Reduced Body Weight Research Articles

Non-clinical and first-in-human characterization of ECC5004/AZD5004, a novel once-daily, oral small-molecule GLP-1 receptor agonist.

GLP-1 receptor agonists (GLP-1 RAs) are proven therapies for type 2 diabetes mellitus (T2DM) and overweight or obesity. We performed non-clinical and first-in-human (FIH) evaluation of ECC5004/AZD5004, an oral small-molecule GLP-1 RA. ECC5004 was profiled in cell lines overexpressing human GLP-1R, in glucose-stimulated insulin secretion (GSIS) assays in a human β-cell line and non-human primates (NHPs). To evaluate safety, ECC5004 was orally administered to NHPs for 9 months and a phase I, double-blind, placebo-controlled FIH study was conducted. This study evaluated single doses of ECC5004 (1-300 mg) in healthy volunteers, and multiple daily doses (5, 10, 30 and 50 mg) in patients with T2DM for 28 days. ECC5004 bound to the hGLP-1R (IC50 = 2.4 nM) augmented cAMP signalling without β-arrestin-2 recruitment or receptor internalization. ECC5004 potentiated GSIS in both EndoC-βH5 cells (EC50 = 5.9 nM) and in vivo in NHPs (EC50 = 0.022 nM). Dose-dependent body weight changes compared to control were seen in the 9-month NHP toxicity study. In the first-in-human study, ECC5004 was well tolerated with no serious adverse events. Dose-dependent reductions in glucose and body weight were observed with a dose-proportional exposure at doses ≥25 mg. ECC5004 engaged the GLP-1R across the therapeutic dose range tested and had a safety and tolerability profile consistent with other GLP-1 RAs, along with a pharmacokinetic profile compatible with once-daily oral dosing. These data support continued development of ECC5004 as a potential therapy for T2DM and overweight or obesity. NCT05654831.

Gut microbiota and metabolomics unveil the mechanisms of Lomatogonium rotatum in ameliorating visceral fat and serum lipids in high-fat diet-induced obese mice

Lomatogonium rotatum (LR) is a folk medicinal herb traditionally used as a lipid-lowering and anti-obesity agent; but its pharmacological mechanism is unclear. In this study, we assessed the alterations of LR on gut microbes and serum metabolites in obese mice and their associated mechanisms of modulation on visceral fat and serum lipid by integrating gut microbiota and metabolomics analyses. Mice were fed a high-fat diet (HFD) to generate obesity and were then given LR and Orlistat orally at different doses (0.18, 0.9, 1.8 g/kg for LR and 0.048 g/kg for Orlistat) for a duration of 9 weeks. The impact of LR on weight loss was assessed through the examination of fat deposition, serum lipid indices, liver indices, and HE pathohistology. The effects of LR on gut microbiota and serum metabolites in obese mice were then investigated by 16S rRNA sequencing technology and untargeted metabolomics, and correlation analysis was performed. LR significantly reduced body weight, feed intake, Lee’s index, visceral fat accumulation, serum TG, TC, AST and ALT, and elevated serum HDL levels in obese mice. In addition, 16S rRNA sequencing results indicated that the LR intervention remodeled microbial diversity and composition, increased the relative abundance of gut microbes Bacteroidetes and Porphyromonadaceae in HFD-induced obese mice, and decreased the Deferribacteres, Firmicutes and the Firmicutes/Bacteroidetes ratio. Correlation analyses showed that LR regulation of L-tyrosine and hesperetin metabolism, as well as alterations in the metabolic pathways of Phenylalanine, tyrosine and tryptophan biosynthesis, were associated with the changes in abundance of Bacteroidetes, Firmicutes, Porphyromonadaceae and Deferribacteres. Our study demonstrated that LR has lipid lowering and visceral fat reduction effects and its function may be closely related to the improvement of the gut microbiota and its associated metabolites.

Euglena Attenuates High-Fat-Diet-Induced Obesity and Especially Glucose Intolerance.

