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Open Veterinary Journal Jan 2024Obesity is one of the most prevalent and perilous health affairs. Male obesity-associated secondary hypogonadism (MOSH) is one of many of its complexities, which is...
The corrective role of superparamagnetic iron oxide nanoparticles for the genes controlling hypothalamus-pituitary-testis-axis in male obesity-associated secondary hypogonadism.
BACKGROUND
Obesity is one of the most prevalent and perilous health affairs. Male obesity-associated secondary hypogonadism (MOSH) is one of many of its complexities, which is mounting in parallel with the aggravation of obesity. Magnetic nanoparticles seem to be an advanced favorable trend in multiple biomedical fields.
AIM
In this study, we explore the therapeutic effects of superparamagnetic iron oxide nanoparticles (SPIONs) coated with carboxymethyl cellulose (CMC) on an obese male rat model with MOSH syndrome, comparing their impacts with a well-known anti-obesity medication (Orlistat).
METHODS
42 male albino rats split into 7 equal groups: 1-negative control: nonobese, untreated; 35 rats fed the high fat-high fructose (HFHF) diet for a period of 12 weeks. Obese rats splitted into 6 equal groups; 2-positive control: obese untreated; 3-obese given Orlistat (30 mg/kg); 4-obese given CMC-SPIONs (25 mgFe/kg); 5-obese given CMC-SPIONs (50 mgFe/kg); 6-obese given CMC-SPIONs(25 mgFe/kg) + Orlistat (30 mg/kg), 7-obese given CMC-SPIONs (50 mgFe/kg) + Orlistat (30 mg/kg); all treatments given orally for 4 weeks. During sacrifice, blood serum and sectioned hypothalamic, pituitary, testicular, and adipose tissues were collected for biochemical and biomolecular assessments.
RESULTS
The HFHF diet for 12 weeks resulted in a significant upsurge in body weight, body mass index, serum fasting glucose, insulin resistance, TAG, total cholesterol, and LDL-c; HDL-c was dropped. Serum FSH, LH, and testosterone values declined. A significant disorder in expression levels of genes regulating the hypothalamic-pituitary-testicular-axis pathway. Hypothalamic GnRH, Kisspeptin-1, Kisspeptin-r1, and Adipo-R1 values declined. GnIH and Leptin-R1 values raised up. Pituitary GnRH-R values declined. Testicular tissue STAR, HSD17B3, and CYP19A1 values declined. Adipose tissue adiponectin declined, while leptin raised up. CMC-SPIONs 25-50 mg could modulate the deranged biochemical parameters and correct the deranged expression levels of all previous genes. Co-treatments revealed highly synergistic effects on all parameters. Overall, CMC-SPIONs have significant efficiency whether alone or with Orlisat in limiting obesity and consequence subfertility.
CONCLUSION
CMC-SPIONs act as an incoming promising contender for obesity and MOSH disorders management, and need more studies on their mechanisms.
Topics: Rats; Male; Animals; Leptin; Orlistat; Testis; Obesity; Hypogonadism; Hypothalamus; Gonadotropin-Releasing Hormone; Magnetic Iron Oxide Nanoparticles; Rodent Diseases
PubMed: 38633156
DOI: 10.5455/OVJ.2024.v14.i1.39 -
Journal of Endocrinological... Jun 2024This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic...
AIM
This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification.
METHODS
Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote.
RESULTS
The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m and < 40 kg/m associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative.
CONCLUSION
The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.
Topics: Humans; Obesity; Overweight; Adult; Italy; Comorbidity; Behavior Therapy; Practice Guidelines as Topic; Disease Management; Bariatric Surgery
PubMed: 38630213
DOI: 10.1007/s40618-024-02361-y -
The British Journal of General Practice... Apr 2024Orlistat is recommended as an adjunct to diet and exercise for weight loss in type 2 diabetes mellitus (T2DM). The aims were to explore (i) associations between patient...
AIMS
Orlistat is recommended as an adjunct to diet and exercise for weight loss in type 2 diabetes mellitus (T2DM). The aims were to explore (i) associations between patient characteristics and orlistat prescribing and to determine (ii) associations of orlistat with weight loss in T2DM/prediabetes.
