Effects of Gossypetin on Glucose Homeostasis in Diet-Induced Pre-Diabetic Rats.

Natural flavonoids exert many potential health benefits, including anti-hyperglycaemic effects. However, the effects of gossypetin (GTIN) on glucose homeostasis in pre-diabetes have not yet been investigated. This study examined the effects of GTIN on key markers of glucose homeostasis in a diet-induced pre-diabetic rat model. Pre-diabetes was induced by allowing the animals to feed on a high-fat high-carbohydrate (HFHC) diet supplemented with 15% fructose water for 20 weeks. Following pre-diabetes induction, the pre-diabetic animals were sub-divided into five groups (n = 6), where they were either orally treated with GTIN (15 mg/kg) or metformin (MET) (500 mg/kg), both with and without dietary intervention, over a 12-week period. The results demonstrated that animals in the untreated pre-diabetic (PD) control group exhibited significantly higher fasting and postprandial blood glucose levels, as well as elevated plasma insulin concentrations and increased homeostatic model assessment for insulin resistance (HOMA2-IR) index, relative to the non-pre-diabetic (NPD) group. Similarly, increased caloric intake, body weight and plasma ghrelin levels were observed in the PD control group. Notably, these parameters were significantly reduced in the PD animals receiving GTIN treatment. Additionally, glycogen levels in the liver and skeletal muscle, which were disturbed in the PD control group, showed significant improvement in both GTIN-treated groups. These findings may suggest that GTIN administration, with or without dietary modifications, may offer therapeutic benefits in ameliorating glucose homeostasis disturbances associated with the PD state.

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

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

Age and duration of obesity modulate the inflammatory response and expression of neuroprotective factors in mammalian female brain.

Obesity has become a global epidemic and is associated with comorbidities, including diabetes, cardiovascular, and neurodegenerative diseases, among others. While appreciable insight has been gained into the mechanisms of obesity-associated comorbidities, effects of age, and duration of obesity on the female brain remain obscure. To address this gap, adolescent and mature adult female mice were subjected to a high-fat diet (HFD) for 13 or 26 weeks, whereas age-matched controls were fed a standard diet. Subsequently, the expression of inflammatory cytokines, neurotrophic/neuroprotective factors, and markers of microgliosis and astrogliosis were analyzed in the hypothalamus, hippocampus, and cerebral cortex, along with inflammation in visceral adipose tissue. HFD led to a typical obese phenotype in all groups independent of age and duration of HFD. However, the intermediate duration of obesity induced a limited inflammatory response in adolescent females' hypothalamus while the hippocampus, cerebral cortex, and visceral adipose tissue remained unaffected. In contrast, the prolonged duration of obesity resulted in inflammation in all three brain regions and visceral adipose tissue along with upregulation of microgliosis/astrogliosis and suppression of neurotrophic/neuroprotective factors in all brain regions, denoting the duration of obesity as a critical risk factor for neurodegenerative diseases. Importantly, when female mice were older (i.e., mature adult), even the intermediate duration of obesity induced similar adverse effects in all brain regions. Taken together, our findings suggest that (1) both age and duration of obesity have a significant impact on obesity-associated comorbidities and (2) early interventions to end obesity are critical to preserving brain health.

Dietary Milk Phospholipids Increase Body Fat and Modulate Gut Permeability, Systemic Inflammation, and Lipid Metabolism in Mice.

