Sample Size Determination and Study Design Impact on Dose-Scale Pharmacodynamic Bioequivalence: a Case Study Using Orlistat.

Dose-scale pharmacodynamic bioequivalence is recommended for evaluating the consistency of generic and innovator formulations of certain locally acting drugs, such as orlistat. This study aimed to investigate the standard methodology for sample size determination and the impact of study design on dose-scale pharmacodynamic bioequivalence using orlistat as the model drug. A population pharmacodynamic model of orlistat was developed using NONMEM 7.5.1 and utilized for subsequent simulations. Three different study designs were evaluated across various predefined relative bioavailability ratios of test/reference (T/R) formulations. These designs included Study Design 1 (2×1 crossover with T1 60 mg, R1 60 mg, and R2 120 mg), Study Design 2 (2×1 crossover with T2 120 mg, R1 60 mg, and R2 120 mg), and Study Design 3 (2×2 crossover with T1 60 mg, T2 120 mg, R1 60 mg, and R2 120 mg). Sample sizes were determined using a stochastic simulation and estimation approach. Under the same T/R ratio and power, Study Design 3 required the minimum sample size for bioequivalence, followed by Study Design 1, while Study Design 2 performed the worst. For Study Designs 1 and 3, a larger sample size was needed on the T/R ratio < 1.0 side for the same power compared to that on the T/R ratio > 1.0 side. The opposite asymmetry was observed for Study Design 2. We demonstrated that Study Design 3 is most effective for reducing the sample size for orlistat bioequivalence studies, and the impact of T/R ratio on sample size shows asymmetry.

Effect of Oleuropein on Anti-Obesity and Uncoupling Protein 1 Level in Brown Adipose Tissue in Mild Treadmill Walking Rats with Diet-Induced Obesity.

Oleuropein aglycone (OA), which is the absorbed form of oleuropein, is a major phenolic compound in extra virgin olive oil. We analyzed the anti-obesity effect of OA intake combined with mild treadmill walking (MTW, 4 m/min for 20 min/d, 5-6 d/wk, without electric shocks and slope) in rats under a high-fat diet (HF). Four-week-old male Sprague-Dawley rats (n=28) were equally divided into four groups: control (HF), 0.08% oleuropein-supplemented HF (HFO), HF with MTW (HF+W), and HFO with MTW (HFO+W) groups. After 28 d, the inguinal subcutaneous fat content and weight gain were significantly lower in the HFO+W group than in the control group. The HFO+W group also had significantly higher levels of urinary noradrenaline secretion, interscapular brown adipose tissue, uncoupling protein 1, brain transient receptor potential ankyrin subtype 1 (TRPA1), vanilloid subtype 1 (TRPV1), and brain-derived neurotrophic factor (BDNF) than the control group. Especially, the HFO+W group showed a synergistic effect on noradrenaline secretion. Therefore, OA combined with MTW may accelerate the enhancement of UCP1 and BDNF levels in rats with HF-induced obesity by increasing noradrenaline secretion after TRPA1 and TRPV1 activation.

Seventeen years since rimonabant's downfall: reassessing its suicidality risk profile.

Targeting the cannabinoid type 1 receptor (CB1) is a clinically validated antiobesity therapeutic approach. The only such drug approved, rimonabant, was launched in 2006 in Europe but subsequently rejected by the US Food and Drug Administration (FDA) in 2007. The FDA cited the increased risk of suicidality in its opposition to rimonabant's approval, leading to the drug's eventual worldwide withdrawal and the abandonment of this class of therapeutics. Seventeen years later, a new class of CB1-targeting drugs is emerging, but the impact of the 2007 FDA decision remains a formidable obstacle to its clinical development. We revisit the suicidality data presented by the FDA in light of the evolution of suicidality assessment and cross-reference this with the data in the subsequently published clinical trials. We conclude that the publicly available data do not support the FDA's conclusion that the use of rimonabant was associated with an increase in the risk of suicidality.

