Timosaponin A3 Induces Anti-Obesity and Anti-Diabetic Effects In Vitro and In Vivo.

Obesity is a serious global health challenge, closely associated with numerous chronic conditions including type 2 diabetes. Anemarrhena asphodeloides Bunge (AA) known as Jimo has been used to address conditions associated with pathogenic heat such as wasting-thirst in Korean Medicine. Timosaponin A3 (TA3), a natural compound extracted from AA, has demonstrated potential therapeutic effects in various disease models. However, its effects on diabetes and obesity remain largely unexplored. We investigated the anti-obesity and anti-diabetic properties of TA3 using in vitro and in vivo models. TA3 treatment in NCI-H716 cells stimulated the secretion of glucagon-like peptide 1 (GLP-1) through the activation of phosphorylation of protein kinase A catalytic subunit (PKAc) and 5'-AMP-activated protein kinase (AMPK). In 3T3-L1 adipocytes, TA3 effectively inhibited lipid accumulation by regulating adipogenesis and lipogenesis. In a high-fat diet (HFD)-induced mice model, TA3 administration significantly reduced body weight gain and food intake. Furthermore, TA3 improved glucose tolerance, lipid profiles, and mitigated hepatic steatosis in HFD-fed mice. Histological analysis revealed that TA3 reduced the size of white adipocytes and inhibited adipose tissue generation. Notably, TA3 downregulated the expression of lipogenic factor, including fatty-acid synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP1c), emphasizing its potential as an anti-obesity agent. These findings revealed that TA3 may be efficiently used as a natural compound for tackling obesity, diabetes, and associated metabolic disorders, providing a novel approach for therapeutic intervention.

The Effects of Body Fat Reduction through the Metabolic Control of Steam-Processed Ginger Extract in High-Fat-Diet-Fed Mice.

The prevalence of metabolic syndrome is increasing globally due to behavioral and environmental changes. There are many therapeutic agents available for the treatment of chronic metabolic diseases, such as obesity and diabetes, but the data on their efficacy and safety are lacking. Through a pilot study by our group, Zingiber officinale rhizomes used as a spice and functional food were selected as an anti-obesity candidate. In this study, steam-processed ginger extract (GGE) was used and we compared its efficacy at alleviating metabolic syndrome-related symptoms with that of conventional ginger extract (GE). Compared with GE, GGE (25-100 µg/mL) had an increased antioxidant capacity and α-glucosidase inhibitory activity in vitro. GGE was better at suppressing the differentiation of 3T3-L1 adipocytes and lipid accumulation in HepG2 cells and promoting glucose utilization in C2C12 cells than GE. In 16-week high-fat-diet (HFD)-fed mice, GGE (100 and 200 mg/kg) improved biochemical profiles, including lipid status and liver function, to a greater extent than GE (200 mg/kg). The supplementation of HFD-fed mice with GGE (200 mg/kg) resulted in the downregulation of SREBP-1c and FAS gene expression in the liver. Collectively, our results indicate that GGE is a promising therapeutic for the treatment of obesity and metabolic syndrome.

Anti-Obesity Effect of Jeju Roasted Citrus Peel Extract in High-Fat Diet-Induced Obese Mice and 3T3-L1 Adipocytes Via Lipid Metabolism Regulation.

