Development Of Anti-obesity Drugs Research Articles

Structure based exploration of mitochondrial alpha carbonic anhydrase inhibitors as potential leads for anti-obesity drug development.

Obesity has emerged as a major health challenge globally in the last two decades. Dysregulated fatty acid metabolism and de novo lipogenesis are prime causes for obesity development which ultimately trigger other co-morbid pathological conditions thereby risking life longevity. Fatty acid metabolism and de novo lipogenesis involve several biochemical steps both in cytosol and mitochondria. Reportedly, the high catalytically active mitochondrial carbonic anhydrases (CAVA/CAVB) regulate the intercellular depot of bicarbonate ions and catalyze the rapid carboxylation of pyruvate and acetyl-co-A to acetyl-co-A and malonate respectively, which are the precursors of fatty acid synthesis and lipogenesis. Several in vitro and in vivo investigations indicate inhibition of mitochondrial carbonic anhydrase isoforms interfere in the functioning of pyruvate, fatty acid and succinate pathways. Targeting of mitochondrial carbonic anhydrase isoforms (CAVA/CAVB) could thereby modulate gluconeogenetic as well as lipogenetic pathways and pave way for designing of novel leads in the development pipeline of anti-obesity medications. The present review unveils a diverse chemical space including synthetic sulphonamides, sulphamates, sulfamides and many natural bioactive molecules which selectively inhibit the mitochondrial isoform CAVA/CAVB with an emphasis on major state-of-art drug design strategies. More than 60% similarity in the structural framework of the carbonic anhydrase isoforms has converged the drug design methods towards the development of isoform selective chemotypes. While the benzene sulphonamide derivatives selectively inhibit CAVA/CAVB in low nanomolar ranges depending on the substitutions on the phenyl ring, the sulpamates and sulpamides potently inhibit CAVB. The virtual screening and drug repurposing methods have also explored many non-sulphonamide chemical scaffolds which can potently inhibit CAVA. The review could pave way for the development of novel and effective anti-obesity drugs which can modulate the energy metabolism.

Identification of novel pharmacological activators of circadian clock with anti-adipogenic properties

The circadian clock drives rhythmic oscillations of metabolic processes to orchestrate metabolic homeostasis, and disruption of this mechanism predisposes to obesity and insulin resistance. Preserving or augmenting clock function could be a potential therapeutic target for metabolic diseases, particularly with the wide-spread of circadian misalignment in a modern lifestyle. To date, targeting the clock for metabolic disease prevention or treatment remains to be explored. Adipocyte possesses cell-autonomous clocks that exert transcriptional control of the Wnt pathway to inhibit adipocyte development. Using a high through-put screening pipeline, we recently identified Chlorhexidine as a novel clock-activating molecule that targets the key driver of the circadian clock transcriptional feedback loop, the CLOCK protein. Based on clock function in suppressing adipogenesis, we hypothesize that Chlorhexidine and related compounds may possess adipogenic-inhibitory properties suitable for anti-obesity drug development. In distinct adipogenic progenitor models, we demonstrate the activity of Chlorhexidine in inhibiting adipogenic lineage commitment and terminal differentiation. Furthermore, we report the structural optimization of Chlorhexidine chemical scaffold that led to the discovery of new analogs with improved anti-adipogenic effcacy. Consistent with its activity for clock activation, in adipogenic progenitors containing a Period2::dLuc luciferase reporter, Chlorhexidine induced significant shortening of clock period length with induction of core clock components. Chlorhexidine treatment of adipogenic mesenchymal precursors robustly suppressed their adipogenic maturation, with a comparable effect observed on inhibiting terminal differentiation of primary preadipocytes in a clock-dependent manner. Mechanistically, Chlorhexidine stimulates clock-controlled Wnt signaling that mediates its anti-adipogenic effect. Through medicinal chemistry modification of its chemical scaffold, we generated a panel of Chlorhexidine analogs with validation for their clock-modulatory activities. Structure activity relationship analysis of these analogs led to the identification of CM002 as a new clock activator with improved clock-dependent anti-adipogenic activity. Collectively, our findings uncovered a new class of clock-modulatory compounds that inhibit adipocyte development for potential anti-obesity drug discovery and provide clock-targeting chemical probes for dissecting clock function in metabolic physiology. This project was supported by grants from National Institute of Aging R56AG080294 and Arthur Riggs-Diabetes & Metabolism Research Institute T2D and T1D Innovative Awards to KM. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