Anti-Obesity Properties of Blackberries Fermented with L. plantarum JBMI F5 via Suppression of Adipogenesis Signaling Mechanisms.

Blackberries (Rubus fruticosus), which are known to include a variety of bioactive substances, have been extensively studied for their antioxidant properties. Blackberries possess multiple health beneficial effects, including anti-inflammation, anti-atherosclerosis, anti-tumor and immunomodulatory activity. However, the potential biological effects and precise molecular mechanisms of the fermented extracts remain largely unexplored. In this research, we demonstrate the effect of blackberries fermented with Lactobacillus for addressing obesity. We investigated the effect of blackberries fermented by Lactobacillus on mice fed a high-fat (60% kcal) diet for 12 weeks. Fermented blackberry administration reduced the body weight and epididymal fat caused by a high-fat diet compared to the obese group. The triglyceride and total cholesterol, which are blood lipid indicators, and the levels of leptin, which is an insulin resistance indicator, were significantly increased in the obese group but were significantly decreased in the fermented blackberries-treated group. Additionally, the expression of adipogenesis marker proteins, such as CEBPα, PPAR-γ and SREBP-1, was significantly increased in the obese group, whereas it was decreased in the fermented blackberries-treated group. These results suggest that fermented blackberries have a protective effect against high-fat-diet-induced obesity by inhibiting adipogenesis and are a potential candidate for the treatment of obesity.

Structural Variances in Curcumin Degradants: Impact on Obesity in Mice.

Some thermal degradants of curcuminoids have demonstrated moderate health benefits in previous studies. Feruloyl acetone (FER), recently identified as a thermal degradant of curcumin, has been previously associated with anticancer and antioxidative effects, yet its other capabilities remain unexplored. Moreover, earlier reports suggest that methoxy groups on the aromatic ring may influence the functionality of the curcuminoids. To address these gaps, an animal study was conducted to investigate the antiobesity effects of both FER and its demethoxy counterpart (DFER) on mice subjected to a high-fat diet. The results demonstrated the significant prevention of weight gain and enlargement of the liver and various adipose tissues by both samples. Furthermore, these supplements exhibited a lipid regulatory effect in the liver through the adiponectin/AMPK/SIRT1 pathway, promoted thermogenesis via AMPK/PGC-1α activation, and positively influenced gut-microbial-produced short-chain fatty acid (SCFA) levels. Notably, DFER demonstrated superior overall efficacy in combating obesity, while FER displayed a significant effect in modulating inflammatory responses. It is considered that SCFA may be responsible for the distinct effects of FER and DFER in the animal study. Future studies are anticipated to delve into the efficacy of curcuminoid degradants, encompassing toxicity and pharmacokinetic evaluations.

The Anti-Obesogenic Effects of Muscadine Grapes through Ciliary Neurotrophic Factor Receptor (Cntfr) and Histamine Receptor H1 (Hrh1) Genes in 3T3-L1 Differentiated Mouse Cells.

Obesity and type 2 diabetes are prevalent metabolic diseases that have significant links to several chronic diseases, including cancer, diabetes, hypertension, and cardiovascular disease. Muscadine grape extracts have shown the potential to reduce adiposity and improve insulin sensitivity and glucose control. Thus, this study was designed to determine the potential of muscadine grape berries extract (Pineapple and Southern Home) for its antiobesity properties in 3T3-L1 cells as a model for obesity research. The current study's data indicated the total phenolic content (TPC) and 2,2-diphenyl-1-picrylhydraziyl (DPPH) activity were higher in cultivar (CV) Southern Home, meanwhile, elevated the total flavonoid content (TFC) in Pineapple. Both extracts were safe across the tested range (0-5 mg/mL). A noticeable reduction in lipid accumulation was also found in extract-treated cells. In preadipocytes and adipocytes, the tested extracts showed significant alterations in various genes involved in glucose homeostasis and obesity. The most remarkable findings of the current study are the upregulation of two genes, Cntfr (+712.715-fold) and Hrh1 (+270.11-fold) in CV Pineapple extract-treated adipocytes 3T3-L1 and the high fold increase in Ramp3 induced by both Pineapple and Southern Home in pre-adipose cells. Furthermore, the tested extracts showed a potential to alter the mRNA of various genes, including Zfp91, B2m, Nr3c1, Insr, Atrn, Il6ra, Hsp90ab1, Sort1, and Npy1r. In conclusion, the data generated from the current study suggested that the two extracts under investigation are considered potential candidates for controlling insulin levels and managing obesity.