METHODS
This cohort study used anonymised records of T2DM/prediabetes (2016-2017) patients ≥18 years, from the UK Clinical Practice Research Datalink (CPRD) database. Multivariable logistic regression models determined associations with starting orlistat and stopping it early (<12 weeks of prescriptions) and orlistat's associations with weight loss in those not prescribed 2nd line anti-diabetic medications.
RESULTS
Out of 100,552 patients with incident T2DM/prediabetes, 655 (0.8%) T2DM and 128 (0.7%) prediabetes patients were prescribed orlistat. Younger people, females, those in more deprived regions, current smokers, co-prescribed metformin and recorded with hypertension were significantly more likely to be prescribed orlistat while higher baseline HbA1c levels were associated with early stopping. Those who continued orlistat for >12 weeks were more likely to lose ≥5% weight (adjusted OR: 1.69; 95% CI: 1.07, 2.67) than those not on orlistat, but those who stopped orlistat early were less likely (adjusted OR: 0.56; 95% CI: 0.29, 1.09).
CONCLUSIONS
Orlistat was significantly associated with weight loss in T2DM/prediabetes when taken for at least 12 weeks. However, orlistat is infrequently prescribed and often taken for <12 weeks. Orlistat may be a useful adjunct to lifestyle modifications in T2DM/prediabetes however barriers to continuing orlistat means it may not be effective for everyone in managing weight loss.
PubMed: 38621802
DOI: 10.3399/BJGP.2023.0684 -
European Journal of Pharmaceutical... Jun 2024Lipid-based formulations (LBFs) are an enabling-formulation approach for lipophilic poorly water-soluble compounds. In LBFs, drugs are commonly pre-dissolved in lipids,...
Lipid-based formulations (LBFs) are an enabling-formulation approach for lipophilic poorly water-soluble compounds. In LBFs, drugs are commonly pre-dissolved in lipids, and/or surfactants/cosolvents, hereby avoiding the rate-limiting dissolution step. According to the Lipid formulation classification system, proposed by Pouton in 2006, in type II LBFs a surfactant with an HLB-value lower than 12 is added to the lipids. If high drug doses are required, e.g. for preclinical toxicity studies, supersaturated LBFs prepared at elevated temperatures may be a possibility to increase drug exposure. In the present study, the impact of digestion on drug absorption in rats was studied by pre-dosing of the lipase inhibitor orlistat. The lipid chain length of the type II LBFs was varied by administration of a medium-chain- (MC) and a long-chain (LC)-based formulation. Different drug doses, both non-supersaturated and supersaturated, were applied. Due to an inherent precipitation tendency of cinnarizine in supersaturated LBFs, the effect of the addition of the precipitation inhibitor Soluplus® was also investigated. The pharmacokinetic results were also evaluated by multiple linear regression. In most cases LC-based LBFs did not perform better in vivo, in terms of a higher area under the curve (AUC) and maximal plasma concentration (C), than MC-based LBFs. The administration of supersaturated LBFs resulted in increased AUC (1.5 - 3.2-fold) and C (1.1 - 2.6-fold)-values when compared to the non-supersaturated equivalents. Lipase inhibition led to a decreased drug exposure in most cases, especially for LC formulations (AUC reduced to 47 - 67%, C to 46 - 62%). The addition of Soluplus® showed a benefit to drug absorption from supersaturated type II LBFs (1.2 - 1.7-fold AUC), due to an increased solubility of cinnarizine in the formulation. Upon dose-normalization of the pharmacokinetic parameters, no beneficial effect of Soluplus® could be demonstrated.
Topics: Cinnarizine; Animals; Male; Lipids; Solubility; Lactones; Rats, Wistar; Orlistat; Intestinal Absorption; Rats; Polyethylene Glycols; Lipase; Polyvinyls; Chemical Precipitation; Surface-Active Agents; Chemistry, Pharmaceutical
PubMed: 38608735
DOI: 10.1016/j.ejps.2024.106765 -
Lancet (London, England) Apr 2024Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs.