G protein-coupled receptor-biased signaling: potential drug discovery to facilitate treatment of metabolic diseases

G protein-coupled receptors (GPCRs) are important, potential drug targets for the treatment of metabolic disorders, such as obesity. GPCRs crosstalk with several transducers, including heterotrimeric G proteins, GPCR kinases (GRKs), and β-arrestins. GPCR-biased agonism has raised the potential of novel drug development to preferentially activate therapeutic signaling pathways over pathways that lead to unwanted side effects. The obesity epidemic and its metabolic complications continue to be a major global public health threat but effective treatments are limited. The accelerated development of structural techniques, like X-ray crystallography and cryo-electron microscopy, has paved the way to understanding how biased agonism measured at GPCRs results in specific downstream physiologic responses. Herein some well-validated GPCR targets are briefly summarized and several new and promising receptors for obesity treatment are outlined. This review highlights the significance of deciphering the role of GPCRs in obesity pathology and biased signaling for drug development. We anticipate the review will facilitate the development of novel GPCR-targeted anti-obesity drugs that lead to heightened therapeutic efficacy with decreased side effect profiles.

Management of Obesity-Related Inflammatory and Cardiovascular Diseases by Medicinal Plants: From Traditional Uses to Therapeutic Targets.

Inflammation is a crucial factor in the development and progression of cardiovascular diseases (CVD). Cardiac remodeling in the presence of persistent inflammation leads to myocardial fibrosis and extracellular matrix changes, which reduce cardiac function, induce arrhythmias, and finally, cause heart failure. The majority of current CVD treatment plans concentrate on reducing risk factors such as hyperlipidemia, type 2 diabetes, and hypertension. One such strategy could be inflammation reduction. Numerous in vitro, animal, and clinical studies indicate that obesity is associated with low-grade inflammation. Recent studies have demonstrated the potential of medicinal plants and phytochemicals to cure and prevent obesity and inflammation. In comparison to conventional therapies, the synergistic effects of several phytochemicals boost their bioavailability and impact numerous cellular and molecular targets. Focusing on appetite, pancreatic lipase activity, thermogenesis, lipid metabolism, lipolysis and adipogenesis, apoptosis in adipocytes, and adipocyte life cycle by medicinal plants and phytochemicals represent an important goal in the development of new anti-obesity drugs. We conducted an extensive review of the literature and electronic databases, including Google Scholar, PubMed, Science Direct, and MedlinePlus, for collecting data on the therapeutic effects of medicinal plants/phytochemicals in curing obesity and its related inflammation and CVD diseases, including cellular and molecular mechanisms, cytokines, signal transduction cascades, and clinical trials.

Structure-guided Design and Optimization of small Molecules as Pancreatic Lipase Inhibitors using Pharmacophore, 3D-QSAR, Molecular Docking, and Molecular Dynamics Simulation Studies.

Obesity has now become a global issue due to the increase in the population of obese people. It also substantially impacts the individual's social, financial, and psychological well-being, which may contribute to depression. Being overweight induces many metabolic and chronic disorders, urging many researchers to focus on developing the drug for obesity treatment. Pancreatic lipase inhibitors and natural product/compound-derived pancreatic lipase inhibitors have recently received much attention because of their structural variety and low toxicity. This study aimed to build pharmacophores and QSAR for analyzing the necessary structure of pancreatic lipase inhibitors and designing new molecules with the best activity. Ligand-based pharmacophore modeling and Atom-Based 3D-QSAR were carried out using the PHASE module of Schrodinger to determine the critical structural properties necessary for pancreatic lipase (PL) inhibitory activity. A total of 157 phytoconstituents and a standard drug, orlistat, were selected for the present study. Considering the important features for pancreatic lipase inhibition, 15 new molecules were designed and subjected to molecular docking studies and molecular dynamics simulations. The activity of designed molecules was predicted using the Atom- Based QSAR tool of the PHASE module. The top docked score molecule is structure-7 with a docking score of -6.094 Kcal/mol, whereas the docking score of orlistat and tristin is -3.80Kcal/mol and -5.63Kcal/mol, respectively. The designed molecules have a high docking score and good stability, are in the desirable ADME range and are derived from natural products, so they might be used as lead molecules for anti-obesity drug development.