Anti-obesity Medications: Ethical, Policy, and Public Health Concerns.

New anti-obesity medications (AOMs) have received widespread acclaim in medical journals and the media, but they also raise critical ethical, public health, and public policy concerns that have largely been ignored. AOMs are very costly, need to be taken by a patient in perpetuity (since significant rebound weight gain otherwise occurs), and threaten to shift resources and focus away from other crucial efforts at obesity treatment and prevention. Many people may feel less motivated to exercise or reduce their caloric consumption, if they assume that obesity is now medically treatable. Policy-makers may similarly come to feel that the solution to the obesity pandemic is simply to prescribe medications and that prevention efforts are far less necessary. These drugs raise concerns about justice (since AOMs will disproportionately benefit the wealthy), medicalization, and marketing. Policy-makers, clinicians, and others need to engage in multipronged educational and policy efforts to address these challenges.

Comprehensive assessment of the anti-obesity effects of highland barley total, insoluble, and soluble dietary fiber through multi-omics analysis.

The impact of different forms of dietary fiber (total, insoluble or soluble) derived from the same source on health remains incompletely understood. In this study, the effects of total, insoluble, and soluble dietary fiber extracted from highland barley (HDF, HIDF, and HSDF) on combating obesity were evaluated and compared. A high-fat diet (HFD) was used to induce obesity in a murine model, followed by gavage administration of HDF, HIDF, or HSDF, and a comprehensive multi-omics approach was utilized to assess and compare the effects of these dietary fibers on obesity-related parameters. The results showed that all three dietary fibers significantly reduced body weight, modified blood lipid profiles, and ameliorated tissue damage in HFD-fed mice. Additionally, 16S rRNA sequencing analysis of mice feces showed that three types of dietary fiber exerted varying degrees of impact on the composition and abundance of gut microbiota while simultaneously promoting the biosynthesis of short-chain fatty acids. Specifically, HDF supplementation remarkably enhanced the abundance of Coprococcus, while HIDF and HSDF supplementation elevated the levels of Akkermansia and Allobaculum, respectively. Transcriptomic and proteomic results suggested the PPAR signaling pathway as a central regulatory mechanism influenced by these fibers. HDF and HIDF were particularly effective in modulating biological processes related to triglyceride and fatty acid metabolism, identifying Abcc3 and Dapk1 as potential targets. Conversely, HSDF primarily affected processes related to membrane lipids, ceramides, and phospholipids metabolism, with Pck1 identified as a potential target. Collectively, HDF, HIDF, and HSDF demonstrated distinct mechanisms in exerting exceptional anti-obesity properties. These insights may inform the development of personalized dietary interventions for obesity.

Targeting obesity for therapeutic intervention in heart failure patients.

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) is a highly heterogeneous syndrome, making it challenging to improve prognosis with pharmacotherapy. Obesity is one of the leading phenotypes of HFpEF, and its prevalence continues to grow worldwide. Consequently, obesity-targeted interventions have attracted attention as a novel treatment strategy for HFpEF. AREAS COVERED: The authors review the association between the pathogenesis of obesity and HFpEF and the potential for obesity-targeted pharmacotherapeutic strategies in HFpEF, together with the latest evidence. The literature search was conducted in PubMed up to April 2024. EXPERT OPINION: The STEP HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) and SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trials recently demonstrated that the glucagon-like peptide 1 analogue, semaglutide, improves various aspects of clinical outcomes in obese HFpEF patients and significantly reduces cardiovascular and heart failure events in non-diabetic obese patients, along with a substantial weight loss. Future clinical trials with other incretin mimetics with more potent weight loss and sub-analyses of the SELECT trial may further emphasize the importance of the obesity phenotype-based approach in the treatment of HFpEF.

