Obese Rat Model Research Articles

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

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

Novel Expression of Apical Bile Acid Transport (ASBT) More Proximally Than Distal Ileum Contributing to Enhanced Intestinal Bile Acid Absorption in Obesity

Dietary lipid absorption is facilitated by bile acids. In the Zucker rat (ZR) model of obesity, bile acid absorption, mediated by the apical sodium bile acid transporter (ASBT), was increased in villus cells from the distal ileum. However, whether ASBT may be de novo expressed more proximally in the small intestine during obesity to facilitate additional bile acid absorption is not known. For this, starting from the end of the ileum to the mid jejunum, caudal-orally, five intestinal segments of equal length (S1–S5) were separated from lean and obese ZRs (LZR and OZR). Intestinal mucosa obtained from these segments were used for total RNA extraction, RT-qPCR and 3H-TCA uptake. The results showed that bile acid absorption along with the mRNA expression of ASBT and FXR progressively decreased caudal-orally in both LZRs and OZRs but was significantly higher in all small intestinal segments in OZRs. The expression of GATA4 was absent in the distal ileum (S1) in both LZRs and OZRs, but steadily increased along the proximal length in both. However, this steady increase was significantly reduced in the comparative obese proximal intestinal segments S2, S3, S4 and S5. The expressions of bile acid-activated G-protein-coupled bile acid receptor TGR5 and S1PR2 were unaltered in segments S1–S4 but were significantly increased in OZR S5. The paradigm changing observation of this study is that ASBT is expressed more proximally in the small intestine in obesity. This likely increases overall bile acid absorption and thereby lipid absorption in the proximal small intestine in obesity.

Highland Barley Alleviates High-Fat Diet-Induced Obesity and Liver Injury Through the IRS2/PI3K/AKT Signaling Pathway in Rats.

Objectives: Highland barley (HB) consumption offers numerous health benefits; however, its impact on glycolipid metabolism abnormalities induced by a high-fat diet remains unclear. Consequently, this study aimed to investigate the therapeutic effects and underlying molecular mechanisms of HB in the context of obesity; Methods: Rats were fed either a high-fat diet (HFD) to induce obesity or a standard diet (SD) for six weeks. The rats in the HFD group were randomly assigned into five groups: HFD+HFD, HFD+SD, and low (30%), medium (45%), and high (60%) doses of the HB diet for an additional ten weeks. Analyses of serum lipid profiles, liver histology, transcriptomes, and untargeted metabolomes were conducted; Results: HB intake resulted in decreased weight gain, reduced feed intake, lower serum triglyceride and cholesterol levels, and diminished hepatic lipid accumulation. It also improved insulin and fasting blood glucose levels, and antioxidant capacity in the HFD-fed rats. Transcriptome analysis revealed that HB supplementation significantly suppressed the HFD-induced increase in the expression of Angptl8, Apof, CYP7A1, GDF15, Marveld1, and Nr0b2. Furthermore, HB supplementation reversed the HFD-induced decrease in Pex11a expression. Untargeted metabolome analysis indicated that HB primarily influenced the pentose phosphate pathway, the Warburg effect, and tryptophan metabolism. Additionally, integrated transcriptome and metabolome analyses demonstrated that the treatments affected the expression of genes associated with glycolipid metabolism, specifically ABCG8, CYP2C12, CYP2C24, CYP7A1, and IRS2. Western blotting confirmed that HB supplementation impacted the IRS2/PI3K/AKT signaling pathway; Conclusions: HB alleviates HFD-induced obesity and liver injury in an obese rat model possibly through the IRS2/PI3K/Akt signaling pathway.