The study aimed at how dietary milk polar lipids affect gut permeability, systemic inflammation, and lipid metabolism during diet-induced obesity (DIO). C57BL/6J mice (n = 6x3) were fed diets with 34% fat as energy for 15 weeks: (1) modified AIN-93G diet (CO); (2) CO with milk gangliosides (GG); (3) CO with milk phospholipids (MPL). Gut permeability was assessed by FITC-dextran and sugar absorption tests. Intestinal tight junction proteins were evaluated by Western blot. Plasma cytokines were measured by immunoassay. Body composition was assessed by magnetic resonance imaging. Tissue lipid profiles were obtained by thin layer chromatography. Hepatic expression of genes associated with lipid metabolism was assessed by RT-qPCR. MPL increased the efficiency of converting food into body fat and facilitated body fat accumulation compared with CO. MPL and GG did not affect fasting glucose or HOMA-IR during DIO. MPL increased while GG decreased plasma TG compared with CO. MPL decreased phospholipids subclasses in the muscle while increased those in the liver compared with CO. GG and MPL had little effect on hepatic expression of genes associated with lipid metabolism. Compared with CO, MPL decreased polar lipids content in colon mucosa. Small intestinal permeability decreased while colon permeability increased and then recovered during the feeding period. High-fat feeding increased plasma endotoxin after DIO but did not affect plasma cytokines. MPL and GG did not affect plasma endotoxin, adipokines and inflammatory cytokines. After the establishment of obesity, MPL increased gut permeability to large molecules but decreased intestinal absorption of small molecules while GG tended to have the opposite effects. MPL and GG decreased mannitol and sucralose excretions, which peaked at d 45 in the CO group. MPL decreased occludin in jejunum mucosa compared with CO. GG and MPL did not affect zonula occludens-1 in gut mucosa. In conclusion, during DIO, milk GG decreased gut permeability, and had little effect on systemic inflammation and lipid metabolism; MPL facilitated body fat accumulation, decreased gut permeability, did not affect systemic inflammation.

Paternal high-fat diet affects weight and DNA methylation of their offspring.

Obesity poses a public health threat, reaching epidemic proportions. Our hypothesis suggests that some of this epidemic stems from its transmission across generations via paternal epigenetic mechanisms. To investigate this possibility, we focused on examining the paternal transmission of CpG methylation. First-generation male Wistar rats were fed either a high-fat diet (HF) or chow and were mated with females fed chow. We collected sperm from these males. The resulting offspring were raised on a chow diet until day 35, after which they underwent a dietary challenge. Diet-induced obese (DIO) male rats passed on the obesogenic trait to both male and female offspring. We observed significant hypermethylation of the Pomc promoter in the sperm of HF-treated males and in the hypothalamic arcuate nucleus (Arc) of their offspring at weaning. However, these differences in Arc methylation decreased later in life. This hypermethylation is correlated with increased expression of DNMT3B. Further investigating genes in the Arc that might be involved in obesogenic transgenerational transmission, using reduced representation bisulfite sequencing (RRBS) we identified 77 differentially methylated regions (DMRs), highlighting pathways associated with neuronal development. These findings support paternal CpG methylation as a mechanism for transmitting obesogenic traits across generations.

Beneficial metabolic effects of PAHSAs depend on the gut microbiota in diet-induced obese mice but not in chow-fed mice.

Dietary lipids play an essential role in regulating the function of the gut microbiota and gastrointestinal tract, and these luminal interactions contribute to mediating host metabolism. Palmitic Acid Hydroxy Stearic Acids (PAHSAs) are a family of lipids with antidiabetic and anti-inflammatory properties, but whether the gut microbiota contributes to their beneficial effects on host metabolism is unknown. Here, we report that treating chow-fed female and male germ-free (GF) mice with PAHSAs improves glucose tolerance, but these effects are lost upon high fat diet (HFD) feeding. However, transfer of feces from PAHSA-treated, but not vehicle-treated, chow-fed conventional mice increases insulin sensitivity in HFD-fed GF mice. Thus, the gut microbiota is necessary for, and can transmit, the insulin-sensitizing effects of PAHSAs in HFD-fed GF male mice. Analyses of the cecal metagenome and lipidome of PAHSA-treated mice identified multiple lipid species that associate with the gut commensal Bacteroides thetaiotaomicron (Bt) and with insulin sensitivity resulting from PAHSA treatment. Supplementing live, and to some degree, heat-killed Bt to HFD-fed female mice prevented weight gain, reduced adiposity, improved glucose tolerance, fortified the colonic mucus barrier and reduced systemic inflammation compared to HFD-fed controls. These effects were not observed in HFD-fed male mice. Furthermore, ovariectomy partially reversed the beneficial Bt effects on host metabolism, indicating a role for sex hormones in mediating the Bt probiotic effects. Altogether, these studies highlight the fact that PAHSAs can modulate the gut microbiota and that the microbiota is necessary for the beneficial metabolic effects of PAHSAs in HFD-fed mice.