A comprehensive review on the pancreatic lipase inhibitory peptides: A future anti-obesity strategy

Dysregulation of lipid homeostasis contributes to obesity and can directly lead to several critical public health concerns globally. This paper aimed to present a brief review of related properties and the use of pancreatic lipase inhibitors as the future weight loss drug discovery and development procured from a wide range of natural sources. A total of 176 pancreatic lipase inhibitory peptides were identified from recent publications and peptide databases. These peptides were classified into three categories according to their peptide length and further analyzed using bioinformatic approaches to identify their structural activity relationship. Molecular docking analyses were conducted for each amino acid at the terminal position of the peptides to predict the binding affinity between peptide-enzyme protein complexes based on intermolecular contact interactions. Overall, the observations revealed the features of the inhibitory peptides and their inhibitory mechanisms and interactions. These findings strived to benefit scientists whose research may be relevant to anti-obesity drug development and/or discovery thereby support effective translation of preclinical research for humans’ health being.

Hormonal Gut-Brain Signaling for the Treatment of Obesity.

The brain, particularly the hypothalamus and brainstem, monitors and integrates circulating metabolic signals, including gut hormones. Gut-brain communication is also mediated by the vagus nerve, which transmits various gut-derived signals. Recent advances in our understanding of molecular gut-brain communication promote the development of next-generation anti-obesity medications that can safely achieve substantial and lasting weight loss comparable to metabolic surgery. Herein, we comprehensively review the current knowledge about the central regulation of energy homeostasis, gut hormones involved in the regulation of food intake, and clinical data on how these hormones have been applied to the development of anti-obesity drugs. Insight into and understanding of the gut-brain axis may provide new therapeutic perspectives for the treatment of obesity and diabetes.

Recent advancements in pharmacological strategies to modulate energy balance for combating obesity.

The prevalence of obesity along with its related metabolic diseases has increased globally in recent decades. Obesity originates from a heterogeneous physiological state, which is further complicated by the influence of factors such as genetic, behavioural, and environmental. Lifestyle interventions including exercise and diet have limited success, necessitating the development of pharmacological approaches. Mechanistically, strategies target either reducing energy intake or increasing consumption through metabolism boosting. Current drugs lower energy intake via inducing satiety or inhibiting substrate absorption, while targeting mitochondria or cytosolic energy sensors has shown limited success due to toxicity. Nonshivering thermogenesis (NST) has provided hope for activating these processes selectively without significant side effects. The internet-based marketing of plant-based formulations for enhancing metabolism has surged. This review compiles scientific articles, magazines, newspapers, and online resources on anti-obesity drug development. Combination therapy of metabolic boosters and established anti-obesity compounds appears to be a promising future approach that requires further research.

GRP78 Activity Moderation as a Therapeutic Treatment against Obesity.

Glucose-regulated protein 78 (GRP78), a molecular chaperone, is overexpressed in patients suffering from obesity, fatty liver, hyperlipidemia and diabetes. GRP78, therefore, can be not only a biomarker to predict the progression and prognosis of obesity and metabolic diseases but also a potential therapeutic target for anti-obesity treatment. In this paper, GRP78 inhibitors targeting its ATPase domain have been reviewed. Small molecules and proteins that directly bind GRP78 have been described. Putative mechanisms of GRP78 in regulating lipid metabolism were also summarized so as to investigate the role of GRP78 in obesity and other related diseases and provide a theoretical basis for the development and design of anti-obesity drugs targeting GRP78.

A Comprehensive Review on Anti-obesity Potential of Medicinal Plants and their Bioactive Compounds