Aerobic Exercise Improved Diacylglycerol/Protein Kinase C and Phosphatidylinositol 4,5-Biphosphate Pathway in Cardiac Tissue of Obese Rats

Background: Obesity, characterized by abnormal accumulation or excess lipids, is a major cause of increased incidence of cardiovascular diseases. Objectives: The purpose of this experiment is to investigate the effect of aerobic exercise on the expression of sn-1,2-diacylglycerol (DAG), Protein kinase C (PKC), and Phosphatidylinositol 4,5-biphosphate (PIP2) genes in experimental rat models of diet-induced obesity. Methods: Twenty-four Wistar rats were randomly divided into four groups: (1) control, (2) obesity, (3) exercise, and (4) obesity + exercise. At the end of the experiment, cardiac hypertrophy markers and real-time PCR were used to evaluate and compare the gene expression levels of DAG, PKC, and PIP2 in cardiac tissue across all groups. Results: A high-fat diet containing fructose significantly increased the gene expression levels of DAG, PKC, and PIP2 in the cardiac tissue of obese rats compared to the control group. However, 6 weeks of aerobic exercise led to a significant decrease in DAG and PKC gene expression compared to the obese rats. Although there was no significant change in PIP2 gene expression in the obesity + exercise group compared to obese rats. Conclusions: Based on the results of this study, it appears that aerobic exercise can modulate the expression of DAG and PKC genes, which play a critical role in cardiac remodeling.

The Effects of 1-Kestose on the Abundance of Inflammation-Related Gene mRNA in Adipose Tissue and the Gut Microbiota Composition in Rats Fed a High-Fat Diet.

Chronic inflammation in adipose tissue is thought to contribute to insulin resistance, which involves the gut microbiota. Our previous studies have demonstrated that ingestion of 1-kestose can alter the gut microbiota composition, increase cecal butyrate levels, and improve insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Additionally, we found that 1-kestose supplementation ameliorated insulin resistance in obese rat models fed a high-fat diet (HFD), although the effects of 1-kestose on the abundance of inflammation-related gene in adipose tissue and gut microbiota composition in these rats were not explored. This study aimed to investigate the impact of 1-kestose on these parameters in HFD-fed rats, compared to OLETF rats. Male Sprague-Dawley rats were divided into two dietary groups, control or HFD, for 19 wk. Each group was further subdivided to receive either tap water or tap water supplemented with 2% (w/v) 1-kestose throughout the study. We evaluated gene expression in adipose tissue, as well as short-chain fatty acids (SCFAs) levels and microbial composition in the cecum contents. 1-Kestose intake restored the increased relative abundance of tumor necrosis factor (Tnf) mRNA in adipose tissue and the reduced level of butyrate in the cecum contents of HFD-fed rats to those observed in control diet-fed rats. Additionally, 1-kestose consumption changed the composition of the gut microbiota, increasing Butyricicoccus spp., decreasing UGC-005 and Streptococcus spp., in the cecum contents of HFD-fed rats. Our findings suggest that 1-kestose supplementation reduces adipose tissue inflammation and increases butyrate levels in the gut of HFD-fed rats, associated with changes in the gut microbiota composition, distinct from those seen in OLETF rats.

Effect of ginger (Zingiber officinale roscoe) inclusisve diet on testicular disorder in high cholesterol diet-induced obese rats: Involvement of cholesterol pathway.

BackgroundObesity, which is typically associated with hypercholesterolemia, has become a worldwide problem in recent times, raising alarming concerns on the testicular function in men in countries around the world. AimHence, this study focused at discovering the potency of ginger inclusive diet in correcting testicular disorder in a high cholesterol diet (HCD)-induced obese rat model focusing on cholesterol pathway. MethodsThe rodents were split up into seven separate groups (n = 10): healthy rats fed basal diet; obese untreated rats fed HCD; reference drug-treated obese rats, clomiphene citrate (CC, 2 mg/kg BW/day); obese rats fed high cholesterol diet with 2 % raw ginger (RG) inclusion; obese rats fed high cholesterol diet with 4 % RG inclusion; obese rats fed high cholesterol diet with 2 % boiled ginger (BG) inclusion; obese rats fed high cholesterol diet with 4 % BG inclusion for twenty-four weeks. Thereafter, the testosterone level, semen parameters, steroidogenic enzymes, lipid-metabolism related biomolecules, inflammation-related and apoptosis-related markers enzymes expression were assayed using testicular tissue. ResultResult showed that HCD disrupted the semen parameters, and affected testosterone level by causing a down-regulation in the gene expression of steroidogenic enzymes as well as up-regulation in the gene expression of inflammatory and apoptotic markers when compared with healthy control rats. Interestingly, treatment with ginger inclusive diet attenuated these effects with boiled ginger treatment having better results relative to the raw ginger treatment. ConclusionThis study confirms that a diet rich in ginger prevents testicular tissue by modulating the expression of key enzymes involved in inflammation, cholesterol metabolism, apoptosis, and steroidogenesis in HCD-induced obese rats, with boiled ginger possessing the greatest therapeutic benefit in the management of obesity-induced male fertility derangements, even beyond its impact on body weight regulation.