Housing mice near vs. below thermoneutrality affects drug-induced weight loss but does not improve prediction of efficacy in humans.

Evaluation of weight loss drugs is usually performed in diet-induced obese mice housed at ∼22°C. This is a cold stress that increases energy expenditure by ∼35% compared to thermoneutrality (∼30°C), which may overestimate drug-induced weight loss. We investigated five anti-obesity mechanisms that have been in clinical development, comparing weight loss in mice housed at 22°C vs. 30°C. Glucagon-like peptide-1 (GLP-1), human fibroblast growth factor 21 (hFGF21), and melanocortin-4 receptor (MC4R) agonist induced similar weight losses. Peptide YY elicited greater vehicle-subtracted weight loss at 30°C (7.2% vs. 1.4%), whereas growth differentiation factor 15 (GDF15) was more effective at 22°C (13% vs. 6%). Independent of ambient temperature, GLP-1 and hFGF21 prevented the reduction in metabolic rate caused by weight loss. There was no simple rule for a better prediction of human drug efficacy based on ambient temperature, but since humans live at thermoneutrality, drug testing using mice should include experiments near thermoneutrality.

The LIDPAD Mouse Model Captures the Multisystem Interactions and Extrahepatic Complications in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents an impending global health challenge. Current management strategies often face setbacks, emphasizing the need for preclinical models that faithfully mimic the human disease and its comorbidities. The liver disease progression aggravation diet (LIDPAD), a diet-induced murine model, extensively characterized under thermoneutral conditions and refined diets is introduced to ensure reproducibility and minimize species differences. LIDPAD recapitulates key phenotypic, genetic, and metabolic hallmarks of human MASLD, including multiorgan communications, and disease progression within 4 to 16 weeks. These findings reveal gut-liver dysregulation as an early event and compensatory pancreatic islet hyperplasia, underscoring the gut-pancreas axis in MASLD pathogenesis. A robust computational pipeline is also detailed for transcriptomic-guided disease staging, validated against multiple harmonized human hepatic transcriptomic datasets, thereby enabling comparative studies between human and mouse models. This approach underscores the remarkable similarity of the LIDPAD model to human MASLD. The LIDPAD model fidelity to human MASLD is further confirmed by its responsiveness to dietary interventions, with improvements in metabolic profiles, liver histopathology, hepatic transcriptomes, and gut microbial diversity. These results, alongside the closely aligned changing disease-associated molecular signatures between the human MASLD and LIDPAD model, affirm the model's relevance and potential for driving therapeutic development.

Gut microbiota metabolite tyramine ameliorates high-fat diet-induced insulin resistance via increased Ca2+ signaling.

The gut microbiota and their metabolites are closely linked to obesity-related diseases, such as type 2 diabetes, but their causal relationship and underlying mechanisms remain largely elusive. Here, we found that dysbiosis-induced tyramine (TA) suppresses high-fat diet (HFD)-mediated insulin resistance in both Drosophila and mice. In Drosophila, HFD increases cytosolic Ca2+ signaling in enterocytes, which, in turn, suppresses intestinal lipid levels. 16 S rRNA sequencing and metabolomics revealed that HFD leads to increased prevalence of tyrosine decarboxylase (Tdc)-expressing bacteria and resulting tyramine production. Tyramine acts on the tyramine receptor, TyrR1, to promote cytosolic Ca2+ signaling and activation of the CRTC-CREB complex to transcriptionally suppress dietary lipid digestion and lipogenesis in enterocytes, while promoting mitochondrial biogenesis. Furthermore, the tyramine-induced cytosolic Ca2+ signaling is sufficient to suppress HFD-induced obesity and insulin resistance in Drosophila. In mice, tyramine intake also improves glucose tolerance and insulin sensitivity under HFD. These results indicate that dysbiosis-induced tyramine suppresses insulin resistance in both flies and mice under HFD, suggesting a potential therapeutic strategy for related metabolic disorders, such as diabetes.

