Treatment Of Metabolic Diseases Research Articles

Unlocking the therapeutic potential of Geraniol: an alternative perspective for metabolic disease management.

Natural substance geraniol has anti-inflammatory and antioxidant qualities. It may be used to treat metabolic diseases such as diabetes, obesity, and cardiovascular illnesses. Innovations in nanoformulations enhance geraniol's absorption, stability, and targeted distribution, augmenting its therapeutic effectiveness and mitigating side effects, despite the limits of traditional treatment. The therapeutic potential of geraniol in the management of metabolic disorders such as diabetes, obesity, neuroinflammation, and cardiovascular disease is examined in this review. It highlights the anti-inflammatory, antioxidant, and lipid-lowering qualities of geraniol as well as the potential for nanoformulations to increase bioavailability and therapeutic efficacy. A collection of pertinent research articles about the potential of geraniol in metabolic illnesses, including obesity, type 2 diabetes, as well as cardiovascular diseases, was compiled from PubMed, Scopus, and Google Scholar. Terms such as "metabolic syndrome," "antioxidant," "anti-inflammatory," "geraniol," and "nanoformulations" were employed. Google Patents were also examined in order to offer insights into current and upcoming research. The potential of geraniol to treat metabolic disorders, including obesity, diabetes, hyperlipidemia, and cardiovascular illnesses, is thoroughly reviewed in this article. Recent research has demonstrated the lipid-lowering, antioxidant, and anti-inflammatory properties of geraniol as well as its ability to improve endothelial function and reduce oxidative stress in preclinical animals. The paper delves into the various nanoformulations, including liposomes, nanoparticles, and nanoemulsions, which enhance geraniol's therapeutic efficacy and bioavailability, making it a viable option for managing metabolic syndrome. The antioxidant, anti-inflammatory, and lipid-lowering qualities of geraniol make it a promising treatment for metabolic diseases. Its bioavailability along with therapeutic efficacy are increased by nanoformulations, which makes it a compelling option for the treatment of conditions such as neuroinflammation, diabetes, and obesity.

Branched-chain amino acid metabolism: Pathophysiological mechanism and therapeutic intervention in metabolic diseases.

Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential for maintaining physiological functions and metabolic homeostasis. However, chronic elevation of BCAAs causes metabolic diseases such as obesity, type 2 diabetes (T2D), and metabolic-associated fatty liver disease (MAFLD). Adipose tissue, skeletal muscle, and the liver are the three major metabolic tissues not only responsible for controlling glucose, lipid, and energy balance but also for maintaining BCAA homeostasis. Under obese and diabetic conditions, different pathogenic factors like pro-inflammatory cytokines, lipotoxicity, and reduction of adiponectin and peroxisome proliferator-activated receptors γ (PPARγ) disrupt BCAA metabolism, leading to excessive accumulation of BCAAs and their downstream metabolites in metabolic tissues and circulation. Mechanistically, BCAAs and/or their downstream metabolites, such as branched-chain ketoacids (BCKAs) and 3-hydroxyisobutyrate (3-HIB), impair insulin signaling, inhibit adipogenesis, induce inflammatory responses, and cause lipotoxicity in the metabolic tissues, resulting in multiple metabolic disorders. In this review, we summarize the latest studies on the metabolic regulation of BCAA homeostasis by the three major metabolic tissues-adipose tissue, skeletal muscle, and liver-and how dysregulated BCAA metabolism affects glucose, lipid, and energy balance in these active metabolic tissues. We also summarize therapeutic approaches to restore normal BCAA metabolism as a treatment for metabolic diseases.

The Role of Informal Social Support for Patients Undergoing Bariatric Surgery.

Bariatric surgery is underutilized as a treatment for metabolic disease and its associated comorbidities. While social support is known to play a crucial role in outcomes following bariatric surgery, little is known about the role of social support prior to surgery, which may impact preparedness for and willingness to undergo surgery. The study's objective was to examine the role of informal social support prior to bariatric surgery, the types of support received, and patient attitudes toward different demonstrations of support. We conducted semi-structured interviews with patients who had previously undergone bariatric surgery (n = 20) from two high-volume bariatric surgery centers. Interviews focused on patient engagement with and attitudes about social support during the preoperative process. Transcripts from each interview were iteratively analyzed through steps informed by deductive and inductive thematic analysis. Four major themes emerged characterizing social support among patients undergoing bariatric surgery: (1) emotional support, (2) instrumental support, (3) informational support, and (4) self-support. Examples of meaningful support participants received included "cheerleading" (i.e., unconditional encouragement), advice from role models who had previously undergone surgery (e.g., receiving information on the process), shared experiences with loved ones regarding dietary and activity modifications (e.g., exercising with friends), and self-support measures (e.g., seeking therapy). A comprehensive understanding of how patients receive informal social support can offer valuable insights for individuals considering surgery. Further, such knowledge may enable providers to effectively counsel patients through the decision-making process and to ensure the establishment of support systems both pre- and post-surgery.