Combination of Metformin and Epigallocatechin-3-Gallate Lowers Cortisol, 11β-Hydroxysteroid Dehydrogenase Type 1, and Blood Glucose Levels in Sprague Dawley Rats with Obesity and Diabetes.

The combined effects of metformin and epigallocatechin-3-gallate (EGCG) on cortisol, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), and blood glucose levels have not been investigated. This study evaluated the effectiveness of combining EGCG with metformin in regulating those levels in a rat model of diet-induced diabetes and obesity. Thirty diabetic and obese rats on a high-fat diet were treated daily for 28 days with EGCG (100 mg/kg of body weight/day), metformin (200 mg/kg of body weight/day), or both. Control groups comprised lean rats, untreated obese diabetic rats, and metformin-only-treated rats. Blood samples were collected to measure cortisol and fasting blood glucose (FBG) levels and liver tissue samples were examined for 11β-HSD1 levels. Rats receiving combination therapy had significantly reduced cortisol levels (from 36.70±15.13 to 31.25±7.10 ng/mL) compared with the untreated obese diabetic rats but not the rats receiving monotherapy. Rats receiving combination therapy and EGCG monotherapy had significantly lower 11β-HSD1 levels compared with the untreated obese diabetic rats (92.68±10.82 and 93.74±18.11 ng/L vs. 120.66±14.00 ng/L). Combination therapy and metformin monotherapy significantly reduced FBG levels (440.83±133.30 to 140.50±7.36 mg/dL and 480.67±86.32 to 214.17±102.78 mg/dL, respectively) by approximately 68.1% and 55.4% compared with rats receiving EGCG monotherapy and untreated obese diabetic rats. Combining EGCG with metformin exhibited synergistic effects compared with monotherapy for managing diabetes, leading to improved outcomes in reduction of baseline cortisol levels along with reduction in 11β-HSD1 and blood glucose levels.

Extraction, Characterization, and Nutraceutical Potential of Prosthechea karwinskii Orchid for Insulin Resistance and Oxidative Stress in Wistar Rats.

Prosthechea karwinskii is an endemic orchid of Mexico with cultural significance for its ornamental, food, religious, and medicinal uses. In traditional medicine, diabetic patients use the leaves of this plant to lower glucose levels. The present study evaluated the effect of P. karwinskii leaves extract on the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in a model of obese rats with insulin resistance for its nutraceutical potential to reduce insulin resistance and oxidative stress. Obesity and insulin resistance were induced with 40% sucrose in water for 20 weeks. Four groups (control rats, obese rats, obese rats administered the extract, and obese rats administered metformin) were evaluated. Extract compounds were identified by UHPLC-ESI-qTOF-MS/MS. Glucose, insulin, triglyceride, and insulin resistance indices (HOMA-IR and TyG), as well as the activity of the antioxidant enzymes, increased in rats in the obese group. Administration of P. karwinskii extract and metformin reduced glucose, insulin, triglyceride, and insulin resistance indices and antioxidant enzyme activity to values similar to those of the control group. Therefore, this study shows the nutraceutical potential of P. karwinskii extract as an ingredient in the formulation of dietary supplements or functional foods to help treat diseases whose pathophysiology is related to oxidative stress and insulin resistance.