Exercise Rescues Obesogenic-Related Genes in the Female Hypothalamic Arcuate Nucleus: A Potential Role of miR-211 Modulation.

Obesity is a major public health concern that is associated with negative health outcomes. Exercise and dietary restriction are commonly recommended to prevent or combat obesity. This study investigates how voluntary exercise mitigates abnormal gene expression in the hypothalamic arcuate nucleus (ARC) of diet-induced obese (DIO) rats. Using a transcriptomic approach, novel genes in the ARC affected by voluntary wheel running were assessed alongside physiology, pharmacology, and bioinformatics analysis to evaluate the role of miR-211 in reversing obesity. Exercise curbed weight gain and fat mass, and restored ARC gene expression. High-fat diet (HFD) consumption can dysregulate satiety/hunger mechanisms in the ARC. Transcriptional clusters revealed that running altered gene expression patterns, including inflammation and cellular structure genes. To uncover regulatory mechanisms governing gene expression in DIO attenuation, we explored miR-211, which is implicated in systemic inflammation. Exercise ameliorated DIO overexpression of miR-211, demonstrating its pivotal role in regulating inflammation in the ARC. Further, in vivo central administration of miR-211-mimic affected the expression of immunity and cell cycle-related genes. By cross-referencing exercise-affected and miR-211-regulated genes, potential candidates for obesity reduction through exercise were identified. This research suggests that exercise may rescue obesity through gene expression changes mediated partially through miR-211.

Moderate-intensity aerobic exercise enhanced dopamine signaling in diet-induced obese female mice without preventing body weight gain.

Obesity continues to rise in prevalence and financial burden despite strong evidence linking it to an increased risk of developing several chronic diseases. Dopamine response and receptor density are shown to decrease under conditions of obesity. However, it is unclear if this could be a potential mechanism for treatment without drugs that have a potential for abuse. Therefore, the aim of this study was to investigate whether moderate-intensity exercise could reduce body weight gain and the associated decreases in dopamine signaling observed with high-fat diet-induced adiposity. We hypothesized that exercise would attenuate body weight gain and diet-induced inflammation in high-fat (HF)-fed mice, resulting in dopamine signaling (release and reuptake rate) comparable to sedentary, low-fat (LF)-fed counterparts. This hypothesis was tested using a mouse model of diet-induced obesity (DIO) and fast-scan cyclic voltammetry to measure evoked dopamine release and reuptake rates. Although the exercise protocol employed in this study was not sufficient to prevent significant body weight gain, there was an enhancement of dopamine signaling observed in female mice fed a HF diet that underwent treadmill running. Additionally, aerobic treadmill exercise enhanced the sensitivity to amphetamine (AMPH) in this same group of exercised, HF-fed females. The estrous cycle might influence the ability of exercise to enhance dopamine signaling in females, an effect not observed in male groups. Further research into females by estrous cycle phase, in addition to determining the optimal intensity and duration of aerobic exercise, are logical next steps.

Experimental colonization with H. hepaticus, S. aureus and R. pneumotropicus does not influence the metabolic response to high-fat diet or incretin-analogues in wildtype SOPF mice.