Background:Obesity is a complex health and global epidemic issue. It is an increasing global health challenge covering high social and economic costs. Abnormal accumulation of fat in the body may increase health risks, including diabetes, hypertension, osteoarthritis, sleep apnea, cardiovascular diseases, stroke, and cancer. Synthetic drugs available in the market are reported to have several side effects. Therefore, the management of obesity needs to involve the traditional use of medicinal plants, which helps in searching for new therapeutic targets and supports the research and development of anti-obesity drugs.Objective:This review aimed to update the data and provide a comprehensive report on currently available knowledge regarding medicinal plants and phytochemicals constituents reported for their anti-obesity activity.Methodology:An electronic search of the periodical databases, like Web of Science, Scopus, Pub- Med, Scielo, Niscair, ScienceDirect, Springerlink, Wiley, SciFinder, and Google Scholar with information reported during 1991-2019, was made to retrieve published data.Results:This review attempts to list the medicinal plants with anti-obesity activity. It focuses on plant extracts, isolated chemical compounds, their mechanism of action, and preclinical, experimental model, and clinical studies for further scientific research.Conclusion:This review summarizes the medicinal plants and their constituents reported for the management of obesity. The data will fascinate the researcher to initiate further research that may lead to the discovery of a drug for the management of obesity and its associated secondary complications. Several herbal plants and their respective lead constituents have been screened by preclinical in-vitro and in-vivo clinical trials and were found to be effective in treating obesity. Therefore, there is a need to develop and screen a large number of plant extracts, and this approach can surely be a driving force for discovering anti-obesity drugs from medicinal plants.

A Simple and Portable Personal Glucose Meter Method Combined with Molecular Docking for Screening of Lipase Inhibitors.

With the increase of obesity incidence, the development of antiobesity drugs has aroused extensive interest. In this study, a simple and portable personal glucose meter (PGM) method based on the lipase-mediated reaction combined with molecular docking was developed for the screening of lipase inhibitors. Lipase can catalyse the hydrolysis of 4-acetamidophenyl acetate to form acetaminophen, which can directly trigger the reduction of K3[Fe(CN)6] to K4[Fe(CN)6] in the glucose test strips and generate an electrical signal that can be detected by the PGM. When lipase inhibitors exist, the yield of acetaminophen will be reduced and results in a corresponding decrease of the PGM signal. Therefore, the activity of lipase can be measured by the PGM. After optimization of the experimental conditions, the inhibitory activity of fourteen small-molecule compounds and fifteen natural product extracts on lipase were evaluated by the developed PGM method. The results indicate that tannic acid, (-)-epigallocatechin gallate, (-)-epigallocatechin, (-)-epicatechin gallate, and epicatechin have good inhibitory effect on lipase (% of inhibition higher than 40.0%). Besides, the natural product extracts of Galla Chinensis, lemon, and Rhei Radix et Rhizoma have a good inhibitory effect on lipase with % of inhibition of (97.5 ± 0.6)%, (88.1 ± 0.7)%, and (79.1 ± 1.6)%, respectively. Finally, the binding sites and modes of six small-molecule compounds on lipase were investigated by the molecular docking study. The results show that the developed PGM method is an effective approach for the discovery of potential lipase inhibitors.

Critical review on anti-obesity effects of phytochemicals through Wnt/β-catenin signaling pathway

Phytochemicals have been used as one of the sources for the development of anti-obesity drugs. Plants are rich in a variety of bioactive compounds including polyphenols, saponins and terpenes. Phytochemicals inhibit adipocyte differentiation by inhibiting the transcription and translation of adipogenesis transcription factors such as C/EBPα and PPARγ. It has been proved that phytochemicals inhibit the genes and proteins associated with adipogenesis and lipid accumulation by activating Wnt/β-catenin signaling pathway. The activation of Wnt/β-catenin signaling pathway by phytochemicals is multi-target regulation, including the regulation of pathway critical factor β-catenin and its target gene, the downregulation of destruction complex, and the up-regulation of Wnt ligands, its cell surface receptor and Wnt antagonist. In this review, the literature on the anti-obesity effect of phytochemicals through Wnt/β-catenin signaling pathway is collected from Google Scholar, Scopus, PubMed, and Web of Science, and summarizes the regulation mechanism of phytochemicals in this pathway. As one of the alternative methods of weight loss drugs, Phytochemicals inhibit adipogenesis through Wnt/β-catenin signaling pathway. More progress in relevant fields may pose phytochemicals as the main source of anti-obesity treatment.