Lipid accumulation in adipocytes occurs through multifactorial effects such as overnutrition due to unbalanced eating habits, reduced physical activity, and genetic factors. In addition, obesity can be intensified by the dis-regulation of various metabolic systems such as differentiation, lipogenesis, lipolysis, and energy metabolism of adipocytes. In this study, the Jeju roasted peel extract from Citrus unshiu S.Markov. (JRC), which is discarded as opposed to the pulp of C. unshiu S.Markov., is commonly consumed to ameliorate obesity. To investigate the anti-obesity effect of JRC, these studies were conducted on differentiated 3T3-L1 cells and in high-fat diet-induced mice, and related methods were used to confirm whether it decreased lipid accumulation in adipocytes. The mechanism of inhibiting obesity by JRC was confirmed through mRNA expression studies. JRC suppressed lipid accumulation in adipocytes and adipose tissue, and significantly improved enzymes such as alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase and serum lipid profiles. In addition, it effectively modulated the expression of genes related to lipid and energy metabolism in adipose tissue. As a result, these findings suggest that JRC could be a therapeutic regulator of body fat accumulation by significantly alleviating the dis-regulation of intracellular lipid metabolism in adipocytes and by enhancement of energy metabolism (Approval No. CNU IACUC-YB-2023-98).

Hypolipidemic and Anti-Obesity Effect of Anserine on Mice Orally Administered with High-Fat Diet via Regulating SREBP-1, NLRP3, and UCP-1.

To investigate the efficacy of anserine on antiobesity, C57BL/6 mice are orally administered with a high-fat diet (HFD) and different doses of anserine (60, 120, and 240 mg/kg/day) for 16 weeks. Body weight, lipid, and epididymal fat content in mice are measured, and their liver damage is observed. The results display that the body weight, epididymal fat content, and low-density lipoprotein cholesterol (LDL-C) content in anserine groups are decreased by 4.36-18.71%, 7.57-35.12%, and 24.32-44.40%, respectively. To further investigate the antiobesity mechanism of anserine, the expression of SREBP-1, NLRP3, NF-κB p65 (p65), and p-NF-κB p65 (p-p65) proteins in the liver and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1-α) and UCP-1 proteins in brown adipose tissue (BAT) is analyzed by Western blot. Results show that anserine can significantly decrease the expression of the NLRP3, p65, p-p65, and the SREBP-1 proteins and increase the expression of the PGC1-α and UCP-1 proteins. This study demonstrates that anserine lowered blood lipids and prevented obesity; its antiobesity mechanism may be related to the activation of brown fat by inflammation.

The Antiobesity Effects of Rosehip (Rosa canina) Flesh by Antagonizing the PPAR Gamma Activity in High-Fat Diet-Fed Mice.

SCOPE: The rosehip (Rosa canina) is a perennial shrub with a reddish pseudofruit that has demonstrated antidiabetic, antiatherosclerotic, and antiobesogenic effects in rodent models but there is low information about the molecular mechanisms underlying these effects on the onset and progression of diet-induced obesity. METHODS AND RESULTS: Four-week-old C57BL/6J male mice are subjected to a high-fat diet (HFD)-supplemented or not with R. canina flesh for 18 weeks. The results indicated that the R. canina flesh exerts a preventive effect on HFD-induced obesity with a significant reduction in body-weight gain and an improvement of hyperglycemia and insulin resistance caused by a HFD. At the tissue level, subcutaneous white adipose tissue exhibits a higher number of smaller adipocytes, with decreased lipogenesis. On its side, the liver shows a significant decrease in lipid droplet content and in the expression of genes related to lipogenesis, fatty acid oxidation, and glucose metabolism. Finally, the data suggest that most of these effects agree with the presence of a putative Perosxisome proliferator-activated receptor gamma (PPARγ) antagonist in the R. canina flesh. CONCLUSIONS: R. canina flesh dietary supplementation slows down the steatotic effect of a HFD at least in part through the regulation of the transcriptional activity of PPARγ.

Phentermine in the Modern Era of Obesity Pharmacotherapy: Does It Still Have a Role in Treatment?