Association Between Overweight/Obesity Metabolic Phenotypes Defined by Two Criteria of Metabolic Abnormality and Cardiovascular Diseases: A Cross-Sectional Analysis in a Chinese Population.

Obesity/overweight and metabolic anomalies are known to be associated with elevated cardiovascular disease (CVD) risk. However, there is a paucity of research exploring the association between different body weights, varying metabolic statuses, and the occurrence of CVD in the Chinese population. Thus, we performed this study to explore the relation between different metabolic overweight/obesity phenotypes and the prevalence of CVD. We analyzed data from 9075 participants in the Risk Evaluation of cAncers in Chinese diabeTic Individuals: A lONgitudinal (REACTION) study. Participants were classified into four metabolic phenotypes based on their metabolic status and obesity/overweight status. Regression analysis was used to evaluate the relationship between CVD and different groups. Additionally, we conducted a subgroup analysis to further explore the relationship between CVD and different metabolic abnormalities. Compared to metabolically healthy non-overweight/obesity (MHNO) individuals, both overweight/obesity and metabolic anomalies were positively associated with CVD prevalence. Among other metabolically unhealthy and overweight/obesity phenotypes, metabolically healthy overweight/obesity (MHO) generally exhibited a comparatively lower association with CVD. In the elderly, high waist circumference was significantly associated with CVD, rather than body weight. Further analysis revealed that hypertension had the strongest association with CVD. Elderly individuals should place more emphasis on managing their waist circumference rather than only on BMI. CVD prevention should focus on both body weight management and treatment of metabolic diseases, with particular emphasis on antihypertensive therapy.

The Role of the AIM2 Gene in Obesity-Related Glucose and Lipid Metabolic Disorders: A Recent Update.

Absent in melanoma 2 (AIM2) is a protein encoded by the AIM2 gene located on human chromosomes, AIM2 can recognize and bind to double stranded DNA (dsDNA), leading to the assembly of the AIM2 inflammasome. The AIM2 inflammasome plays important proinflammation role in many diseases, and can induce pyroptotic cell death. It has also been closely linked to the development and progression of metabolic diseases and can be activated in obesity, diabetes, nonalcoholic fatty liver disease, and atherosclerosis. In this article, we mainly review the role of AIM2 in glucose metabolism, especially in obesity-related disorders of glucose and lipid metabolism, and provide insights to better understand the role of AIM2 in the pathogenesis, and clinical treatment of metabolic disease.

Polysaccharide NAP-3 Synergistically Enhances the Efficiency of Metformin in Type 2 Diabetes via Bile Acid/GLP-1 Axis through Gut Microbiota Remodeling.

The polysaccharides of edible mushrooms are excellent phytochemicals for adjuvant treatment of metabolic diseases, but the potential mechanisms of synergistic effects are unclear. In this work, we discovered that NAP-3 enhanced the efficiency of metformin in lipid and glucose metabolism in type 2 diabetic (T2D) mice in a gut microbiome-dependent way. NAP-3 remodeled the intestinal microbial, resulting in the decreased activity of bile salt hydrolases and upregulation of CYP27A1 and CYP7B1 functions in the alternative pathway of bile acid synthesis, which leads to accumulation of the conjugated bile acids in ileum, specifically TβMCA and TUDCA. The accumulated conjugated bile acids either blocked or stimulated the nuclear receptors Farnesoid-X-receptor and TGR5, inducing the release of GLP-1 and ultimately enhanced glucose metabolism in mice. Collectively, our research indicated that edible mushroom polysaccharide NAP-3 may serve as a promising adjunctive oral therapeutic agent for T2D.

Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice

Beige fat activation involves a fuel switch to fatty acid oxidation following chronic cold adaptation. Mitochondrial acyl-CoA synthetase long-chain family member 1 (ACSL1) localizes in the mitochondria and plays a key role in fatty acid oxidation; however, the regulatory mechanism of the subcellular localization remains poorly understood. Here, we identify an endosomal trafficking component sortilin (encoded by Sort1) in adipose tissues that shows dynamic expression during beige fat activation and facilitates the translocation of ACSL1 from the mitochondria to the endolysosomal pathway for degradation. Depletion of sortilin in adipocytes results in an increase of mitochondrial ACSL1 and the activation of AMPK/PGC1α signaling, thereby activating beige fat and preventing high-fat diet (HFD)-induced obesity and insulin resistance. Collectively, our findings indicate that sortilin controls adipose tissue fatty acid oxidation by substrate fuel selection during beige fat activation and provides a potential targeted approach for the treatment of metabolic diseases.

Gluconeogenesis unraveled: A proteomic Odyssey with machine learning

The metabolic pathway known as gluconeogenesis, which produces glucose from non-carbohydrate substrates, is essential for maintaining balanced blood sugar levels while fasting. It’s extremely important to anticipate gluconeogenesis rates accurately to recognize metabolic disorders and create efficient treatment strategies. The implementation of deep learning and machine learning methods to forecast complex biological processes has been gaining popularity in recent years. The recognition of both the regulation of the pathway and possible therapeutic applications of proteins depends on accurate identification associated with their gluconeogenesis patterns. This article analyzes the uses of machine learning and deep learning models, to predict gluconeogenesis efficiency. The study also discusses the challenges that come with restricted data availability and model interpretability, as well as possible applications in personalized healthcare, metabolic disease treatment, and the discovery of drugs. The predictor utilizes statistics moments on the structures of gluconeogenesis and their enzymes, while Random Forest is utilized as a classifier to ensure the accuracy of this model in identifying the best outcomes. The method was validated utilizing the independent test, self-consistency, 10 k fold cross-validations, and jackknife test which achieved 92.33 %, 91.87 %, 87.88 %, and 87.02 %. An accurate prediction of gluconeogenesis has significant implications for understanding metabolic disorders and developing targeted therapies. This study contributes to the rising field of predictive biology by mixing algorithms for deep learning, and machine learning, with metabolic pathways.

New concepts in the roles of AMPK in adipocyte stem cell biology.

Obesity is a major risk factor for many life-threatening diseases. Adipose tissue dysfunction is emerging as a driving factor in the transition from excess adiposity to comorbidities such as metabolic-associated fatty liver disease, cardiovascular disease, Type 2 diabetes and cancer. However, the transition from healthy adipose expansion to the development of these conditions is poorly understood. Adipose stem cells, residing in the vasculature and stromal regions of subcutaneous and visceral depots, are responsible for the expansion and maintenance of organ function, and are now recognised as key mediators of pathological transformation. Impaired tissue expansion drives inflammation, dysregulation of endocrine function and the deposition of lipids in the liver, muscle and around vital organs, where it is toxic. Contrary to previous hypotheses, it is the promotion of healthy adipose tissue expansion and function, not inhibition of adipogenesis, that presents the most attractive therapeutic strategy in the treatment of metabolic disease. AMP-activated protein kinase, a master regulator of energy homeostasis, has been regarded as one such target, due to its central role in adipose tissue lipid metabolism, and its apparent inhibition of adipogenesis. However, recent studies utilising AMP-activated protein kinase (AMPK)-specific compounds highlight a more subtle, time-dependent role for AMPK in the process of adipogenesis, and in a previously unexplored repression of leptin, independent of adipocyte maturity. In this article, I discuss historic evidence for AMPK-mediated adipogenesis inhibition and the multi-faceted roles for AMPK in adipose tissue.

Managing Gout in Patients with Metabolic Syndrome.

Gout is characterized by monosodium urate (MSU) crystal deposition secondary to hyperuricemia. Gout is associated with metabolic syndrome (MetS) and its related comorbid conditions such as cardiovascular disease (CVD). Major advances have been made in the comprehension of the link between MetS and gout. Despite observational studies suggesting an association between MetS-related conditions and hyperuricemia, there is no proof of causality. Most studies using Mendelian randomization did not find hyperuricemia as a causal factor for MetS-related conditions. In contrast, these conditions were found associated with hyperuricemia, which suggests a reverse causality. Among patients with gout, this high CVD risk profile implies the need for systematic screening for MetS-related conditions. Most international guidelines recommend systematic screening for and care of CVD and related risk factors in patients with gout. Some anti-hypertensive agents, such as losartan and calcium channel blockers, are able to decrease serum urate (SU) levels. However, there are potential interactions between gout management therapies and the treatment of metabolic diseases. Some data suggest that anti-inflammatory drugs used for gout flare treatment, such as colchicine or canakinumab, might have benefits for CVD. Regarding the impact of urate-lowering therapies on CVD risk, recent studies found a similar CVD safety profile for allopurinol and febuxostat. Finally, sodium-glucose cotransporter-2 inhibitors are promising for gout because of their ability to decrease SU levels and risk of recurrent flares. In this review, we focus on the clinical challenge of managing MetS in patients with gout, particularly older patients with co-medications.