Heme oxygenase‐1 induction by gallic acid‐ g ‐chitosan is an important event in modulating adipocyte differentiation

Obesity, one of the common worldwide chronic health diseases co-relates with adipogenesis. Adipogenesis is a complex biological action of the emergence of mature adipocytes from the differentiation of pre-adipocytes and the disfunction of this process leads to the development of metabolic issues in obesity. Recently, much attention has been paid to utilizing natural compounds to discover their biological activities. This study focused on investigating the probable anti-adipogenic effects of gallic acid-g-chitosan (GAC) and plain chitosan (PC) through regulating the heme oxygenase-1 (HO-1)/Nrf2 pathway on mesenchymal stem cells. Gallic acid is grafted onto the PC backbone to improve its specific physical and biological properties. GAC showed promising anti-adipogenic effects by enhancing HO-1 expression and lipolysis and as well as suppressing lipid accumulation, reactive oxygen species, and pro-inflammatory cytokines production, transcription factor expression compared to the PC treatment. On the contrary, zinc protoporphyrin ІX (ZnPP), a HO-1 inhibitor reversed these effects of GAC on adipogenesis. Taken all together, this study revealed that grafting GA onto the chitosan improved potential anti-adipogenic activity by induction of the HO-1/Nrf2 pathway on mesenchymal stem cells (MSCs). PRACTICAL APPLICATIONS: GAC is a well-known copolymer with versatile bioactivities such as antimicrobial, antioxidant, and anti-diabetic activity. However, the anti-adipogenic effect of GAC has not been explored in MSCs. This study demonstrated that GAC inhibited adipocyte differentiation in MSCs through HO-1 activation. These findings suggest that GAC can be applied practically from different perspectives. GAC can be applied in the pharmacological industry to the development of anti-obesity drugs, medicinal perspectives for the treatment of obesity and obesity-related diseases, and in the food industry as a functional food to promote health and decrease the risk of diseases.

Anti-Obesity Effect of <i>Boscia senegalensis</i> in Rabbits

Introduction: Obesity is defined as excessive and abnormal accumulation of fatty tissue with significant somatic, psychological and social consequences on quality of life. Obesity has long been considered a simple aesthetic problem linked to excessive gluttony. It is however recognized today as a real pathology, so much so that the WHO has declared it as “the first non-infectious epidemic in history and a major problem of the century”. In addition, many studies have been carried out aimed at the production of less fatty foods and, scientifically, at the development of anti-obesity drugs. Thus, the objective of this study is to evaluate the anti-obesity effect of the extract of Boscia senegalensis (Capparaceae) used in Chad to fight against type II diabetes and metabolic syndrome. Methodology: A bromatological study of Boscia senegalensis extract was carried out at the Food Quality Control Centre (CECOQDA) in Ndjamena (Chad), followed by an in vivo study of rabbits carried out at the IRED Biotechnopôle laboratory (Chad). Results: The results obtained from the 100 g bromatological study of the dry extract of Boscia senegalensis are as follows: protein content (20.24% ± 0.007%), fat content (5.92% ± 0.21%), carbohydrate content (35.16% ± 1.05%), fibre content (2.11% ± 0.26%), moisture content (5.7% ± 0.14%) and ash content (2.90% ± 0.03%). No aflatoxin was detected in the dry extract of Boscia senegalensis. A significant decrease (p = 0.04) in body weight was observed in rabbits treated with Boscia senegalensis extract compared to controls. In addition, histological sections of the various organs (liver, spleen, kidneys) of treated rabbits showed no lesions following the incorporation of the extract of Boscia senegalensis. Conclusion: This study showed the anti-obesity effect of Boscia senegalensis. It also made it possible to verify the harmlessness of the product with regard to the results on chronic toxicity.