Virgin Coconut Oil-based Nanostructured Lipid Carrier Improves the Hypolipidemic Effect of Rosuvastatin.

Monitoring noncommunicable diseases is regarded as a critical concern that has to be managed in order to avoid a wide variety of complications such as increasing blood lipid levels known as dyslipidemia. Statin drugs, mostly, Rosuvastatin (RSV) was investigated for its effectiveness in treating dyslipidemia. However, reaching the most efficient treatment is essential and improving the effect of RSV is crucial. Therefore, a combination therapy was a good approach for achieving significant benefit. Although RSV is hydrophobic, which would affect its absorption and bioavailability following oral administration, overcoming this obstacle was important. To that end, the purpose of the present investigation was to incorporate RSV into certain lipid-based nanocarriers, namely, nanostructured lipid carrier (NLC) prepared with virgin coconut oil (CCO). The optimized RSV-NLC formula was selected, characterized and examined for its in vitro, kinetic, and stability profiles. Eventually, the formula was investigated for its in vivo hypolipidemic action. The optimized NLC formulation showed a suitable particle size (279.3±5.03 nm) with PDI 0.237 and displayed good entrapment efficiency (75.6±1.9%). Regarding in vitro release, it was efficiently prolonged for 24 h providing 93.7±1.47%. The optimized formula was established to be stable after 3 months storage at two different conditions; 4°C and 25°C. Importantly, including CCO in the development of RSV-NLC could impressively enhance lowering total cholesterol level in obese rat models, which endorse the potential synergistic action between RSV and CCO. The study could elucidate the impact of developing NLC using CCO for improving RSV anti-hyperlipidemic activity.

Fructooligosaccharides Ameliorate Renal Injury and Dysfunction Through the Modulation of Gut Dysbiosis, Inhibition of Renal Inflammation, Oxidative Stress, Fibrosis, and Improve Organic Anion Transporter 3 Function in an Obese Rat Model.

High-fat diet (HFD) consumption causes obesity and gut dysbiosis which induces kidney injury. It has been reported that prebiotics improve gut dysbiosis and insulin sensitivity and decelerate the progression of kidney disease. This study investigates the impact of fructooligosaccharides (FOS) on renoprotection and the prevention of gut dysbiosis and intestinal barrier injury in obese rats. Wistar rats are treated with HFD for 16 weeks. Then, the HFD fed rats (HF) are given FOS 1gday-1 (HFFOS1), 2gday-1 (HFFOS2), or metformin 30mgkg-1day-1 (HFMET), by intragastric feeding for 8 weeks. Blood, urine, feces, kidney, and intestine are collected to determine the metabolic changes, gut dysbiosis, and the expression of proteins involved in kidney and intestinal injury. FOS can attenuate insulin resistance and hypercholesterolemia concomitant with the inhibition of renal inflammation, oxidative stress, fibrosis, and apoptosis, which are related to the deceleration of the overexpression of renal Toll-like receptor 4 (TLR4) and NADPH oxidase (NOX4). Moreover, FOS shows a greater efficacy than metformin in the reduction of the intestinal injury and loss of tight junction proteins induced by HFD. FOS may be used as a supplement for therapeutic purposes in an obese condition to improve intestinal integrity and prevent renal complications.