Background: Obesity, a global disease, can lead to different chronic diseases and a series of social health problems. Lifestyle changes, especially dietary changes, are the most effective way to treat obesity. Euglena, a novel food, has attracted much attention. Previous studies have shown that Euglena is an important modulator of the host immune response. In this study, the effects of Euglena as a nutritional intervention in high-fat-diet-induced obese C57BL/6J mice were investigated regarding adipose tissue accumulation and lipid and glucose metabolism by gavage at the dose of 100 mg/kg bodyweight for 9 weeks. This study is one of the few to investigate, in detail, the preventive effects of dietary Euglena on obesity. Methods: Five-week-old male C57BL/6J mice were fed with a high-fat diet (HFD) to induce obesity. An obesity model was created by feeding the high-fat diet for a period of 10 weeks. Obese mice were randomized into 2 groups with the same mean body weight, and no significant differences were observed between the groups: (1) the mice in the HEG group were maintained on a high-fat diet and daily gavaged with Euglena (100 mg/kg body weight) dissolved in saline (n = 7); and (2) the mice in the HFD group were maintained on a high-fat diet and daily gavaged with saline with the same volume (n = 7). The experiment finished after a nine-week period. Results: The results showed that Euglena could reduce the accumulation of white body fat, including subcutaneous fat and visceral fat, and mainly targeted subcutaneous fat. Euglena also reduced adipocyte particle size expansion, promoted lipolysis in adipose (adipose triglyceride lipase and hormone-sensitive triglyceride lipase) and liver tissue (reduced non-esterified fatty acid content), and improved obesity-induced ectopic fat deposition and glucose tolerance. Conclusions: Our findings suggest that Euglena, as a nutritional intervention in HFDs, efficiently reduces body weight and white adipose tissue deposition. The mechanism of Euglena is mainly though enhancing lipolysis. It is worth noting that Euglena β-glucan recovers the hyperglycemia and accumulation of ectopic fat within the liver induced by HFD. Our study is one of the few studies to report in detail the preventive effects of dietary Euglena on obesity in vivo. This study revealed that Euglena also has an important ameliorative effect on obesity and metabolic disorders, which laid a theoretical foundation for its future application in functional foods.

Garcinol enriched fraction of Garcinia morella (Gaertn.) Desr. fruit rind improves gut health and reduces the risk of nonalcoholic fatty liver disease by regulating PCK1/ACC/SREBP1/FASn pathway in a mouse model

Nonalcoholic fatty liver disease (NAFLD), a fast-emerging global burden, is an umbrella term for several liver manifestations that result in excessive accumulation of fat in the liver. NAFLD leads to gut microbiome dysbiosis, loss in gut epithelia, increased gut permeability, etc. The limited availability of registered drugs for NAFLD highlights the urgent need to focus on understanding its pathogenesis and discovering new treatments, including the potential exploration of herbal therapies for managing the condition. In this study, we evaluated the bioactive potential of garcinol enriched fraction from Garcinia morella fruit rind in preventing NAFLD-associated increased gut permeability. Administration of garcinol-enriched fraction (GEF) significantly reduced body weight, serum lipids (triglyceride and total cholesterol) levels, and enzymes (alkaline phosphatase and aspartate aminotransferase) responsible for liver dysfunction in high-fat diet (HFD)-fed C57BL/6 mice. GEF treatment also regulated the alteration in signaling pathways of lipid metabolism in HFD-fed mice by inhibiting the overexpression of genes involved in de novo lipogenesis. Mice treated with GEF had increased gut microbial diversity, reduced pathogenic bacteria, and increased Lactococcus and Streptococcaceae genera. Additionally, GEF treatment could increase the expression of intestinal tight junction proteins, which were otherwise decreased in HFD-fed mice, stipulating its protective effect in maintaining gut barrier integrity. Our study demonstrated that GEF treatment reduces obesity in mice and improves gut health by keeping junctions tight and maintaining a healthy gut microbiome.

The Sex Dependent and Independent Effects of Dietary Whey Proteins Are Passed from the Mother to the Offspring.

The study assesses the metabolic impact of dietary whey proteins across generations. Virgin females are fed 20% energy whey proteins with 70% energy carbohydrates, which reduces body weight gain and visceral adipose compared to controls fed dietary casein. In contrast, the males are unresponsive. The effect is accentuated in reproductive females that also have reduced plasma levels of glucose. The responsive females have increased cecal levels of pyruvic and lactic acid, suggesting a greater catabolism of carbohydrates in the gut. While the male and female offspring born to mothers on whey proteins continue to reduce body weight gain, the female offspring further decreases the visceral and subcutaneous tissues and increases the gut capacity to breakdown dietary carbohydrates and proteins, whereas the male offspring are able to only decrease the visceral and increase protein catabolism in the gut. The ileum of male mice responded by reducing the gene expression for fibroblast growth factor 15 and increasing the expression of chymotrypsinogen B1. The effect of whey proteins on growth can be passed from the mother to the offspring without a sex preference, whereas the transmission of gut activity and adiposity are dependent on the sex of the offspring.

