral hypothalamic area (LHA) regulates food intake and energy balance. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we show that GABRA5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity mouse models in males. Chemogenetic inhibition of GABRA5LHA suppresses fat thermogenesis and increases weight gain, whereas gene silencing of GABRA5 in LHA decreases weight gain. In the diet-induced obesity mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by monoamine oxidase B (Maob). Gene silencing of astrocytic Maob in LHA facilitates fat thermogenesis and reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a Maob inhibitor, KDS2010. We propose that firing of GABRA5LHA suppresses fat accumulation and selective inhibition of astrocytic GABA is a molecular target for treating obesity.

Mutational landscape of intestinal crypt cells after long-term in vivo exposure to high fat diet

Obesity is a modifiable risk factor in cancer development, especially for gastrointestinal cancer. While the etiology of colorectal cancer is well characterized by the adenoma-carcinoma sequence, it remains unclear how obesity influences colorectal cancer development. Dietary components of a high fat diet along with obesity have been shown to modulate the cancer risk by perturbing the homeostasis of intestinal stem cells, yet how adiposity impacts the development of genomic instability has not been studied. Mutational signatures are a powerful way to understand how a complex biological response impacts genomic stability. We utilized a mouse model of diet-induced obesity to study the mutational landscape of intestinal crypt cells after a 48-week exposure to an experimental high fat diet in vivo. By clonally enriching single crypt derived cells in organoid culture and obtaining whole genome sequences, we analyzed and compared the mutational landscape of intestinal epithelial cells from normal diet and high fat diet mice. Single nucleotide substitution signatures and indel signatures present in our cohort are found equally active in both diet groups and reflect biological processes of normal aging, cellular replication, and oxidative stress induced during organoid culturing. Thus, we demonstrate that in the absence of activating mutations or chemical exposure, high fat diet alone is not sufficient to increase genomic instability.

223 Beta cell-derived C3 is protective in a mouse model of diet-induced obesity and diabetes

223 Beta cell-derived C3 is protective in a mouse model of diet-induced obesity and diabetes

Malonate induces the browning of white adipose tissue in high-fat diet induced obesity model

Obesity increases the risk of various diseases, and many studies have examined prevention and treatment strategies. Browning of white adipocytes promotes triglyceride (TG) metabolism and is the new focus for treating obesity. This study investigated the role of malonate—a modulator of mitochondrial function—in adipocyte browning, and its potential as a therapeutic agent in obesity. Our findings revealed that malonate increased oxygen consumption without inhibiting ATP synthesis. Malonate induced expression of PRDM16—an important transcription factor for browning—and uncoupling protein 1 (beige adipocyte marker), suggesting that malonate induces browning in white adipocytes. In an obesity mouse model induced by a high-fat diet, malonate significantly reduced body weight and white adipose tissue weight, as well as improved insulin resistance. Importantly, malonate stimulated browning in white adipose tissue and maintained the mass of brown adipose tissue in the high-fat diet-induced obesity mouse model. We propose that manipulation of mitochondrial function by malonate is a promising therapeutic approach for obesity.

Obesity May Impairs Mice Testicular Structure by STAT3/CYP19A1/Testosterone

Obesity is an increasing serious global public health issue and a risk factor for male infertility. Aromatase expression level is elevated in obese men, and this high level is as-sociated with diminished serum testosterone levels. We explored the underlying mechanism of infertility in obese men. Genome-wide association study datasets were used to predict the causal relationship between obesity and male infertility. An obese male mouse model was generated by feeding mice a high-fat diet while control model was generated by feeding mice a normal chow diet. Serum indicators including free fatty acids, insulin, Follicle-stimulating hormone, and testosterone were measured using ELISA, and impaired fertility in mice was demonstrated using immunohistochemistry. The expression levels of STAT3 and CYP19A1 were measured by RT-qPCR and western blotting, respectively. Simultaneous bioinformatics analysis of publicly available data was performed using the R programming language and JASPAR database. Obesity might lead to male infertility from a genomic perspective. Obese mice displayed reduced serum testosterone and follicle stimulating hormone levels along with structural abnormalities, ectopic lipid deposition, and chronic inflammation in the testes. Upregulation of STAT3/CYP19A1 expression in obese mice was linked to reduced serum testosterone levels and impaired fertility. Our observation may support the hypothesis that since the elevation of STAT3 expression in obesity, the promoted expressed CYP19A1 could increase a shift from testosterone to estrogens. The persistently elevated level of estrogen will further stimulate STAT3, which may constitute a positive feedback loop. These findings provide new insights into the mechanisms of obesity-mediated male fertility impairment.