OBJECTIVES: We here assessed whether typical pathogens of laboratory mice affect the development of diet-induced obesity and glucose intolerance, and whether colonization affects the efficacy of the GLP-1R agonist liraglutide and of the GLP-1/GIP co-agonist MAR709 to treat obesity and diabetes. METHODS: Male C57BL/6J mice were experimentally infected with Helicobacter hepaticus, Rodentibacter pneumotropicus and Staphylococcus aureus and compared to a group of uninfected specific and opportunistic pathogen free (SOPF) mice. The development of diet-induced obesity and glucose intolerance was monitored over a period of 26 weeks. To study the influence of pathogens on drug treatment, mice were then subjected for 6 days daily treatment with either the GLP-1 receptor agonist liraglutide or the GLP-1/GIP co-agonist MAR709. RESULTS: Colonized mice did not differ from SOPF controls regarding HFD-induced body weight gain, food intake, body composition, glycemic control, or responsiveness to treatment with liraglutide or the GLP-1/GIP co-agonist MAR709. CONCLUSIONS: We conclude that the occurrence of H. hepaticus, R. pneumotropicus and S. aureus does neither affect the development of diet-induced obesity or type 2 diabetes, nor the efficacy of GLP-1-based drugs to decrease body weight and to improve glucose control in mice.

Multiomics reveals the ameliorating effect and underlying mechanism of aqueous extracts of polygonatum sibiricum rhizome on obesity and liver fat accumulation in high-fat diet-fed mice.

BACKGROUND: Polygonatum sibiricum polysaccharides protect against obesity and NAFLD. However, the potential effects of PS rhizome aqueous extracts (PSRwe) on adiposity and hepatic lipid accumulation remains unexplored. PURPOSE: Elucidating the impact and underlying mechanism of PSRwe on HFD-induced obesity and liver fat depostition. STUDY DESIGN: 56 male mice, aged eight weeks, were divided into seven groups: Positive, four doses of PSRwe, Model, and Control. HFD was fed for eight weeks, followed by alternate-day gavage of orlistat and PSRwe for an additional eight-week period. Integrative analysis encompassing multiomics, physiological and histopathological, and biochemical indexes was employed. METHODS: Body weight (BW); liver, fat and Lee's indexes; TC, TG, LDL-C, HDL-C, AST, ALT, FFA, leptin, and adiponectin in the liver and blood; TNFα, IL-6, and LPS in the colon, plasma, and liver; H&E, PAS and oil red O staining on adipose and liver samples were examined. OGTT and ITT were conducted The gut microbiome, microbial metabolome, colonic and liver transcriptome, plasma and liver metabolites were investigated. RESULTS: PSRwe at the dosage of 7.5 mg/kg demonstrated significant and consistent reduction in BW and hepatic fat deposition than orlistat. PSRwe significantly decreased TC, TG, LDL-C, LEP, FFA levels in blood and liver. PSRwe significantly enhanced the relative abundance of probiotics including Akkermansia muciniphila, Bifidobacterium pseudolongum, Lactobacillus reuteri, and metabolic pathways including glycolysis and fatty acids ß-oxidation. The 70 up-regulated microbial metabolites in PSRwe-treated mice mainly involved in nucleotides and amino acids metabolism, while 40 decreased metabolites primarily associated with lipid metabolism. The up-regulated colonic differentially expressed genes (DEGs) participate in JAK-STAT/PI3K-Akt/FoxO signaling pathway, serotonergic/cholinergic/glutamatergic synapses, while the down-regulated DEGs predominantly focused on fat absorption and transport. The up-regulated liver DEGs mainly concentrated on fatty acid oxidation and metabolism. Liver metabolisms revealed 131 differential metabolites, among which carnitine and oxidized lipids significantly increased in PSRwe-treated mice. In plasma, the 58 up-regulated metabolites mainly participate in co-factors/vitamins metabolism while 154 down-regulated ones in fatty acids biosynthesis. Comprehensive multiomics association analysis revealed significant associations between gut microbiota and colonic/liver gene expression, and suggested exogenous and endogenous betaine may be active compound in alleviating HFD-induced symptoms. CONCLUSION: PSRwe effectively mitigate HFD-induced obesity and hepatic steatosis by increasing beneficial bacteria, reducing colonic fat digestion/absorption, increasing hepatic lipid metabolism, and elevating betaine levels.

Diet induced thermogenesis, older and newer data with emphasis on obesity and diabetes mellitus - A narrative review.