METHODS
This systematic review and network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) from inception to March 23, 2021, for randomised controlled trials of weight-lowering drugs in adults with overweight and obesity. We performed frequentist random-effect network meta-analyses to summarise the evidence and applied the Grading of Recommendations Assessment, Development, and Evaluation frameworks to rate the certainty of evidence, calculate the absolute effects, categorise interventions, and present the findings. The study was registered with PROSPERO, CRD 42021245678.
FINDINGS
14 605 citations were identified by our search, of which 132 eligible trials enrolled 48 209 participants. All drugs lowered bodyweight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification. High to moderate certainty evidence established phentermine-topiramate as the most effective in lowering weight (odds ratio [OR] of ≥5% weight reduction 8·02, 95% CI 5·24 to 12·27; mean difference [MD] of percentage bodyweight change -7·98, 95% CI -9·27 to -6·69) followed by GLP-1 receptor agonists (OR 6·33, 95% CI 5·00 to 8·00; MD -5·79, 95% CI -6·34 to -5·25). Naltrexone-bupropion (OR 2·69, 95% CI 2·10 to 3·44), phentermine-topiramate (2·40, 1·68 to 3·44), GLP-1 receptor agonists (2·22, 1·74 to 2·84), and orlistat (1·71, 1·42 to 2·05) were associated with increased adverse events leading to drug discontinuation. In a post-hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs for both likelihood of weight loss of 5% or more (OR 9·82, 95% CI 7·09 to 13·61) and percentage bodyweight change (MD -11·40, 95% CI -12·51 to -10·29).
INTERPRETATION
In adults with overweight and obesity, phentermine-topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide might be the most effective.
FUNDING
1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.
Topics: Adult; Humans; Overweight; Network Meta-Analysis; Topiramate; Obesity; Weight Loss; Phentermine; Randomized Controlled Trials as Topic
PubMed: 38582569
DOI: 10.1016/S0140-6736(24)00351-9 -
Molecular Nutrition & Food Research Apr 2024The identification of novel therapeutic agents capable of modulating lipid metabolism holds a promising potential in combating obesity and its associated complications....
SCOPE
The identification of novel therapeutic agents capable of modulating lipid metabolism holds a promising potential in combating obesity and its associated complications. This study is conducted to evaluate the lipid lowering effect of dietary taurine administration on high-fat fed C57BL6 mice and to study the mechanism by which taurine impacts lipid metabolism.
METHODS AND RESULTS
C57BL6 mice are grouped into four (n = 6): i) normal diet (ND), ii) a high-fat diet (HFD), iii) HFD + orlistat (STD), iv) HFD + taurine (TAU) group for 12 weeks. The results show that taurine administration for 12 weeks reduces high fat-induced weight gain, and liver weight when compared with HFD fed mice. It also improves serum biochemical parameters like total cholesterol and triglycerides. Sirtuin 1 (SIRT1) activity, Nicotinamide adenine dinucleotide (NAD) levels, SIRT1 mRNA, and protein expression are increased in HFD + TAU diet group as compared to HFD group. Taurine treatment suppresses the expression of lipogenic genes (sterol regulatory element binding protein 1c [SREBP1c], fatty acid synthase [FAS], Peroxisome proliferator-activated receptor gamma [PPARγ]) and increases the expression of β-oxidation (peroxisome proliferator-activated receptor alpha [PPARα], liver x receptor beta [LXRβ], peroxisome proliferator-activated receptor gamma coactivator 1-alpha [PGC1α], AMP-activated protein kinase [AMPK]) and lipolytic (forkhead box protein O1 [FOXO1]) genes. Further, taurine mitigates hepatic inflammation by suppressing nuclear factor kappa B (NF-κB) gene expression and pro-inflammatory cytokine markers (IL-6, IL-1β, and TNFα).
CONCLUSION
Taurine exerts lipid lowering effects through activating SIRT1/AMPK/FOXO1 signaling pathways and regulating their downstream targets.