Long-Lasting Exendin-4-Coated Gold Nanoparticles: Synthesis and In Vivo Evaluation of Hypoglycemic Activity

Background: Gold nanoparticles (NPs) have drawn great attention in the area of biomedical research with their relatively safe and versatile properties. This study aimed to synthesize long-lasting exendin-4-coated gold NPs (EX-ABD-AFF-GoldNPs) and evaluate their anti-diabetic effects in vivo. Methods: In the present study, EX-ABD-AFF-GoldNPs were synthesized using a simple one-step aqueous reduction method. The physical characterization of the prepared particles verified the successful formation of the EX-ABD-AFF-GoldNPs through dynamic light scattering (DLS), transmission electron microscopy (TEM), ultraviolet–visible (UV-VIS) light spectroscopy, and Fourier transform infrared spectroscopy (FTIR). The anti-hyperglycemic and anti-obesity effects were assessed in high-fat diet (HFD)-fed obese diabetic mice. Additionally, pharmacokinetics (PK) and biodistribution studies were performed to verify the long-lasting properties. Results: The EX-ABD-AFF-GoldNPs were conglomerates of smaller globular-shaped particles, and the average size was 110(±14) nm, based on the TEM images. Safety assessments using Min6, HepG2, and B16F10 cell lines demonstrated low cytotoxicity, with over 80% cell viability up to the highest tested concentration of 150 μg/mL (as EX-ABD-AFF). Notably, the animal studies showed that the EX-ABD-AFF-GoldNPs exhibited significant hypoglycemic activity, comparable to the EX-ABD-AFF, in the HFD-fed mice. A 4-week treatment with EX-ABD-AFF-GoldNPs produced similar reductions in blood glucose and body weight to the EX-ABD-AFF, without any apparent toxicity. Furthermore, the PK and biodistribution study results confirmed the long-lasting properties (plasma half-life: 43.6 h) of the particles. Conclusions: Overall, this study demonstrated that the preparation of therapeutic protein-loaded gold NPs is feasible and, despite their much larger size compared with the protein, EX-ABD-AFF-GoldNPs can be successfully absorbed through the subcutaneous route and show nearly equivalent hypoglycemic activity to the EX-ABD-AFF protein. Finally, this study showed that long-lasting properties could be acquired by only coating EX-ABD-AFF onto gold NPs.

Spray paint-derived microplastics and incorporated substances as ecotoxicological contaminants in the Neotropical Bumblebee Bombus atratus

While bumblebees may be exposed to microplastics (MPs), the effects on them are not well studied. Therefore, in this research, we assessed the cytotoxicity of pristine and photodegraded spray paint-derived MPs on the midgut, Malpighian tubules, and hepato-nephrocitic system cells of Bombus atratus workers exposed to 50mg.L-1 MPs for 96hours. Histological and histochemical analyses revealed that pristine MPs caused subtle cellular changes, while the exposure to photodegraded MPs led to significant vacuolization, nuclear condensation, and pyknosis. These effects are possibly linked to the release of potentially toxic elements (PTEs) like Copper, Manganese, and Iron from photodegraded MPs, which exceeded Brazil's CONAMA safety limits. Photodegraded MPs also reduced body weight, disrupting homeostasis and potentially decreasing bumblebee’s fitness. These findings highlight the importance of studying the toxicity of environmentally realistic MPs, as plastic composition and weathering significantly influence their harmful effects.

A polysaccharide from edible red seaweed Bangia fusco-purpurea prevents obesity in high-fat diet-induced C57BL/6 mice