Obesity is a major public health problem with a prevalence increasing at an alarming rate worldwide. There is an urgent need for efficient approaches to weight management. Diet induced thermogenesis (DIT) is the process by which the body increases its energy expenditure in response to a meal. It is estimated to account for approximately 10 % of total energy expenditure and is considered a potentially modifiable component of energy expenditure. The palatability of food, meal's composition in macronutrients, the circadian rhythm and sleep, as well as individual's characteristics such as age, the presence of obesity or diabetes mellitus, and the proportion of physical activity are the main factors that affect DIT. However, studies examining DIT are mostly characterized by small sample size and the methodology varies considerably between studies. It seems that even today there is a lot of contradiction between the relative studies. Inspite of that, future research might lead to the modification of DIT in order to achieve some weight loss in obese people.

Therapeutic effects of Lingguizhugan decoction in a rat model of high-fat diet-induced insulin resistance.

BACKGROUND: Lingguizhugan (LGZG) decoction is a widely used classic Chinese medicine formula that was recently shown to improve high-fat diet (HFD)-induced insulin resistance (IR) in animal studies. AIM: To assess the therapeutic effect of LGZG decoction on HFD-induced IR and explore the potential underlying mechanism. METHODS: To establish an IR rat model, a 12-wk HFD was administered, followed by a 4-wk treatment with LGZG. The determination of IR status was achieved through the use of biochemical tests and oral glucose tolerance tests. Using a targeted meta-bolomics platform to analyze changes in serum metabolites, quantitative real-time PCR (qRT-PCR) was used to assess the gene expression of the ribosomal protein S6 kinase beta 1 (S6K1). RESULTS: In IR rats, LGZG decreased body weight and indices of hepatic steatosis. It effectively controlled blood glucose and food intake while protecting islet cells. Metabolite analysis revealed significant differences between the HFD and HFD-LGZG groups. LGZG intervention reduced branched-chain amino acid levels. Levels of IR-related metabolites such as tryptophan, alanine, taurine, and asparagine decreased significantly. IR may be linked to amino acids due to the contemporaneous increase in S6K1 expression, as shown by qRT-PCR. CONCLUSIONS: Our study strongly suggests that LGZG decoction reduces HFD-induced IR. LGZG may activate S6K1 via metabolic pathways. These findings lay the groundwork for the potential of LGZG as an IR treatment.

High-fat diet-induced increase in glucocorticoids contributes to adipogenesis in obese mice.

BACKGROUND: This study was designed to examine how glucocorticoids (GCs) induced by a long-term ingestion of high-fat diet (HFD) mediate the HFD-induced adipose expansion and obesity. MATERIAL AND METHODS: To address this goal, we used a unique L/L mouse model that fails to induce its corticosterone (CORT) level, a major type of GCs in rodents, after prolonged exposure to an HFD. RESULTS: We found that, after receiving a 12-week HFD feeding, the L/L mice show less weight gain, milder adipose expansion, and higher plasma levels of triglycerides than the wild-type mice. These changes were reversed by replenishing CORT to L/L mice. When examining the expression levels of various molecules linked to lipid uptake and de novo lipogenesis in CORT-induced adipose expansion, we observed a reduction in the expression of adipose preadipocyte factor 1 (Pref-1), a key regulator in adipogenesis. In 3T3-L1 preadipocyte-like cells, dexamethasone, an agonist of the glucocorticoid receptor, also reduced expressions of Pref-1 and facilitated intracellular accumulation of lipids. CONCLUSIONS: Our results suggest that fat ingestion-induced release of CORT contributes to adipose expansion and development of obesity and highlight the pathogenic role of CORT-mediated downregulation of adipose Pref-1 in diet-induced obesity.

Differential Impairment Mechanism of Sperm Production via Induction of miR-34c-Activated Apoptosis and Spermatogenesis Pathway in Diet-Induced Obesity and Resistant Mice and GC-1 Spg Cells.