Chemical Compositions before and after Lactic Acid Fermentation of Isoflavone-Enriched Soybean Leaves and Their Anti-Obesity and Gut Microbiota Distribution Effects.

In this study, we prepared fermented products of isoflavone-enriched soybean leaves (IESLs) and analyzed their nutrients, isoflavones, anti-obesity efficacy, and effects on gut microbiota. Fermented IESLs (FIESLs) were found to be rich in nutrients, especially lauric acid, oleic acid, and linoleic acid. In addition, the concentrations of most essential free amino acids were increased compared to those of IESLs. The contents of bioactive compounds, such as total phenolic, total flavonoid, daidzein, and genistein, significantly increased as well. In addition, FIESLs administration in a high-fat diet (HFD) animal model improved the final body weight, epididymal fat, total lipid, triglyceride, total cholesterol, blood glucose, and leptin levels, as well as reverting microbiota dysbiosis. In conclusion, these findings indicate that FIESLs have the potential to inhibit obesity caused by HFDs and serve as a modulator of gut microbiota, offering the prevention of diet-induced gut dysbiosis and metabolite diseases associated with obesity.

Anti-Obesity Activities of the Compounds from Perilla frutescens var. acuta and Chemical Profiling of the Extract.

Perilla frutescens var. acuta (Lamiaceae) is widely used not only as an oil or a spice, but also as a traditional medicine to treat colds, coughs, fever, and indigestion. As an ongoing effort, luteolin-7-O-diglucuronide (1), apigenin-7-O-diglucuronide (2), and rosmarinic acid (3) isolated from P. frutescens var. acuta were investigated for their anti-adipogenic and thermogenic activities in 3T3-L1 cells. Compound 1 exhibited a strong inhibition against adipocyte differentiation by suppressing the expression of Pparg and Cebpa over 52.0% and 45.0%, respectively. Moreover, 2 inhibited the expression of those genes in a dose-dependent manner [Pparg: 41.7% (5 µM), 62.0% (10 µM), and 81.6% (50 µM); Cebpa: 13.8% (5 µM), 18.4% (10 µM), and 37.2% (50 µM)]. On the other hand, the P. frutescens var. acuta water extract showed moderate thermogenic activities. Compounds 1 and 3 also induced thermogenesis in a dose-dependent manner by stimulating the mRNA expressions of Ucp1, Pgc1a, and Prdm16. Moreover, an LC-MS/MS chromatogram of the extract was acquired using UHPLC-MS2 and it was analyzed by feature-based molecular networking (FBMN) and the Progenesis QI software (version 3.0). The chemical profiling of the extract demonstrated that flavonoids and their glycoside derivatives, including those isolated earlier as well as rosmarinic acid, are present in P. frutescens var. acuta.

Gastrointestinal digestion of food proteins: Anticancer, antihypertensive, anti-obesity, and immunomodulatory mechanisms of the derived peptides.

Food proteins and their peptides play a significant role in the important biological processes and physiological functions of the body. The peptides show diverse biological benefits ranging from anticancer to antihypertensive, anti-obesity, and immunomodulatory, among others. In this review, an overview of food protein digestion in the gastrointestinal tract and the mechanisms involved was presented. As some proteins remain resistant and undigested, the multifarious factors (e.g. protein type and structure, microbial composition, pH levels and redox potential, host factors, etc.) affecting their colonic fermentation, the derived peptides, and amino acids that evade intestinal digestion are thus considered. The section that follows focuses on the mechanisms of the peptides with anticancer, antihypertensive, anti-obesity, and immunomodulatory effects. As further considerations were made, it is concluded that clinical studies targeting a clear understanding of the gastrointestinal stability, bioavailability, and safety of food-based peptides are still warranted.