The study aimed to investigate the impacts of a polysaccharide (BFP) from Bangia fusco-purpurea on high-fat diet (HFD)-induced obesity in C57BL/6 mice, as well as its underlying mechanisms. Our results showed that orally administrated BFP was more effective than inulin (INU) in reducing body weight and fat accumulation in obese mice, indicating its anti-obesity effect. BFP effectively improved the compositions and metabolites of intestinal microbiota in obese mice, leading to enhanced energy metabolism and lipid metabolism, thus contributing to its anti-obesity effect. Notably, the better anti-obesity effect of BFP compared to INU were attributed to their varying degrees of modulation of specific intestinal microbial taxa, such as Clostridium and Aerococcus, as well as the regulation of differential metabolites (including biotin, piperine, G6P, etc.) also varies. Also, both in vitro (3T3-L1 preadipocytes) and in vivo (HFD-induced obese mice) models confirmed that BFP achieved anti-obesity effect attributed to enhance energy metabolism, promote lipolysis, increase fatty acid oxidation, and inhibit adipogenesis via activating the AMP-activated protein kinase and Acetyl-CoA carboxylase signaling pathways and suppressing the peroxisome proliferator-activated receptor γ expression. Our findings suggest that BFP has the potential to be used as prebiotics, dietary agents, and nutritional supplements against obesity.

Effects of water-insoluble wheat bran-fraction powder on disease activity and caecal microbiota in dextran sodium sulphate-induced inflammatory bowel disease mouse model.

Water-soluble arabinoxylan exerts anti-colitic effect and exhibits ameliorative activity in an inflammatory bowel disease (IBD) mouse model. Water soluble fibre from wheat bran (WB) also exhibits anti-colitic effect. However, arabinoxylan is a primary compound of insoluble polysaccharide (hemicellulose) in WB. This study aimed to clarify the anti-IBD effects of the WB water-soluble (WBS) and water-insoluble (WBI) fractions. WB suspension was autoclaved and fractionated to WBS and WBI. C57BL/6 mice were divided into control (CT), dextran sodium sulphate (DSS), WBI, and WBS groups. They were fed as follows from day 1: CT, standard diet and distilled water; DSS and WBI, 3% (w/v) DSS in drinking water; WBI, 8% (w/w) WBI diet; and WBS, 50% (v/v) WBS and 3% (w/v) DSS in water. DSS group mice showed diarrhoea, body weight reduction, and blood in faeces by day 5 and colon tissue damage by day 6. These inflammatory indices were significantly inhibited by treatment with WBI. Amplicon sequencing of the 16S rDNA (V4) gene of the caecal contents of the CT, DSS, and WBI groups showed that the abundances of Escherichia, Allobaculum, and Bacteroidaceae increased and that of Faecalibaculum decreased in the DSS group. KEGG pathway prediction showed that amino acid metabolism and lipopolysaccharide biosynthesis decreased and increased, respectively, in the DSS group. However, WBI treatment tended to suppress these effects. WBI, rather than WBS, reduces inflammation and maintains the gut microbiota. However, further studies are warranted to elucidate the properties of the WBI active components and efficacy of WBI metabolites on gut microbiota, particularly on Faecalibaculum.

Fucosylated chondroitin sulfate alleviates diet-induced obesity by modulating intestinal lipid metabolism and colonic microflora

Fucosylated chondroitin sulfate from Pearsonothuria graeffei (FCS-Pg), a natural macromolecular polysaccharide, has been proven to prevent obesity, but its underlying molecular mechanism is still unclear. C57BL/6 J mice fed on high fat diet (HFD) were administered FCS-Pg lasting for ten weeks. The results demonstrated that FCS-Pg supplementation reduced body weight with dosage manner compared with HFD group. The expressions of intestinal lipid synthesis related proteins such as cluster of differentiation 36 (CD36) in FCS-Pg group were lower than those in the HFD group. Compared with the normal group, HFD caused gut microbiota disorder in the colon. FCS-Pg supplementation at high dosage restored the gut microbiota composition with higher abundance of Alistipes and Bacteroidetes and lower abundance of Colidextribacter, Bilophila and Firmicutes compared with HFD group. Moreover, FCS-Pg decreased the expression of proteins involved in triglyceride synthesis such as glycerol 3-phosphate dehydrogenase 1 (GPD1) and increased the expression of proteins involved in lipolysis and thermogenesis such as adipose triglyceride lipase (ATGL) and uncoupling protein 1 (UCP1) in the white adipose tissue (WAT) compared with HFD group. In conclusion, our study suggested that FCS-Pg significantly prevented obesity and improved WAT function in HFD-fed mice by regulating intestinal lipid metabolism and microflora composition.