PURPOSE OF REVIEW: This review provides an overview of the history, mechanism of action, and expected treatment effects of the anti-obesity medication (AOM), phentermine. It also includes a summary of recent research and practical guidance for prescribing clinicians. RECENT FINDINGS: Recent research on phentermine is sparse and consists primarily of observational studies with methodologic limitations. These studies suggest that phentermine use is associated with clinically significant weight loss in adults and that the medication is generally well tolerated. Large-scale observational studies evaluating phentermine's safety have not identified an increased risk of cardiovascular events or elevations in blood pressure. There is no data to support the notion that phentermine is addictive. Although it remains the most commonly prescribed AOM in the USA, phentermine has little rigorous research to support its efficacy and safety in long-term treatment, which creates a dilemma with guideline-recommended chronic use of AOMs. While we await forthcoming conclusive data on this front, clinicians may consider using phentermine long-term in selected patients, if such prescribing is consistent with local regulatory statutes.

Epigenetics in obesity: Mechanisms and advances in therapies based on natural products.

Obesity is a major risk factor for morbidity and mortality because it has a close relationship to metabolic illnesses, such as diabetes, cardiovascular diseases, and some types of cancer. With no drugs available, the mainstay of obesity management remains lifestyle changes with exercise and dietary modifications. In light of the tremendous disease burden and unmet therapeutics, fresh perspectives on pathophysiology and drug discovery are needed. The development of epigenetics provides a compelling justification for how environmental, lifestyle, and other risk factors contribute to the pathogenesis of obesity. Furthermore, epigenetic dysregulations can be restored, and it has been reported that certain natural products obtained from plants, such as tea polyphenols, ellagic acid, urolithins, curcumin, genistein, isothiocyanates, and citrus isoflavonoids, were shown to inhibit weight gain. These substances have great antioxidant potential and are of great interest because they can also modify epigenetic mechanisms. Therefore, understanding epigenetic modifications to target the primary cause of obesity and the epigenetic mechanisms of anti-obesity effects with certain phytochemicals can prove rational strategies to prevent the disease and develop novel therapeutic interventions. Thus, the current review aimed to summarize the epigenetic mechanisms and advances in therapies for obesity based on natural products to provide evidence for the development of several potential anti-obesity drug targets.

SMART use of medications for the treatment of adolescent severe obesity: A sequential multiple assignment randomized trial protocol.

BACKGROUND: Severe obesity is a complex, chronic disease affecting nearly 9% of adolescents in the U.S. Although the current mainstay of treatment is lifestyle therapy, pediatric clinical practice guidelines recommend the addition of adjunct anti-obesity medication (AOM), such as phentermine and topiramate. However, guidance regarding when adjunct AOM should be started and how AOM should be used is unclear. Furthermore, an inherent limitation of current treatment guidelines is their "one-size-fits-all" approach, which does not account for the heterogeneous nature of obesity and high degree of patient variability in response to all interventions. METHODS: This paper describes the study design and methods of a sequential multiple assignment randomized trial (SMART), "SMART Use of Medications for the Treatment of Adolescent Severe Obesity." The trial will examine 1) when to start AOM (specifically phentermine) in adolescents who are not responding to lifestyle therapy and 2) how to modify AOM when there is a sub-optimal response to the initial pharmacological intervention (specifically, for phentermine non-responders, is it better to add topiramate to phentermine or switch to topiramate monotherapy). Critically, participant characteristics that may differentially affect response to treatment will be assessed and evaluated as potential moderators of intervention efficacy. CONCLUSION: Data from this study will be used to inform the development of an adaptive intervention for the treatment of adolescent severe obesity that includes empirically-derived decision rules regarding when and how to use AOM. Future research will test this adaptive intervention against standard "one-size-fits-all" treatments.

In vitro Adipocyte Differentiation Inhibition and in vivo Effects on Lipid Metabolism in High-Fat Diet-Induced Obesity of Euphorbia humifusa.