Docosapentaenoic acid-rich oil lowers plasma glucose and lipids in a mouse model of diabetes and mild obesity

Many studies have investigated the beneficial effects of n-3 polyunsaturated fatty acids, such as their potential for lowering lipid levels and reducing diabetes risk. However, few studies have specifically examined docosapentaenoic acid (DPA), an n-3 polyunsaturated fatty acid with limited availability in its pure form. We hypothesized that DPA would have lipid-lowering effects and improve insulin resistance in KK/Ta mice. To test our hypothesis, 7-week-old KK/Ta mice were fed a high-fat diet for 12 weeks to induce obesity before being divided into 3 groups and fed an experimental diet for 10 weeks. The experimental diets were: LSO, using lard and safflower oil as fat sources; SO, in which lard in the LSO diet was replaced with safflower oil; and DPA, in which lard in the LSO diet was replaced with DPA oil. After 10 weeks, plasma triglyceride and total cholesterol concentrations were significantly decreased in the DPA group, but not in the SO group. Sterol regulatory element-binding protein-1 and stearoyl-CoA desaturase-1 gene expressions involved in fatty acid synthesis in the liver were significantly lower in the DPA group compared with the LSO group. Plasma glucose concentrations were significantly decreased in both the SO group and the DPA group compared with the LSO group, whereas plasma insulin concentrations were significantly decreased in the DPA group alone. These results indicate that DPA has plasma lipid-lowering and hypoglycemic effects, possibly from suppression of fatty acid synthesis in the liver.

Chitosan oligosaccharide activates brown adipose tissue by modulating the gut microbiota and bile acid pathways based on faecal microbiota transplantation

ObjectiveTo study the effect of chitosan oligosaccharide with a molecular weight ≤3000 Da (COSM) on the energy metabolism of obese mice after faecal bacteria transplantation. Methods: A pseudo-germ-free obese mouse model was established. 16S rRNA was used to analyse the microflora of the caecal contents of mice in each group to judge whether the model was successful or not. The faecal flora of donor mice was transplanted into a pseudo-germ-free obese mouse model by tube feeding, and the lipid-lowering effect of COSM intervention on the intestinal flora was detected. The correlations among the bile acid composition, key intestinal microbial markers, and serum bile acid spectrum were analysed. At the same time, the influence of intestinal microorganisms on the TGR5-Dio2-UCP1 signalling pathway after faecal bacteria transplantation was explored. Conclusion: COSM can regulate the intestinal microecology and serum bile acid pool of pseudo-germ-free obese mice through intestinal microorganisms, thus activating the energy metabolism pathway to play a role in weight loss.

Development of a novel Fc fusion protein dual glucagon-like peptide-1 and gastric inhibitory polypeptide receptor agonists.

To develop and investigate an imbalanced dual gastric inhibitory polypeptide receptor (GIPR)/glucagon-like peptide-1 receptor (GLP-1 R) agonist with Fc fusion protein structure. We designed and constructed an Fc fusion protein that is a dual agonist (HEC-CG115) with an empirically optimized potency ratio for GLP-1R and GIPR. The long-term effects of HEC-CG115 on body weight and glycaemic control were evaluated in diet-induced obese mice and diabetic db/db mice. Repeat dose toxicity assays were performed to investigate the safety profile of HEC-CG115 in Sprague-Dawley rats. HEC-CG115 displayed high potency for GIPR and relatively low potency for GLP-1R, and we labelled it 'imbalanced'. In animal models, HEC-CG115 (3 nmol/kg) led to more weight loss than semaglutide at a higher dose (10 nmol/kg) in diet-induced obese model mice. HEC-CG115 (one dose every 3 days) reduced fasting blood glucose and glycated haemoglobin levels similar to those after semaglutide (once daily) at the same dose. In a 4-week subcutaneous toxicity study conducted to assess the biosafety of HEC-CG115, the no observed adverse effect level was determined to be 3 mg/kg. HEC-CG115 is a novel Fc fusion protein with imbalanced dual agonism that shows superior weight loss, glycaemic control and metabolic improvement in animal models, and has an optimal safety profile according to a repeat-dose toxicity study. Therefore, the use of HEC-CG115 appears to be safe and effective for the treatment of obesity and type 2 diabetes.

Polystyrene nanoplastics aggravate reproductive system damage in obese male mice by perturbation of the testis redox homeostasis.

The potential impact of the combination of a high-fat diet (HFD) and polystyrene nanoplastics (PS-NPs) on fertility cannot be ignored, especially when the fertility rate is declining. However, it has not attracted considerable attention. In this study, an obese mouse model was established using an HFD, and the reproductive function of male mice was evaluated after intragastric administration of 100 μL of a 10 mg/mL PS-NP suspension for 4 weeks. By determining the morphology and vitality of sperm and related indicators of testosterone production, it was found that PS-NPs aggravated the destruction of sperm mitochondrial structure, decrease sperm activity, and testosterone production in HFD-fed mice. To comprehensively analyze the injury mechanism, the integrity of the blood testicular barrier (BTB) and the function of Leydig and Sertoli cells were further analyzed. It was found that PS-NPs could destroy BTB, promote the degeneration of Leydig cells, reduce the number of Sertoli cells, and decrease lactate secretion in HFD-fed mice. PS-NPs further interfered with redox homeostasis in the testicular tissues of HFD-fed mice. This study found that PS-NPs could aggravate the damage to the reproductive system of obese male mice by further perturbing its redox homeostasis and revealed the potential health risk of PS-NPs exposure under an HFD.