Vasohibin inhibition improves myocardial relaxation in a rat model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with increased myocardial stiffness and cardiac filling abnormalities. Prior studies implicated increased α-tubulin detyrosination, which is catalyzed by the vasohibin enzymes, as a contributor to increased stabilization of the cardiomyocyte microtubule network (MTN) and stiffness in failing human hearts. We explored whether increased MTN detyrosination contributed to impaired diastolic function in the ZSF1 obese rat model of HFpEF and designed a small-molecule vasohibin inhibitor to ablate MTN detyrosination in vivo. Compared with ZSF1 lean and Wistar Kyoto rats, obese rats exhibited increased tubulin detyrosination concomitant with diastolic dysfunction, left atrial enlargement, and cardiac hypertrophy with a preserved left ventricle ejection fraction, consistent with an HFpEF phenotype. Ex vivo myocardial phenotyping assessed cardiomyocyte mechanics and contractility. Vasohibin inhibitor treatment of isolated cardiomyocytes from obese rats resulted in reduced stiffness and faster relaxation. Acute in vivo treatment with vasohibin inhibitor improved diastolic relaxation in ZSF1 obese rats compared with ZSF1 lean and Wistar Kyoto rats. Vasohibin inhibition also improved relaxation in isolated human cardiomyocytes from both failing and nonfailing hearts. Our data suggest the therapeutic potential for vasohibin inhibition to reduce myocardial stiffness and improve relaxation in HFpEF.

Perindopril and losartan affect ACE-2 and IL- 6 expression in obese rat model.

Obesity has emerged as a worldwide health concern due to its increasing prevalence. Adipocytes have the ability to express angiotensin-converting enzyme 2 receptors (ACE2) and several adipocytokines. These expressions could lead to the activation of a cytokine storm, which in turn promotes the development of cardiovascular diseases. The aim of this study was to investigate the impact of perindopril and losartan exposure on the ACE2 and interleukin 6 (IL-6) levels in adipocyte cells. This study used an in vivo true experimental design utilizing a post-test-only control group. A total of 24 adult male albino rats were divided into four groups, one group served as the non-obese (negative control), while the other three groups were obese: (1) the positive control (untreated obese rats); (2) perindopril group (2 mg/kg BW/day orally for 4 weeks); and (3) losartan group (20 mg/kg BW/day for 4 weeks). Afterwards, the rats were euthanized, and the visceral fat tissue were obtained during dissection. The levels of ACE2 and IL-6 were measured using the enzyme-linked immunosorbent assay (ELISA). Losartan administration in obese rats resulted in a notable elevation in ACE2 levels compared to both the perindopril group (losartan vs perindopril, p=0.011) and the positive control (p=0.004). In addition, the treatment of perindopril and losartan in obese rats resulted in a significant reduction in IL-6 levels when compared to the positive control (perindopril vs positive control, p=0.020; losartan vs positive control, p=0.002, respectively). This study provides insight into the administration of perindopril and losartan, which could suppress the pro-inflammatory (IL-6) but increase the ACE2 levels in adipose tissue.

Hyperpolarized 13C and 31P MRS detects differences in cardiac energetics, metabolism, and function in obesity, and responses following treatment.

Obesity is associated with important changes in cardiac energetics and function, and an increased risk of adverse cardiovascular outcomes. Multi-nuclear MRS and MRI techniques have the potential to provide a comprehensive non-invasive assessment of cardiac metabolic perturbation in obesity. A rat model of obesity was created by high-fat diet feeding. This model was characterized using in vivo hyperpolarized [1-13C]pyruvate and [2-13C]pyruvate MRS, echocardiography and perfused heart 31P MRS. Two groups of obese rats were subsequently treated with either caloric restriction or the glucagon-like peptide-1 analogue/agonist liraglutide, prior to reassessment. The model recapitulated cardiovascular consequences of human obesity, including mild left ventricular hypertrophy, and diastolic, but not systolic, dysfunction. Hyperpolarized 13C and 31P MRS demonstrated that obesity was associated with reduced myocardial pyruvate dehydrogenase flux, altered cardiac tricarboxylic acid (TCA) cycle metabolism, and impaired myocardial energetic status (lower phosphocreatine to adenosine triphosphate ratio and impaired cardiac ΔG~ATP). Both caloric restriction and liraglutide treatment were associated with normalization of metabolic changes, alongside improvement in cardiac diastolic function. In this model of obesity, hyperpolarized 13C and 31P MRS demonstrated abnormalities in cardiac metabolism at multiple levels, including myocardial substrate selection, TCA cycle, and high-energy phosphorus metabolism. Metabolic changes were linked with impairment of diastolic function and were reversed in concert following either caloric restriction or liraglutide treatment. With hyperpolarized 13C and 31P techniques now available for human use, the findings support a role for multi-nuclear MRS in the development of new therapies for obesity.