Long-acting amylin analogue for weight reduction

Because the causes of obesity involve genetic, epigenetic, biological, environmental, sociocultural, dietary, and behavioural factors and their interactions, 1 Gadde KM Martin CK Berthoud HR Heymsfield SB Obesity: pathophysiology and management. J Am Coll Cardiol. 2018; 71: 69-84 Crossref PubMed Scopus (205) Google Scholar weight management interventions manifest considerable treatment response heterogeneity. For decades, anti-obesity drug development primarily targeted central neurotransmitters regulating appetite and food intake. Although orlistat, a gastric and pancreatic lipase inhibitor approved in 1999, was an exception, its weight loss efficacy is marginal. 1 Gadde KM Martin CK Berthoud HR Heymsfield SB Obesity: pathophysiology and management. J Am Coll Cardiol. 2018; 71: 69-84 Crossref PubMed Scopus (205) Google Scholar Liraglutide, a GLP-1 receptor agonist, at a dose of 3·0 mg injected daily was associated with a placebo-subtracted weight loss of 4·0% to 5·4% over 1 year. 1 Gadde KM Martin CK Berthoud HR Heymsfield SB Obesity: pathophysiology and management. J Am Coll Cardiol. 2018; 71: 69-84 Crossref PubMed Scopus (205) Google Scholar Semaglutide 2·4 mg, another GLP-1 receptor agonist injected weekly, yielded a placebo-subtracted weight loss of 6·2% to 12·4% after 68 weeks in phase 3 trials 2 Davies M Færch L Jeppesen OK et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021; 397: 971-984 Summary Full Text Full Text PDF PubMed Scopus (117) Google Scholar , 3 Wadden TA Bailey TS Billings LK et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA. 2021; 325: 1403-1413 Crossref PubMed Scopus (126) Google Scholar , 4 Wilding JPH Batterham RL Calanna S et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021; 384: 989 Crossref PubMed Scopus (374) Google Scholar and was approved in June, 2021, for obesity treatment. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trialTreatment with cagrilintide in people with overweight and obesity led to significant reductions in bodyweight and was well tolerated. The findings support the development of molecules with novel mechanisms of action for weight management. Full-Text PDF

The beta2 -adrenergic receptor - a re-emerging target to combat obesity and induce leanness?

Treatment of obesity with repurposed or novel drugs is an expanding research field. One approach is to target beta2 -adrenergic receptors because they regulate the metabolism and phenotype of adipose and skeletal muscle tissue. Several observations support a role for the beta2 -adrenergic receptor in obesity. Specific human beta2 -adrenergic receptor polymorphisms are associated with body composition and obesity, for which the Gln27Glu polymorphism is associated with obesity, while the Arg16Gly polymorphism is associated with lean mass in men and the development of obesity in specific populations. Individuals with obesity also have lower abundance of beta2 -adrenergic receptors in adipose tissue and are less sensitive to catecholamines. In addition, studies in livestock and rodents demonstrate that selective beta2 -agonists induce a so-called 'repartitioning effect' characterized by muscle accretion and reduced fat deposition. In humans, beta2 -agonists dose-dependently increase resting metabolic rate by 10-50%. And like that observed in other mammals, only a few weeks of treatment with beta2 -agonists increases muscle mass and reduces fat mass in young healthy individuals. Beta2 -agonists also exert beneficial effects on body composition when used concomitantly with training and act additively to increase muscle strength and mass during periods with resistance training. Thus, the beta2 -adrenergic receptor seems like an attractive target in the development of anti-obesity drugs. However, future studies need to verify the long-term efficacy and safety of beta2 -agonists in individuals with obesity, particularly in those with comorbidities.

Photoaffinity-Based Chemical Proteomics Reveals 7-Oxocallitrisic Acid Targets CPT1A to Trigger Lipogenesis Inhibition.

One of the natural terpenoids isolated from Resina Commiphora, 7-oxocallitrisic acid (7-OCA), has lipid metabolism regulatory activity. To uncover its lipogenesis inhibition mechanism, we developed a photoaffinity and clickable probe based on the 7-OCA scaffold and performed chemical proteomics to profile its potential cellular targets. It was found that 7-OCA could directly interact with carnitine palmitoyl transferase 1A (CPT1A) to promote its activity to reduce lipid accumulation. The present work reveals our understanding of the mode of lipid mebabolism regulation by abietic acids and provides new clues for antiobesity drug development with CPT1A as a main target.

Regulation of Apelin-13 on Bcl-2 and Caspase-3 and Its Effects on Adipocyte Apoptosis.

Objective The effects of apelin-13 on the expression of Bcl-2 and caspase-3 factors and the apoptosis of adipocytes were studied at the cellular and animal levels. Methods 3T3-L1 preadipocytes were cultured and grouped. The third-generation cells were added to the control DMSO solvent and amidation-modified apelin-13. The expression of Bcl-2 and caspase-3 were detected. The cell growth viability and cell apoptosis were detected. DOI model rats were established. The effects of apelin-13 on DOI rat biochemical indicators, the expression of Bcl-2, caspase-3, and cell apoptosis were investigated by injecting amidation-modified apelin-13 through the tail vein. Result In in vitro experiments, amidation-modified apelin-13 can significantly reduce the growth viability of adipocytes and the expression of Bcl-2, increase the expression of caspase-3, and promote the apoptosis of adipocytes. Animal experiments also show that apelin-13 modified by amidation can adjust the abnormal biochemical indicators of DOI rats, decrease the expression of Bcl-2 in adipose tissue, increase the expression of caspase-3, and promote the apoptosis of adipocytes. Conclusion Amidation of apelin-13 can promote fat cell apoptosis and reduce the incidence of obesity. The mechanism may be accomplished by inhibiting Bcl-2 and caspase-3 factors. This study helps us understand the effect of apelin-13 on fat cell apoptosis and hopes to provide a basis for the development of antiobesity drugs.