Male reproductive dysfunction is a clinical disease, with a large number of cases being idiopathic. Reproductive disorders have been found in obese (diet-induced obesity and diet-induced obesity-resistant) mice, but the mechanism behind the male reproductive dysfunction between them may be different. The purpose of this study was to explore the possible role and mechanism of miR-34c on sperm production in high-fat-diet-induced obesity-resistant (DIO-R) mice and GC-1 spg cells, which may differ from those in high-fat-diet-induced obesity (DIO) mice. In vivo and in vitro experiments were performed. C57BL/6J mice were fed a high-fat diet for 10 weeks to establish the DIO and DIO-R mouse model. GC-1 spg cells were used to verify the mechanism of miR-34c on sperm production. During in vivo experiments, sperm production damage was found in both DIO and DIO-R male mice. Compared to the control mice, significantly decreased levels of testosterone, LH, activities of acrosome enzyme (ACE), HAse, and activating transcription factor 1 (ATF1) were found in both DIO and DIO-R male mice (p < 0.05). Compared with the control group, the ratio of B-cell lymphoma-2 (Bcl-2)/bcl-2-associated X protein (Bax) in the DIO group was significantly decreased, and the expression level of cleaved caspase-3 was significantly increased (p < 0.05). Compared with the control group, the Bcl-2 protein expression level in the testes of the DIO-R group significantly decreased (p < 0.05). However, the Bax expression level increased. Thus, the Bcl-2/Bax ratio significantly decreased (p < 0.01); however, the factor-related apoptosis (Fas), Fas ligand (FasLG), cleaved caspase-8, caspase-8, cleaved caspase-3, and caspase-3 protein expression levels significantly increased (p < 0.05). Compared with the DIO group, in DIO-R mice, the activities of ACE, ATF1, Bcl-2, and Bcl-2/Bax's spermatogenesis protein expression decreased, while the apoptosis-promoting protein expression significantly increased (p < 0.05). During the in vitro experiment, the late and early apoptotic ratio in the miR-34c over-expression group increased. MiR-34c over-expression enhanced the expression of apoptosis-related proteins Fas/FasLG and Bax/Bcl-2 while inhibiting the expression of ATF1 and the sperm-associated protein in GC-1 spg cells. DIO and DIO-R could harm sperm production. DIO-R could impair sperm production by inducing the miR-34c-activated apoptosis and spermatogenesis pathway, which may be different from that of DIO.

Bone Fragility in High Fat Diet-induced Obesity is Partially Independent of Type 2 Diabetes in Mice.

Obesity and type 2 diabetes (T2D) are risk factors for fragility fractures. It is unknown whether this elevated risk is due to a diet favoring obesity or the diabetes that often occurs with obesity. Therefore, we hypothesized that the fracture resistance of bone is lower in mice fed with a high fat diet (45% kcal; HFD) than in mice that fed on a similar, control diet (10% kcal; LFD), regardless of whether the mice developed overt T2D. Sixteen-week-old, male NON/ShiLtJ mice (resistant to T2D) and age-matched, male NONcNZO10/LtJ (prone to T2D) received a control LFD or HFD for 21 weeks. HFD increased the bodyweight to a greater extent in the ShiLtJ mice compared to the NZO10 mice, while blood glucose levels were significantly higher in NZO10 than in ShiLtJ mice. As such, the glycated hemoglobin A1c (HbA1c) levels exceeded 10% in NZO10 mice, but it remained below 6% in ShiLtJ mice. Diet did not affect HbA1c. HFD lowered trabecular number and bone volume fraction of the distal femur metaphysis (micro-computed tomography or µCT) in both strains. For the femur mid-diaphysis, HFD significantly reduced the yield moment (mechanical testing by three-point bending) in both strains but did not affect cross-sectional bone area, cortical thickness, nor cortical tissue mineral density (µCT). Furthermore, the effect of diet on yield moment was independent of the structural resistance of the femur mid-diaphysis suggesting a negative effect of HFD on characteristics of the bone matrix. However, neither Raman spectroscopy nor assays of advanced glycation end-products identified how HFD affected the matrix. HFD also lowered the resistance of cortical bone to crack growth in only the diabetic NZO10 mice (fracture toughness testing of other femur), while HFD reduced the ultimate force of the L6 vertebra in both strains (compression testing). In conclusion, the HFD-related decrease in bone strength can occur in mice resistant and prone to diabetes indicating that a diet high in fat deleteriously affects bone without necessarily causing hyperglycemia.