Euphorbia humifusa Willd (Euphorbiaceae) is a functional raw material with various pharmacological activities. This study aimed to validate the inhibitory effect of Euphorbia humifusa extract (EHE) on adipocyte differentiation in vitro and in a high-fat-diet (HFD)-induced mouse model to evaluate the E.a humifusa as a novel anti-obesity and lipid metabolism enhancer agent. EHE effects on obesity and lipid metabolism were assessed in HFD-induced obese mice after 4-week treatments. Results were compared among four treatment groups (n = 7/group): low fat diet (LFD), high fat diet (HFD), and HFD-induced obese mice treated with either 100 or 200 mg/kg/day EHE (EHE100 and EHE200, respectively). EHE (50 to 200 µg/ml) and quercetin (50 µg/ml) significantly reduced 3T3-L1 preadipocyte differentiation (p < 0.001), in a concentration-dependent manner. EHE affected lipid metabolism, as evidenced by changes in serum lipid components. The HFD-EHE100 and HFD-EHE200 groups exhibited significantly (p < 0.05) reduced triglycerides (TG, 97.50 ± 6.56 and 82.50 ± 13.20 mg/dL, respectively) and low-density lipoprotein-cholesterol (LDL-c: 40.25 ± 4.99 and 41.25 ± 6.36 mg/dL, respectively) compared to the HFD group (TG: 129.25 ± 19.81 mg/dL; LDL-c: 51.75 ± 11.59 mg/dL). Haematoxylin and Eosin (H&E) and Oil red O staining showed that EHE markedly reduced lipid accumulation and inhibited lipogenesis in the liver. Interestingly, EHE significantly (p < 0.01) reduced the expression of adipogenic transcription factors in liver tissue. Our results indicated that EHE has the potential to be a therapeutic agent for addressing obesity and lipid metabolism.

Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.

Importance: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. Objective: To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. Design, Setting, and Participants: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. Interventions: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. Main Outcomes and Measures: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. Results: Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. Conclusions and Relevance: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. Trial Registration: ClinicalTrials.gov Identifier: NCT04660643.

Natural compounds as obesity pharmacotherapies.

Obesity has become a serious global public health problem, affecting over 988 million people worldwide. Nevertheless, current pharmacotherapies have proven inadequate. Natural compounds have garnered significant attention due to their potential antiobesity effects. Over the past three decades, ca. 50 natural compounds have been evaluated for the preventive and/or therapeutic effects on obesity in animals and humans. However, variations in the antiobesity efficacies among these natural compounds have been substantial, owing to differences in experimental designs, including variations in animal models, dosages, treatment durations, and administration methods. The feasibility of employing these natural compounds as pharmacotherapies for obesity remained uncertain. In this review, we systematically summarized the antiobesity efficacy and mechanisms of action of each natural compound in animal models. This comprehensive review furnishes valuable insights for the development of antiobesity medications based on natural compounds.

Drynaria rhizome water extract alleviates high­fat diet­induced obesity in mice.

Drynaria rhizome is a herbal medicine used for strengthening bones and treating bone diseases in East Asia. Although obesity is considered to benefit bone formation, it has been revealed that visceral fat accumulation can promote osteoporosis. Given the complex relationship between bone metabolism and obesity, bone­strengthening medicines should be evaluated while considering the effects of obesity. The present study investigated the effects of Drynaria rhizome extract (DRE) on high­fat diet (HFD)­induced obese mice. DRE was supplemented with the HFD. Body weight, food intake, the expression levels of lipogenesis transcription factors, including sterol regulatory element binding protein (SREBP)­1, peroxisome proliferator­activated receptor (PPAR)­Î³ and adenosine monophosphate­activated protein kinase (AMPK)­α, and AMPK activation were evaluated. Mice fed DRE and a HFD exhibited reduced body weight without differences in food intake compared with those in the HFD group. Furthermore, DRE; upregulated AMPK­α of epididymal one; down­regulated SREBP­1 and PPAR­Î³, as determined using western blotting and quantitative polymerase chain reaction, respectively. Decreased lipid accumulation were observed in both fat pad and liver of HFD­fed mice, which were suppressed by DRE treatment. These results demonstrated the potential of DRE as a dietary natural product for strengthening bones and managing obesity.