Metabolic and Epigenetics Action Mechanisms of Antiobesity Medicinal Plants and Phytochemicals.

Ever-growing research efforts are demonstrating the potential of medicinal plants and their phytochemicals to prevent and manage obesity, either individually or synergistically. Multiple combinations of phytochemicals can result in a synergistic activity that increases their beneficial effects at molecular, cellular, metabolic, and temporal levels, offering advantages over chemically synthesized drug-based treatments. Herbs and their derived compounds have the potential for controlling appetite, inhibiting pancreatic lipase activity, stimulating thermogenesis and lipid metabolism, increasing satiety, promoting lipolysis, regulating adipogenesis, and inducing apoptosis in adipocytes. Furthermore, targeting adipocyte life cycle using various dietary bioactives that affect different stages of adipocyte life cycle represents also an important target in the development of new antiobesity drugs. In this regard, different stages of adipocyte development that are targeted by antiobesity drugs can include preadipocytes, maturing preadipocytes, and mature adipocytes. Various herbal-derived active compounds, such as capsaicin, genistein, apigenin, luteolin, kaempferol, myricetin, quercetin, docosahexaenoic acid, quercetin, resveratrol, and ajoene, affect adipocytes during specific stages of development, resulting in either inhibition of adipogenesis or induction of apoptosis. Although numerous molecular targets that can be used for both treatment and prevention of obesity have been identified, targeted single cellular receptor or pathway has resulted in limited success. In this review, we discuss the state-of-the-art knowledge about antiobesity medicinal plants and their active compounds and their effects on several cellular, molecular, and metabolic pathways simultaneously with multiple phytochemicals through synergistic functioning which might be an appropriate approach to better management of obesity. In addition, epigenetic mechanisms (acetylation, methylation, miRNAs, ubiquitylation, phosphorylation, and chromatin packaging) of phytochemicals and their preventive and therapeutic perspective are explored in this review.

Amidation-Modified Apelin-13 Regulates PPARγ and Perilipin to Inhibit Adipogenic Differentiation and Promote Lipolysis.

With the adjustment of human diet and lifestyle changes, the prevalence of obesity is increasing year by year. Obesity is closely related to the excessive accumulation of white adipose tissue (WAT), which can synthesize and secrete a variety of adipokines. Apelin is a biologically active peptide in the adipokines family. Past studies have shown that apelin plays an important regulatory role in the pathogenesis and pathophysiology of diseases such as the cardiovascular system, respiratory system, digestive system, nervous system, and endocrine system. Apelin is also closely related to diabetes and obesity. Therefore, we anticipate that apelin-13 has an effect on lipometabolism and intend to explore the effect of apelin-13 on lipometabolism at the cellular and animal levels. In in vitro experiments, amidation-modified apelin-13 can significantly reduce the lipid content; TG content; and the expression of PPARγ, perilipin mRNA, and protein in adipocytes. Animal experiments also show that amidation modification apelin-13 can improve the abnormal biochemical indicators of diet-induced obesity (DOI) rats and can reduce the average diameter of adipocytes in adipose tissue, the concentration of glycerol, and the expression of PPARγ and perilipin mRNA and protein. Our results show that apelin-13 can affect the metabolism of adipose tissue, inhibit adipogenic differentiation of adipocytes, promote lipolysis, and thereby improve obesity. The mechanism may be regulating the expression of PPARγ to inhibit adipogenic differentiation and regulating the expression of perilipin to promote lipolysis. This study helps us understand the role of apelin-13 in adipose tissue and provide a basis for the elucidation of the regulation mechanism of lipometabolism and the development of antiobesity drugs.