Topics: Animals; Male; Mice; AMP-Activated Protein Kinases; Diet, High-Fat; Forkhead Box Protein O1; Lipid Metabolism; Liver; Mice, Inbred C57BL; Mice, Obese; Obesity; Signal Transduction; Sirtuin 1; Taurine
PubMed: 38549461
DOI: 10.1002/mnfr.202200660 -
Biomedicines Mar 2024The purpose of this narrative review is to describe the mechanisms that are responsible for the development of infertility and PCOS, with a focus on the role of obesity,... (Review)
Review
BACKGROUND
The purpose of this narrative review is to describe the mechanisms that are responsible for the development of infertility and PCOS, with a focus on the role of obesity, insulin sensitivity and treatment with metformin and GLP-1s.
METHODS
The relevant publications were identified after systematic queries of the following sources: PubMed, Google Scholar, Web of Science, and publishers' databases, complemented by a cross-check of the reference lists. We used a combination of the search terms "polycystic ovary syndrome", "obesity" and "insulin resistance" with "metformin", "exenatide", "liraglutide", "semaglutide", "orlistat" and terms relevant to the topic of each paragraph (e.g., "pathophysiology", "metabolism", "infertility", "treatment").
RESULTS
All articles describing the mechanisms responsible for the development of infertility and PCOS, with a focus on the role of obesity, insulin sensitivity and treatment with metformin and GLP-1s, were considered for this review.
CONCLUSIONS
The existing research on GLP-1 receptor agonists (GLP-1RAs) has not conclusively established a specific therapeutic use for these drugs. Additionally, the efficacy of the newer generation of GLP-1RAs, particularly in terms of dosage and duration of exposure, warrants more extensive research. Understanding the optimal dosing and treatment duration could significantly enhance the therapeutic use of GLP-1RAs in managing PCOS and its associated conditions.
PubMed: 38540265
DOI: 10.3390/biomedicines12030653 -
Antioxidants (Basel, Switzerland) Mar 2024This study investigates the potential of formulated systems utilising haskap berry leaf extracts and dextran as carriers, to modulate both antioxidant and enzymatic...
This study investigates the potential of formulated systems utilising haskap berry leaf extracts and dextran as carriers, to modulate both antioxidant and enzymatic inhibitory activities and their impact on the growth of specific bacterial strains. The analysis of antioxidant capacity, assessed through ABTS, CUPRAC, DPPH, and FRAP assays, revealed varying but consistently high levels across extracts, with Extract 3 (loganic acid: 2.974 mg/g, chlorogenic acid: 1.125 mg/g, caffeic acid: 0.083 mg/g, rutin: 1.137 mg/g, and quercetin: 1.501 mg/g) exhibiting the highest values (ABTS: 0.2447 mg/mL, CUPRAC: 0.3121 mg/mL, DPPH: 0.21001 mg/mL, and FRAP: 0.3411 mg/mL). Subsequent enzymatic inhibition assays demonstrated a notable inhibitory potential against α-glucosidase (1.4915 mg/mL, expressed as acarbose equivalent), hyaluronidase (0.2982 mg/mL, expressed as quercetin equivalent), and lipase (5.8715 µg/mL, expressed as orlistat equivalent). Further system development involved integration with dextran, showcasing their preserved bioactive compound content and emphasising their stability and potential bioactivity. Evaluation of the dextran systems' impact on bacterial growth revealed a significant proliferation of beneficial strains, particularly the and lactobacilli genus (Bifidobacterium longum: 9.54 × 10 to 1.57 × 10 CFU/mL and : 1.36 × 10 to 1.62 × 10 CFU/mL), suggesting their potential to modulate gut microbiota. These findings offer a foundation for exploring the therapeutic applications of haskap berry-based dextran systems in managing conditions like diabetes, emphasising the interconnected roles of antioxidant-rich botanical extracts and dextran formulations in promoting overall metabolic health.
PubMed: 38539890
DOI: 10.3390/antiox13030357 -
Clinical and Experimental Pharmacology... May 2024Sotagliflozin is the first dual SGLT1/2 inhibitor antidiabetic drug approved by the US Food and Drug Administration for the management of heart failure. SGLT1/2...