Dahuang Huanglian Xiexin Decoction ameliorates obesity via modulating adipocyte differentiation and lipid degradation through inhibiting endoplasmic reticulum stress

Dahuang Huanglian Xiexin Decoction (DHXD) is the representative clinical formula for treating epigastric oppression. In this study, we aim to explore the effect of DHXD on obesity and attempt to investigate its potential mechanism. 3T3-L1 preadipocytes were differentiated and high-fat diet-induced obese rat model was established. DHXD was used for treatment and tunicamycin, the activator of endoplasmic reticulum (ER) stress, was adopted to investigate the related regulatory mechanism. Cell viability was evaluated using CCK-8 assay. Oil-Red O staining was performed to determine lipid accumulation. Glycerol production and Triglyceride content were measured using their commercial kits. Western blot was conducted to examine the expression of critical proteins. Results indicated that DHXD could greatly reduce intracellular lipid droplets and triglyceride in differentiated 3T3-L1 cells. Moreover, the elevated expression of mature adipocytes markers, PPARγ, aP2, during adipogenesis was decreased by DHXD treatment. In addition, DHXD aggravated the lipolysis in differentiated 3T3-L1 cells, as evidenced by the upregulated ATGL expression and the downregulated HSL expression. Besides, DHXD inhibited endoplasmic reticulum (ER) stress in 3T3-L1 cells. Further experiments indicated that the impacts of DHXD on adipocyte differentiation and lipid degradation were partly abolished by tunicamycin. Finally, DHXD alleviated lipid accumulation and ER stress in obese rats. In conclusion, DHXD ameliorates obesity via modulating adipocyte differentiation and lipid degradation through inhibiting ER stress.

The association between the size of adipocyte-derived extracellular vesicles and fasting serum triglyceride-glucose index as proxy measures of adipose tissue insulin resistance in a rat model of early-stage obesity.

Obesity is a complex disease that predisposes individuals to cardiometabolic alterations. It leads to adipose tissue (AT) dysfunction, which triggers insulin resistance (IR). This suggests that people with obesity develop local IR first and systemic IR later. AT secretes extracellular vesicles, which may be physiopathologically associated with the development of IR. Our aim was to evaluate the effect of a high-fat diet on different parameters of adiposity in a rat model of early-stage obesity and to determine if these parameters are associated with markers of systemic IR. In addition, we sought to explore the relationship between fasting blood measures of IR (Triglycerides/High Density Lipoprotein-cholesterol [TAG/HDL-c] and Triglycerides-Glucose Index [TyG Index]) with the size of adipocyte-derived extracellular vesicles (adEV). We used a model of diet-induced obesity for ten weeks in Wistar rats exposed to a high-fat diet. Final weight gain was analyzed by Dual X-ray absorptiometry. Visceral obesity was measured as epididymal AT weight. IR was evaluated with fasting TyG Index & TAG/HDL-c, and adEV were isolated from mature adipocytes on ceiling culture. In the high-fat diet group, glucose and triglyceride blood concentrations were higher in comparison to the control group (Log2FC, 0.5 and 1.5 times higher, respectively). The values for TyG Index and adEV size were different between the control animals and the high-fat diet group. Multiple linear regression analyses showed that adEV size can be significantly associated with the TyG Index value, when controlling for epididymal AT weight. Our results show that lipid and glucose metabolism, as well as the size and zeta potential of adEV are already altered in early-stage obesity and that adEV size can be significantly associated with liver and systemic IR, estimated by TyG Index.