Adipocyte-specific Nrf2 deletion negates nitro-oleic acid benefits on glucose tolerance in diet-induced obesity.

Obesity is commonly linked with white adipose tissue (WAT) dysfunction, setting off inflammation and oxidative stress, both key contributors to the cardiometabolic complications associated with obesity. To improve metabolic and cardiovascular health, countering these inflammatory and oxidative signaling processes is crucial. Offering potential in this context, the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by nitro-fatty acids (NO2-FA) promote diverse anti-inflammatory signaling and counteract oxidative stress. Additionally, we previously highlighted that nitro-oleic acid (NO2-OA) preferentially accumulates in WAT and provides protection against already established high fat diet (HFD)-mediated impaired glucose tolerance. The precise mechanism accounting for these protective effects remained largely unexplored until now. Herein, we reveal that protective effects of improved glucose tolerance by NO2-OA is absent when Nrf2 is specifically ablated in adipocytes (ANKO mice). NO2-OA treatment did not alter body weight between ANKO and littermate controls (Nrf2fl/fl) mice on both the HFD and low-fat diet (LFD). As expected, at day 76 (before NO2-OA treatment) and notably at day 125 (daily treatment of 15 mg/kg NO2-OA for 48 days), both HFD-fed Nrf2fl/fl and ANKO mice exhibited increased fat mass and reduced lean mass compared to LFD controls. However, throughout the NO2-OA treatment, no distinction was observed between Nrf2fl/fl and ANKO in the HFD-fed mice as well as in the Nrf2fl/fl mice fed a LFD. Glucose tolerance tests revealed impaired glucose tolerance in HFD-fed Nrf2fl/fl and ANKO compared to LFD-fed Nrf2fl/fl mice. Notably, NO2-OA treatment improved glucose tolerance in HFD-fed Nrf2fl/fl but did not yield the same improvement in ANKO mice at days 15, 30, and 55 of treatment. Unraveling the pathways linked to NO2-OA's protective effects in obesity-mediated impairment in glucose tolerance is pivotal within the realm of precision medicine, crucially propelling future applications and refining novel drug-based strategies.

Spinal cord injury-induced metabolic impairment and steatohepatitis develops in non-obese rats and is exacerbated by premorbid obesity.

Impaired sensorimotor functions are prominent complications of spinal cord injury (SCI). A clinically important but less obvious consequence is development of metabolic syndrome (MetS), including increased adiposity, hyperglycemia/insulin resistance, and hyperlipidemia. MetS predisposes SCI individuals to earlier and more severe diabetes and cardiovascular disease compared to the general population, which trigger life-threatening complications (e.g., stroke, myocardial infarcts). Although each comorbidity is known to be a risk factor for diabetes and other health problems in obese individuals, their relative contribution or perceived importance in propagating systemic pathology after SCI has received less attention. This could be explained by an incomplete understanding of MetS promoted by SCI compared with that from the canonical trigger diet-induced obesity (DIO). Thus, here we compared metabolic-related outcomes after SCI in lean rats to those of uninjured rats with DIO. Surprisingly, SCI-induced MetS features were equal to or greater than those in obese uninjured rats, including insulin resistance, endotoxemia, hyperlipidemia, liver inflammation and steatosis. Considering the endemic nature of obesity, we also evaluated the effect of premorbid obesity in rats receiving SCI; the combination of DIO + SCI exacerbated MetS and liver pathology compared to either alone, suggesting that obese individuals that sustain a SCI are especially vulnerable to metabolic dysfunction. Notably, premorbid obesity also exacerbated intraspinal lesion pathology and worsened locomotor recovery after SCI. Overall, these results highlight that normal metabolic function requires intact spinal circuitry and that SCI is not just a sensory-motor disorder, but also has significant metabolic consequences.