Sotagliflozin is the first dual SGLT1/2 inhibitor antidiabetic drug approved by the US Food and Drug Administration for the management of heart failure. SGLT1/2 inhibition is observed to potentiate the secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1). The current preclinical research sought to investigate the effect of sotagliflozin on the secretion of fat-regulating peptides such as GLP-1, glucagon and fibroblast growth factor 21 (FGF21) and their prospective association with sotagliflozin's potential beneficial effects on dyslipidaemia. During an oral fat tolerance test in mice, sotagliflozin substantially increased GLP-1 and insulin concentrations. Although sotagliflozin alone did not ameliorate postprandial lipemia, its combination with linagliptin (DPP-IV inhibitor) significantly improved lipid tolerance comparable to orlistat (lipase inhibitor). In a triton-induced hypertriglyceridemia model, sotagliflozin, along with other medications (fenofibrate, exenatide and linagliptin) reduced fat excursion; however, co-administration with linagliptin provided no extra advantage. Furthermore, sotagliflozin stimulated glucagon secretion in the alpha TC1.6 cells and healthy mice, which resulted in an increased circulating FGF21 and β-hydroxybutyrate concentration. Finally, chronic treatment of sotagliflozin in high-fat diet (HFD)-fed obese mice resulted in reduced body weight gain, liver triglyceride, cholesterol, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α) levels compared with the placebo group. However, the addition of linagliptin did not provide any additional benefit. In conclusion, sotagliflozin was found to have an effect on GLP-1 and also stimulate the release of glucagon and FGF21, which are important for regulating fat metabolism. Therefore, sotagliflozin might represent a potential therapeutic approach for the treatment of diabetic dyslipidemia and steatohepatitis.
Topics: Mice; Animals; Glucagon; Glucagon-Like Peptide 1; Linagliptin; Insulin; Dyslipidemias; Blood Glucose; Fibroblast Growth Factors; Glycosides
PubMed: 38527859
DOI: 10.1111/1440-1681.13854 -
Drug Design, Development and Therapy 2024Anti-obesity medications (AOMs), along with lifestyle interventions, are effective means of inducing and maintaining weight loss in patients with obesity. Although the...
PURPOSE
Anti-obesity medications (AOMs), along with lifestyle interventions, are effective means of inducing and maintaining weight loss in patients with obesity. Although the efficacy of AOMs has been reported, there have been no direct comparisons of these drugs. Therefore, in the present study, we aimed to compare the efficacy of all the AOMs available in Korea in a real-world setting.
PATIENTS AND METHODS
The body weight and composition of 205 adults treated with phentermine, phentermine/topiramate, liraglutide, naltrexone/bupropion, lorcaserin, or orlistat for at least 6 months were analyzed at 2 month intervals. The prevalence of the achievement of a ≥5% weight loss and the changes in body composition were compared between participants using each AOM at each visit.
RESULTS
A total of 132 (64.4%) participants achieved ≥5% weight loss within 6 months (prevalence of ≥5% weight loss after 6 months: phentermine, 87.2%; phentermine/topiramate, 67.7%; liraglutide, 58.1%; naltrexone/bupropion, 35.3%; lorcaserin, 75%; orlistat, 50%). At each visit, after adjustment for age, sex, and baseline body weight, phentermine use was associated with a significantly higher prevalence of ≥5% weight loss than the use of the other AOMs, except for liraglutide. There were significant differences in the body weight, body mass index and body fat mass among the AOM groups by visit (P for interaction <0.05), but not in their waist circumference, skeletal muscle mass, percentage body fat, or visceral fat area.
CONCLUSION
All the AOMs were effective at inducing and maintaining weight loss, in the absence of significant changes in muscle mass, over a 6 month period, and the short-term use of phentermine and the long-term use of phentermine/topiramate or liraglutide would be practical choices for the treatment of obesity. However, further, large-scale studies are necessary to confirm these findings.
Topics: Adult; Humans; Orlistat; Topiramate; Liraglutide; Naltrexone; Bupropion; Fructose; Anti-Obesity Agents; Obesity; Body Weight; Phentermine; Weight Loss
PubMed: 38524878
DOI: 10.2147/DDDT.S445415