Synergistic effects of Lianhuaqingwen in combination with Oseltamivir and Baloxavir against seasonal influenza virus: in vitro and in vivo assessment

Ethnopharmacological relevanceLianhuaqingwen (LH), a traditional Chinese medicine, presents a broad-spectrum antiviral effect and has been widely used to treat influenza. Given the potential rise of drug-resistant influenza viruses, it is necessary to develop new antiviral drugs and explore combination therapies involving LH in tandem with existing antivirals such as Oseltamivir acid (Osel) or Baloxavir (Bal). These multidrug combinations could help effectively control the seasonal influenza epidemics and reduce the disease burden. Aim of the studyThis study aimed to evaluate the antiviral effects of LH, alone and in combination with Osel or Bal, against human seasonal influenza viruses in vitro and in vivo models. Materials and methodsThe antiviral efficacy of LH alone and LH in combination with Osel/Bal against seasonal influenza A viruses (IAVs) (H1N1 and H3N2 subtypes) and influenza B viruses (IBVs) (BV- and BY-lineages) was assessed in vitro using MDCK cells. The median effective concentration (EC50) was determined, and the drug synergies were analyzed. Additionally, the antiviral activity of LH monotherapy and LH + Osel/Bal combination therapy were evaluated in vivo using an H1N1-infected BABL/c mouse model by monitoring changes in body weight, survival rate, lung viral titer, pathological damage, and inflammatory reaction. ResultsIn vitro, LH alone and in combination with Osel/Bal exhibited antiviral activity against both IAVs and IBVs. The addition of LH to Osel/Bal improved the therapeutic efficacy compared to Osel/Bal alone. In vivo, LH monotherapy reduced body weight loss and increased the survival rates of H1N1-infected mice. LH in combination with Osel/Bal resulted in lower virus titers, more effective relief of pathological damage, and comparable low expression of inflammatory factors in the lungs of H1N1-infected mice compared to the use of Osel/Bal alone. Transcriptomic analysis of the lungs revealed that LH+Osel/Bal significantly increased the expression of genes associated with antiviral and anti-inflammatory effects. ConclusionsThis study evaluated the antiviral effects of LH monotherapy and combination therapy with Osel/Bal against human seasonal influenza viruses in vitro and in vivo models. The results suggest that combining LH with Osel or Bal could enhance the antiviral efficiency for influenza viruses compared to the monotherapy using any of these three drugs.

Low-dose valine attenuates diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) in mice by enhancing leptin sensitivity and modulating the gut microbiome

Elevated circulating branched-chain amino acids (BCAAs) have been associated with obesity, insulin resistance, and MASLD, yet BCAA supplementation has been shown to provide protective outcomes towards the intervention of MASLD. Currently, there is a lack of study towards the contribution of the BCAA: valine on MASLD. This study investigates the effects of low-dose valine supplementation on MASLD in a high-fat/high-cholesterol diet (HFD) model. Low-dose valine was found to attenuate the progression of MASLD, significantly reducing body weight, liver weight, and eWAT weight, attenuating hyperglycemia and improving serum lipid profiles. It also decreased hyperleptinemia and enhanced hypothalamic leptin sensitivity, leading to reduced food intake. In the eWAT, metabolic flexibility was improved, as indicated by upregulated adipogenesis-related gene expressions and suppressed leptin expression. In the liver, valine improved hepatic leptin sensitivity, alleviated hepatic steatosis, and reduced triglycerides, cholesterol, TNFα, and IL-6 levels. Mechanistically, valine increased hepatic antioxidant capacity and modulated lipid metabolism and antioxidant pathways, downregulating de novo lipogenesis and cholesterol synthesis while increasing fatty acid oxidation, autophagy-related gene expressions. Moreover, hepatic AMPK pathway activity was enhanced, contributing to improved leptin sensitivity and signalling. Additionally, low-dose valine supplementation also modulated the gut microbiome, suggesting a multifaceted approach to managing MASLD.