HPP-1S attenuates oleic acid-induced steatosis in HepG2 cells and nonalcoholic fatty liver disease in a rat model of high-fat diet-induced obesity

HPP-1S is a new polysaccharide that was isolated and purified from the gonads of sea urchins in our laboratory. The aim of this study was to investigate the therapeutic effect of the polysaccharide HPP-1S on nonalcoholic fatty liver disease (NAFLD). The results showed that HPP-1S suppressed lipid accumulation in oleic acid (OA)-treated HepG2 cells. In vivo experiments shown that treatment with HPP-1S can reduce lipid accumulation and inhibit liver damage. Further mechanistic investigation indicated that HPP-1S treatment increased the phosphorylation of AMP-activated protein kinase (AMPK). Additionally, the expression of sterol regulatory element-binding protein-1 (SREBP1) and fatty acid synthase (FAS) decreased. After treatment with HPP-1S, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Sirtuin 1 (SIRT1) increased. These results reveal the promising role of HPP-1S in the prevention and treatment of NAFLD. These findings contribute to the development of new therapeutic strategies for the clinical treatment of NAFLD.

The enduring metabolic improvement of combining dual amylin and calcitonin receptor agonist and semaglutide treatments in a rat model of obesity and diabetes.

Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects on body weight, glucose control, and insulin action. However, how the metabolic benefits are maintained after long-lasting treatment is unknown. This study investigates the long-term anti-obesity and anti-diabetic treatment efficacy of the DACRA KBP-336 alone and combined with the GLP-1 analog semaglutide. Zucker diabetic Sprague Dawley (ZDSD) rats with obesity and diabetes received KBP-336 (4.5 nmol/kg Q3D), semaglutide (50 nmol/kg Q3D), or the combination for 7 mo, and the treatment impact on body weight, food intake, glucose control, and insulin action was evaluated. Furthermore, serum levels of the cardiac fibrosis biomarker endotrophin were evaluated. KBP-336, semaglutide, and the combination lowered body weight significantly compared with the vehicle, with the combination inducing a larger and more sustained weight loss than either monotherapy. All treatments resulted in reduced fasting blood glucose levels and HbA1c levels and improved glucose tolerance compared with vehicle-treated rats. Furthermore, all treatments protected against lost insulin secretory capacity and improved insulin action. Serum levels of endotrophin were significantly lowered by KBP-336 compared with vehicle. This study shows the benefit of combining KBP-336 and semaglutide to obtain significant and sustained weight loss, as well as improved glucose control. Furthermore, KBP-336-driven reductions in circulating endotrophin indicate a clear reduction in the risk of complications. Altogether, KBP-336 is a promising candidate for the treatment of obesity and type 2 diabetes both alone and in combination with GLP-1 analogs.NEW & NOTEWORTHY These studies describe the benefit of combining dual amylin and calcitonin receptor agonists (DACRA) with semaglutide for long-term treatment of obesity and type 2 diabetes. Combination treatment induced sustained weight loss and improved glucose control. A DACRA-driven reduction in a serological biomarker of cardiac fibrosis indicated a reduced risk of complications. These results highlight DACRAs as a promising candidate for combination treatment of obesity and type 2 diabetes and related long-term complications.

The Metabolic and Endocrine Effects of a 12-Week Allulose-Rich Diet

The global rise in type 2 diabetes (T2D) and obesity necessitates innovative dietary interventions. This study investigates the effects of allulose, a rare sugar shown to reduce blood glucose, in a rat model of diet-induced obesity and T2D. Over 12 weeks, we hypothesized that allulose supplementation would improve body weight, insulin sensitivity, and glycemic control. Our results showed that allulose mitigated the adverse effects of high-fat, high-sugar diets, including reduced body weight gain and improved insulin resistance. The allulose group exhibited lower food consumption and increased levels of glucagon-like peptide-1 (GLP-1), enhancing glucose regulation and appetite control. Additionally, allulose prevented liver triglyceride accumulation and promoted mitochondrial uncoupling in adipose tissue. These findings suggest that allulose supplementation can improve metabolic health markers, making it a promising dietary component for managing obesity and T2D. Further research is needed to explore the long-term benefits and mechanisms of allulose in metabolic disease prevention and management. This study supports the potential of allulose as a safe and effective intervention for improving metabolic health in the context of dietary excess.