Effects of Cinnamon (Cinnamomum zeylanicum) Extract on Adipocyte Differentiation in 3T3-L1 Cells and Lipid Accumulation in Mice Fed a High-Fat Diet.

Flavonoids and phenolic acid are two of the rich polyphenols found in cinnamon (Cinnamomum zeylanicum). The effects of cinnamon extract on the inhibition of adipocyte differentiation in 3T3-L1 fibroblast cells and prohibitory lipid accumulation in male mice fed a high-fat diet were examined. Upon treating 3T3-L1 cells with cinnamon for 3 days, the cinnamon inhibited lipid accumulation and increased gene expression levels, such as those of adiponectin and leptin. In in vivo experiments, mice were randomized into four groups after a one-week acclimation period, as follows: normal diet, normal diet + 1% cinnamon extract, high-fat diet, and high-fat diet + 1% cinnamon extract. After 14 weeks of supplementation, we found that cinnamon extract increased the expression of lipolysis-related proteins, such as AMPK, p-ACC, and CPT-1, and reduced the expression of lipid-synthesis-related proteins, such as SREBP-1c and FAS, in liver tissue. Our results show that cinnamon extract may exhibit anti-obesity effects via the inhibition of lipid synthesis and adipogenesis and the induction of lipolysis in both 3T3-L1 fibroblast cells and mice fed a high-fat diet. Accordingly, cinnamon extract may have potential anti-obesity effects.

The Hexane Extract of Citrus sphaerocarpa Ameliorates Visceral Adiposity by Regulating the PI3K/AKT/FoxO1 and AMPK/ACC Signaling Pathways in High-Fat-Diet-Induced Obese Mice.

Obesity is an emerging global health issue with an increasing risk of disease linked to lifestyle choices. Previously, we reported that the hexane extract of Citrus sphaerocarpa (CSHE) suppressed lipid accumulation in differentiated 3T3-L1 adipocytes. In this study, we conducted in vivo experiments to assess whether CSHE suppressed obesity in zebrafish and mouse models. We administered 10 and 20 µg/mL CSHE to obese zebrafish juveniles. CSHE significantly inhibited visceral fat accumulation compared to untreated obese fish. Moreover, the oral administration (100 µg/g body weight/day) of CSHE to high-fat-diet-induced obese mice significantly reduced their body weight, visceral fat volume, and hepatic lipid accumulation. The expression analyses of key regulatory genes involved in lipid metabolism revealed that CSHE upregulated the mRNA expression of lipolysis-related genes in the mouse liver (Pparα and Acox1) and downregulated lipogenesis-related gene (Fasn) expression in epididymal white adipose tissue (eWAT). Fluorescence immunostaining demonstrated the CSHE-mediated enhanced phosphorylation of AKT, AMPK, ACC, and FoxO1, which are crucial factors regulating adipogenesis. CSHE-treated differentiated 3T3L1 adipocytes also exhibited an increased phosphorylation of ACC. Therefore, we propose that CSHE suppresses adipogenesis and enhances lipolysis by regulating the PI3K/AKT/FoxO1 and AMPK/ACC signaling pathways. These findings suggested that CSHE is a promising novel preventive and therapeutic agent for managing obesity.

The combination of Ephedrae herba and coixol from Coicis semen attenuate adiposity via glucocorticoid receptor regulation.