066. Sleeve Gastrectomy Decrease of TNF-a and Increase TGF-a Gene Expression in the Abdominal Aorta of Rats with Obesity and Diabetes Mellitus

Background: Sleeve gastrectomy (SG) is one option to significantly reduce body weight while also protecting the cardiovascular system by controlling hyperglycaemia and inflammatory markers. Secretion of tumour necrosis factor (TNF)-? could induce inflammation, meanwhile, the transforming growth factor-? (TGF-?) are anti-inflammatory cytokines, both of which play a role in the process of atherosclerosis. This study aimed to analyse the effect of SG procedure on TNF-? and TGF-? gene expression in the abdominal aorta of obese and DM rats. Method: Fifteen rats were divided into 3 groups: lean-non-DM rats model (C1 group), obese-DM rats model (C2 group), and obese-DM rats model underwent SG (T group). Before and 10 days after the SG procedure, rats’ body weight and fasting blood glucose (FBG) were measured. Ten days after the procedure, TNF-? and TGF-? gene expression were also evaluated by PCR. Results: At the end of the study, mean body weight, FBG levels, and TNF-? gene expression in the C1 group (231.80±4.32 gram; 68.60±2.07 mg/dL; 1.01±0.01 rfu) and T group (232.00±5.33 gram; 114.40±3.20 mg/dL; 1.97±0.57 rfu) were significantly lower than in C2 group (264.60± 3.28 gram; 271.00±6.89 mg/dL; 224.12±47.59 rfu). TGF-? gene expression was found to be considerably higher in T group (25.62 ± 3.03 rfu) compared to C1 group (1.05 ± 0.01 rfu) and C2 group (1.63 ± 0.21 rfu). Conclusion: SG could decrease body weight and FBG, as well as TNF-? gene expression, and increase TGF-? gene expression in the abdominal aorta of rats with obesity and DM.

A Comprehensive Review on the Anti-Obesity Potential of Limonia acidissima L., and its Bioactive Compounds: Mechanisms and Applications in Weight Management

Introduction: Obesity is a global health challenge associated with numerous metabolic disorders, including diabetes and cardiovascular disease. With growing interest in natural remedies for weight management, Limonia acidissima L., has garnered attention due to its rich bioactive composition. Objectives: This systematic review evaluates the anti-obesity potential of Limonia acidissima L., and its key bioactive compounds, including fibres, phytosterols, saponins, polyphenols, flavonoids, and ascorbic acid. Methods: A comprehensive search of databases such as PubMed, Scopus, and Google Scholar was conducted, focusing on studies published between 2000 and 2023 that investigated the metabolic effects of these compounds on lipid and carbohydrate metabolism, fat absorption, and glucose regulation. Results: The results demonstrated that Limonia acidissima L., significantly reduced body weight and fat mass, improved lipid profiles, and enhanced insulin sensitivity in both animal and human studies.Phytosterols and saponins played key roles in modulating lipid metabolism, while fibres and polyphenols were found to regulate carbohydrate metabolism and improve glycemic control. Additionally, the synergistic effects of multiple bioactive compounds amplified their collective anti-obesity potential, with few reported adverse effects, suggesting a favourable safety profile. The discussion highlights the multifaceted mechanisms through which Limonia acidissima L., combats obesity, emphasizing its ability to target multiple metabolic pathways simultaneously.While the findings are promising, the need for further large-scale clinical trials to validate these effects in diverse populations is underscored. Conclusions: In conclusion, Limonia acidissima L., emerges as a potent natural remedy for obesity management, with strong potential for inclusion in weight loss supplements and functional foods.Its bioactive compounds offer a comprehensive and safe approach to addressing the global obesity epidemic, although further research is needed to establish its long-term efficacy and optimal use.

Efficacy and Safety of Novel Twincretin Tirzepatide, a Dual GIP/GLP-1 Receptor Agonist, as an Anti-obesity Medicine in Individuals Without Diabetes: A Systematic Review and Meta-analysis.

Aims: To date, no meta-analysis has analyzed the efficacy and safety of tirzepatide as an anti-obesity medication in individuals without diabetes. This meta-analysis was undertaken to address this knowledge gap. Materials and methods: Electronic databases were searched for randomized controlled trials (RCTs) involving individuals with obesity without diabetes receiving tirzepatide in the intervention arm and placebo in the control arm. The primary outcome was the percentage change in weight from baseline, and the secondary outcomes included the change in weight from baseline; a weight reduction of ≥5%, ≥10%, ≥15%, ≥20% and ≥25%; glycaemic parameters; lipid parameters and adverse events. Results: From 281 initially screened articles, data from 2 RCTs involving 1,852 participants were analyzed. The efficacy and safety of tirzepatide 15 mg (or the highest tolerable dose) versus placebo were analyzed. The percentage change in body weight was higher with tirzepatide than with placebo (mean difference [MD]: -19.44%; 95% confidence interval [CI]: -22.48 to -16.41; p<0.00001). Tirzepatide also had a higher absolute reduction in body weight (MD: -17.55 kg; 95% CI: -32.15 to -2.95; p<0.00001). Higher percentages of people on tirzepatide had a weight reduction of ≥5%, ≥10%, ≥15%, ≥20% and ≥25% compared with placebo. Improvements in glycaemic and cardiometabolic parameters were observed with tirzepatide. Tirzepatide was associated with a higher number of participants with one or more adverse events, which leads to treatment discontinuation, and severe or serious gastrointestinal events. Conclusion: This meta-analysis provides exciting data on the impressive weight loss properties of tirzepatide over 72 weeks of clinical use in individuals with obesity without diabetes.

Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis

BackgroundWeight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied.MethodsWe conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).ResultsA total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was −13.7% with semaglutide and −3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was −41.7 points with semaglutide and −27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.ConclusionsAmong participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.)

Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes.

Pathogenic variants in subunits of succinyl-CoA synthetase (SCS) are associated with mitochondrial encephalomyopathy in humans. SCS catalyses the conversion of succinyl-CoA to succinate coupled with substrate-level phosphorylation of either ADP or GDP in the TCA cycle. This report presents a muscle-specific conditional knock-out (KO) mouse model of Sucla2, the ADP-specific beta subunit of SCS, generating a novel invivo model of mitochondrial myopathy. The mouse model was generated using the Cre-Lox system, with the human skeletal actin (HSA) promoter driving Cre-recombination of a CRISPR-Cas9-generated Sucla2 floxed allele within skeletal muscle. Inactivation of Sucla2 was validated using RT-qPCR and western blot, and both enzyme activity and serum metabolites were quantified by mass spectrometry. To characterize the model invivo, whole-body phenotyping was conducted, with mice undergoing a panel of strength and locomotor behavioural assays. Additionally, exvivo contractility experiments were performed on the soleus (SOL) and extensor digitorum longus (EDL) muscles. SOL and EDL cryosections were also subject to imaging analyses to assess muscle fibre-specific phenotypes. Molecular validation confirmed 68% reduction of Sucla2 transcript within the mutant skeletal muscle (p < 0.001) and 95% functionally reduced SUCLA2 protein (p < 0.0001). By 3 weeks of age, Sucla2 KO mice were 44% the size of controls by body weight (p < 0.0001). Mutant mice also exhibited 34%-40% reduced grip strength (p < 0.01) and reduced spontaneous exercise, spending about 88% less cumulative time on a running wheel (p < 0.0001). Contractile function was also perturbed in a muscle-specific manner; although no genotype-specific deficiencies were seen in EDL function, SUCLA2-deficient SOL muscles generated 40% less specific tetanic force (p < 0.0001), alongside slower contraction and relaxation rates (p < 0.001). Similarly, a SOL-specific threefold increase in mitochondria (p < 0.0001) was observed, with qualitatively increased staining for both COX and SDH, and the proportion of Type 1 myosin heavy chain expressing fibres within the SOL was nearly doubled (95% increase, p < 0.0001) in the Sucla2 KO mice compared with that in controls. SUCLA2 loss within murine skeletal muscle yields a model of SCS-deficient mitochondrial myopathy with reduced body weight, muscle weakness and exercise intolerance. Physiological and morphological analyses of hindlimb muscles showed remarkable differences in exvivo function and cellular consequences between the EDL and SOL muscles, with SOL muscles significantly more impacted by Sucla2 inactivation. This novel model will provide an invaluable tool for investigations of muscle-specific and fibre type-specific pathogenic mechanisms to better understand SCS-deficient myopathy.

Role of Obeticholic Acid, a Farnesoid X Receptor Agonist, in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis.