Effect of polymethoxylated flavonoids on glucose and lipid metabolism in rat model of obesity induced by a high-fat diet

This study established a rat model of obesity by using a high-fat diet(HFD) to explore the effect of polymethoxylated flavonoids on glucose and lipid metabolism in the model rats and decipher the role and mechanism of polymethoxylated flavonoids in mitigating obesity. Thirty normal SD rats were selected and randomized into normal, model, ezetimibe(0.1 mg·kg~(-1)), and polymethoxylated flavonoids(62.5 mg·kg~(-1) and 125 mg·kg~(-1)) groups based on the body weight. Except the normal group receiving a conventional diet, the other groups received a HFD. Rats were administrated with corresponding doses of drugs by gavage. During the administration period, the body weight of each group of rats was regularly weighed, and the serum lipid and glucose levels were measured by a fully automated biochemical analyzer. Islet homeostasis and serum levels of obesity factors were measured by ELISA. The 16S rRNA high-throughput sequencing was employed to study the gut microbiota. Hematoxylin-eosin staining was employed to observe the histomorphology of white fat, brown fat, and pancreas. After the wet weights of white fat and brown fat were measured, the organ index was calculated. Immunohistochemistry and Western blot were employed to determine the protein levels. The results showed that polymethoxylated flavonoids reduced the body weight and Lee's index and improved blood lipid levels of the model rats. Polymethoxylated flavonoids reduced blood glucose and insulin secretion, increased insulin responsiveness, and alleviated insulin resistance. In addition, polymethoxylated flavonoids regulated the serum levels of obesity factors and reduced the weights and indexes of white fat and brown fat, the diameter of white adipocytes, and the number of fat vacuoles in brown fat and pancreatic islet cells. The intervention with polymethoxylated flavonoids increased the diversity of gut microbiota in the model rats, increasing the beneficial bacteria associated with glucose and lipid metabolism and reduced the harmful bacteria at the genus level. In addition, polymethoxylated flavonoids up-regulated the protein levels of glucose transporter 4(GLUT4), phosphorylated AMP-activated protein kinase(p-AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α), and uncoupling protein 1(UCP1). In summary, polymethoxylated flavonoids may increase the body utilization of glucose and lipids by regulating the homeostasis of insulin, the serum levels of obesity factors, the diversity of gut microbiota, and the expression of mitochondrial metabolism-related proteins in brown adipocytes, thereby mitigating obesity in rats.

Effects of a Functional Food Made with Salvia hispanica L. (Chia Seed), Amaranthus hypochondriacus L. (Amaranth), and an Ethanolic Extract of Curcuma longa L. (Curcumin) in a Rat Model of Childhood Obesity.

Obesity is a global health problem and is increasing in prevalence in most countries. Although obesity affects all age groups, children are the most vulnerable sector. Functional foods are novel formulated foods containing substances (i.e., nutrients, phytochemicals, probiotics, etc.) that have potential health-enhancing or disease-preventing value. The research objective was to study the possible beneficial effects of providing a functional food made with amaranth flour, chia seed, and curcumin extract on the metabolism and behavior of a rat model of childhood obesity. Male Wistar rat pups from two litters of different sizes, a normal litter (NL) (10 pups) and a small litter (SL) (4 pups), were used. After weaning, the rats were fed a hypercaloric diet (HD) or an HD supplemented with the functional food mixture. Body weight and energy intake were measured for seven weeks, and locomotor activity, learning, and memory tests were also performed. At the end of the experiment, glucose and lipid metabolism parameters were determined. The results showed that in this model of obesity produced by early overfeeding and the consumption of a hypercaloric diet, anxiety-like behaviors and metabolic alterations occurred in the rat offspring; however, the provision of the functional food failed to reduce or prevent these alterations, and an exacerbation was even observed in some metabolic indicators. Interestingly, in the NL rats, the provision of the functional food produced some of the expected improvements in health, such as significant decreases in body weight gain and liver cholesterol and non-significant decreases in adipose tissue and leptin and insulin serum levels.