Do anti-obesity medical treatments have a direct effect on adipose tissue?

During the past years, several drugs have been developed for the treatment of obesity. Some are already used in clinical practice: orlistat, GLP-1 receptor agonists (RA), GLP-1/GIP biagonists and the melanocortin 4 receptor (MC4R) agonist, setmelanotide. Some should be available in the future: GLP-1/glucagon biagonists, GLP-1/GIP/glucagon triagonists. These drugs act mainly by reducing food intake or fat absorption. However, many of them show specific effects on the adipose tissue. All these drugs show significant reduction of fat mass and, more particularly of visceral fat. If most of the drugs, except orlistat, have been shown to increase energy expenditure in rodents with enhanced thermogenesis, this has not yet been clearly demonstrated in humans. However, biagonists or triagonist stimulating glucagon seem to a have a more potent effect to increase thermogenesis in the adipose tissue and, thus, energy expenditure. Most of these drugs have been shown to increase the production of adiponectin and to reduce the production of pro-inflammatory cytokines by the adipose tissue. GLP-1RAs reduce the size of adipocytes and promote their differentiation. GLP-1RAS and GLP-1/GIP biagonists reduce, in the adipose tissue, the expression of several genes involved in lipogenesis. Further studies are still needed to clarify the precise roles, on the adipose tissue, of these drugs dedicated for the treatment of obesity.

Rhabdomyolysis secondary to a weight-loss prescription.

We present a case of a case of a man in his 70s on multiple medications (including treatment of ischemic heart disease and diabetes who developed significant rhabdomyolysis, complicated by acute kidney injury (AKI) and encephalopathy, while using a compounded medication for weight loss. The patient was admitted to the intensive care unit and progressed favourably after haemodialysis and supportive care. Information regarding the ingestion of weight-loss drugs was unknown at the time of admission and was only discovered after resolution of encephalopathy, raising the possibility of toxin-associated rhabdomyolysis. This case emphasises the need for a thorough clinical history and scrutiny of the safety of weight-loss prescriptions, including preparations that comprise a combination of drugs and supplements that may adversely interact with chronic medications, especially in polymedicated patients.

Genetics, pharmacotherapy, and dietary interventions in childhood obesity.

Childhood obesity has emerged as a major global health issue, contributing to the increased prevalence of chronic conditions and adversely affecting the quality of life and future prospects of affected individuals, thereby presenting a substantial societal challenge. This complex condition, influenced by the interplay of genetic predispositions and environmental factors, is characterized by excessive energy intake due to uncontrolled appetite regulation and a Westernized diet. Managing obesity in childhood requires specific considerations compared with adulthood, given the vulnerability of the critical juvenile-adolescent period to toxicity and developmental defects. Consequently, common treatment options for adult obesity may not directly apply to younger populations. Therefore, research on childhood obesity has focused on genetic defects in regulating energy intake, alongside pharmacotherapy and dietary interventions as management approaches, with an emphasis on safety concerns. This review aims to summarize canonical knowledge and recent findings on genetic factors contributing to childhood obesity. Additionally, it assesses the efficacy and safety of existing pharmacotherapies and dietary interventions and suggests future research directions. By providing a comprehensive understanding of the complex dynamics of childhood obesity, this review aims to offer insights into more targeted and effective strategies for addressing this condition, including personalized healthcare solutions.

Updates in Medical and Surgical Weight Loss.

The number of individuals with obesity is at an all-time high, and the rate of obesity continues to climb each year. Obesity is a chronic disease with widespread effects throughout the body. Midwives and perinatal care providers need an understanding of the etiology, pathophysiology, and interventions for obesity. A review of evidence-based diet and lifestyle modifications, medications, and surgical procedures is presented.