The enhanced therapeutic effects and mechanisms of certain herbal combination in various herbal prescriptions are mostly unclear. A combination of two herbs, namely Ephedrae herba (EH) and Coicis semen (CS), has been commonly prescribed for obesity. In our previous work, the combination of EH and CS was studied using network pharmacological approach to predict its pharmacological targets and in vitro experiments to evaluate its efficacy on obesity. Although we demonstrated enhanced anti-adiposity effects of the combination on matured adipocytes, the molecular mechanisms and contributing compounds underlying the effects of EH-CS combination on adiposity or adipogenesis were not fully elucidated. The current study adopted integrated bioinformatics analysis to precisely validate potential targets of EH-CS by screening differentially expressed genes (DEGs) of morbid obesity patients from NCBI gene expression omnibus (GEO). Based on the functional cluster analysis of down-regulated DEGs, the anti-adipogenesis mechanism of EH-CS combination was speculated with KEGG enrichment analysis. Furthermore, we investigated the combinational effects of EH and coixol, or stigmasterol, the two compounds in CS which were expected to have main beneficial effects in metabolic diseases. Moreover, distinct effect of the combination on transcriptional activity of glucocorticoid receptor (GR) was investigated using electrophoretic mobility shift assay (EMSA). The EH-CS combination was predicted to modulate down-regulated genes which are involved in KEGG pathways crucial to metabolic disease in morbidly obese individuals. The combination of EH with CS compounds significantly increased the phosphorylation of acetyl-coA carboxylase (ACC), AMP-activated protein kinase (AMPK), and protein kinase B (AKT) in 3T3-L1 cells and decreased intracellular lipid accumulation. The two CS compounds significantly increased the anti-adipogenesis/lipogenesis effects of EH by inhibiting the gene expression levels. Finally, the combination of EH and coixol inhibited dexamethasone-induced GR translocation to the nucleus and transcriptional binding activity in adipocytes. The combination of EH and CS could be considered a therapeutic strategy for treating metabolic diseases, including obesity.

Anthocyanin-enriched extract from Ribes nigrum inhibits triglyceride and cholesterol accumulation in adipocytes.

Aim: Obesity is a chronic pathology of epidemic proportions. Mature adipocytes from a 3T3-L1 cell line were used as in vitro obesity model to test different bioactive compounds. We aim to evaluate cassis (Ribes nigrum) extract antioxidant activity and its antiadipogenic effect on mature adipocytes. Results: We produced an extract by using enzyme that combines cellulase and pectinase; we obtained high yield of the bioactive compound anthocyanin. Extract showed high antioxidant capacity. We conducted in vitro assays by adding the extract to adipocytes culture medium. Extract reduced intracellular levels of triglyceride by 62% and cholesterol by 32%. Conclusion: Enzymatic extract's high antioxidant activity was likely attributable to its high concentration of anthocyanin. This extract inhibits lipid accumulation in adipocytes.

Obesity is a disease all over the world. By 2030, nearly 20% of adults are predicted to be obese. The consumption of processed foods is related to obesity in some countries such as Argentina. More natural food is needed. There are many different anti-obesity medicines but there is no good one to lose weight. We took extracts from cassis fruits and tested whether they could decrease fats like cholesterol within fat cells. We found that these extracts could successfully reduce the fat levels in the cells. Our results indicate that natural compounds like cassis fruit extract may be helpful in preventing future obesity epidemics.

Anti-obesity effects of olivetol in adult zebrafish model induced by short-term high-fat diet.

Obesity is a complex disease caused by various factors, and synthetic drugs used to treat it can have side effects. Natural compounds, such as olivetol, could be a promising alternative. Olivetol is a substance found in certain lichen species and has anti-inflammatory and anti-cancer properties. In this study, researchers conducted in-silico molecular docking studies and found that olivetol had significant binding affinity with receptors involved in obesity. They also investigated the effects of olivetol on a diet-induced obese zebrafish model and found that high doses of olivetol reduced excessive fat accumulation and triglyceride and lipid accumulation. The low dose of olivetol showed a significant reduction in liver enzymes' levels. However, the high dose of olivetol resulted in a significant increase in HMG-CoA levels. These results suggest that olivetol may be a promising anti-obesity agent for the treatment of hyperlipidemia-related disorders, but further research is necessary to understand its full effects on the body.

Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss.

This database study examines the association between glucagon-like peptide 1 agonists (eg, semaglutide, liraglutide) used for weight loss and reports of gastrointestinal adverse events.