Background. Obeticholic acid (OCA) has emerged as a promising drug in the management of nonalcoholic fatty liver disease (NAFLD). This meta-analysis aimed to analyse the therapeutic effect of OCA on NAFLD. Methods. Randomized controlled trials (RCTs) involving patients with NAFLD receiving OCA in the intervention arm and placebo in the control arm were searched throughout the electronic databases. The primary outcomes were changes in non-invasive markers of hepatic fibrosis and liver histology. The secondary outcomes included changes in liver enzymes, metabolic parameters from baseline and adverse events (AEs). Results. Four RCTs involving 1,278 subjects met the inclusion criteria. Over 6 weeks to 18 months of clinical use, OCA outperformed placebo in resolving definite nonalcoholic steatohepatitis (odds ratio [OR] 1.60, 95% confidence interval [CI] [1.04-2.48], p=0.03) and improving fibrosis (OR 2.23, 95% CI [1.56-3.20], p<0.0001), hepatocellular ballooning (OR 1.83, 95% CI [1.35-2.47], p<0.0001) and lobular inflammation (OR 1.62, 95% CI [1.13-2.32], p=0.009). OCA did not improve the enhanced liver fibrosis score and steatosis better than placebo, and demonstrated superior efficacy compared with the placebo in reducing serum alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase levels. Although a favourable effect of OCA over placebo was seen in body-weight reduction, the OCA use was associated with adverse changes in lipid parameters. Except for the greater risk of pruritus and constipation, the AE profile was comparable between the OCA and placebo groups. Conclusions. OCA has a favourable efficacy in improving liver histology and liver enzymes. However, the worsening of lipid parameters and other AEs with the OCA use warrants further investigation.

Nutritional Assessment and Sub-acute Toxicity Study in Wistar Rats Fed with a Compounded Diet of Roasted Plantain and Fish Sold in Otuoke, Nigeria

The widespread consumption of roasted plantain and fish (Bolle), a common delicacy in Bayelsa State has raised concerns over potential health risks associated with food processing contaminants such as acrylamides, polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs). The roasted plantain and fish are usually prepared by placing the peeled plantain and the dressed fish on a wired gauze and placed over a burning charcoal. The subacute toxicity study of this diet was investigated using twenty adult male rats averagely weighing 117.22 \(\pm\) 4.48 g. The rats were divided into four groups of five rats per group. Group A (Control), was fed with the standard rat chow, Group B; was fed with only the roasted plantain, Group C; was fed with only the roasted fish, and Group D; was fed with a combination of the roasted plantain and fish. The rats were given free access to the feed and portable water ad-libitum throughout the experimental protocol. Body/organ weight data were recorded before and after the completion of the experimental protocol. On day 15th of the experimental protocol, the rats were euthanized and blood specimens were obtained by cardiac puncture for biochemical analysis. The liver, kidney and heart were dissevered instantaneously and weighed. Findings from the study showed that the roasted plantain-fed group had significantly reduced body weight gain, and increased liver and kidney to body weight ratio (p&gt;0.05). The plasma enzyme activity (AST, ALT and ALP) of the plantain-fed group were also significantly increased (p&lt;0.05) while other groups showed non-significant differences (p&gt;0.05) with the control group. The antioxidant status (CAT, SOD and GPx), haematological parameters (RBC, PCV, Hb, MCV, MCH, MCHC and platelet) of the plantain-fed groups were also significantly decreased (p&lt;0.05) while other groups had non-significant changes (p&gt;0.05) when compared to the control group. Malondialdehyde levels in the roasted plantain-fed group were also significantly increased (p&lt;0.05).

Role of Dual GIP and GLP-1 Receptor Agonist, Tirzepatide in the Management of Weight Loss; A Systematic Review.

The eventuality of tirzepatide, a binary GIP and GLP- 1 receptor agonist, as a treatment for rotundity and metabolic diseases is addressed in this comprehensive review. A definition of tirzepatide is that it is an implicit intervention for rotundity, given its effectualness per the cure-dependent effect. Beyond the beneficial effects on body weight loss, tirzepatide also brings about an improvement in lipid biographies and insulin perceptivity, in harmony with binary receptor activation. Assaying data from seven phases 3 trials, it's constantly shown that tirizepatide reduces body weight in a significant and clinically meaningful way for a variety of party biographies and lengths of time. The drug's effect was supported by its favorable safety profile, which shows low prevalence rates of common adverse goods. Its efficacy in the management of type 2 diabetes is supported by relative evaluations, underscoring the inevitability of its breakthrough as a therapeutic volition. Treatment individualization is key, as evidenced by the tailor-made response proposed by group analysis based on birth BMI. The efficacy, safety, and demand for personalized treatment plans of tirzepatide are each supported in recommendations for clinical practice. Tirzepatide's eventuality as a long-term strategy for habitual rotundity is corroborated by long-term follow-up studies that show sustained weight loss. Indeed with these encouraging results, further study and clinical experience are demanded to completely comprehend the safety, optimal integration, and long-term effectiveness of tirzepatide in a multiplicity of patient populations.