Transcriptional regulation of adipocyte lipolysis by IRF2BP2.

Adipocyte lipolysis controls systemic energy levels and metabolic homeostasis. Lipolysis is regulated by post-translational modifications of key lipolytic enzymes. However, less is known about the transcriptional mechanisms that regulate lipolysis. Here, we identify the transcriptional factor interferon regulatory factor-2 binding protein 2 (IRF2BP2) as a repressor of adipocyte lipolysis. Deletion of IRF2BP2 in primary human adipocytes increases lipolysis without affecting glucose uptake, whereas IRF2BP2 overexpression decreases lipolysis. RNA-seq and ChIP-seq analyses reveal that IRF2BP2 directly represses several lipolysis-related genes, including LIPE ( HSL , hormone sensitive lipase), which encodes the rate-limiting enzyme in lipolysis. Adipocyte-selective deletion of Irf2bp2 in mice increases Lipe expression and free fatty acid levels, resulting in elevated adipose tissue inflammation and glucose intolerance. Altogether, these findings demonstrate that IRF2BP2 restrains adipocyte lipolysis and opens new avenues to target lipolysis for the treatment of metabolic disease.

Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease.

The secretin-like, class B1 subfamily of seven transmembrane-spanning G protein-coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and use a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via an N-terminal extracellular domain that forms a hydrophobic ligand-binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogs of several class B1 ligands for therapeutic use. Among the most accepted of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multifunctional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of polypharmacologic ligands. Furthermore, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complexes with either native ligands or multifunctional agonists are provided, supporting the pharmacological basis of such therapeutic agents.

Ramadan Fasting in Individuals with Metabolic Dysfunction-Associated Steatotic Liver Disease, Liver Transplant, and Bariatric Surgery: A Narrative Review.

Metabolic dysfunction-associated steatotic liver disease is a growing worldwide pandemic. A limited number of studies have investigated the potential effect of Ramadan fasting on metabolic dysfunction-associated steatotic liver disease (MASLD). There is no single medication for the treatment of MASLD. There is a growing interest in dietary intervention as potential treatment for metabolic diseases including MASLD. The aim of this study was to discuss the epidemiology, pathogenesis, and risk factors of MASLD and the potential effects of Ramadan fasting on MASLD, liver transplant, and bariatric surgery. We searched PubMed and SCOPUS databases using different search terms. The literature search was based on research studies published in English from the year 2000 to the 2024. Thirty-two studies were included in this review. Ramadan fasting reduced body weight and improved lipid profile, anthropometric indices, fasting plasma glucose, plasma insulin, and inflammatory cytokines. Ramadan fasting improved risk factors of nonalcoholic fatty liver disease and might improve MASLD through weight reduction. However, further studies are needed to assess the safety and effectiveness of Ramadan fasting in liver transplant recipients and bariatric surgery.

A novel phosphodiesterase inhibitor for the treatment of chronic liver injury and metabolic diseases.

Chronic liver disease (CLD) leads to approximately two million deaths annually. Cyclic adenosine monophosphate (cAMP) signaling has long been studied in liver injury, particularly in the regulation of fatty acid (FA) β-oxidation and pro-inflammatory polarization of tissue-resident lymphocytes. Phosphodiesterase 4B (PDE4B) inhibition has been explored as a therapeutic modality, but these drugs have had limited success and are known to cause significant adverse effects. The PDE4 inhibitor 2-(4-([2-(5-Chlorothiophen-2-yl)-5-ethyl-6-methylpyrimidin-4-yl]amino)phenyl)acetic acid) (known as A-33) has yet to be explored for the treatment of metabolic diseases. Herein, we evaluated the efficacy of A-33 in the treatment of animal models of alcohol-associated liver disease (ALD) and steatotic liver disease (SLD). We demonstrated that A-33 effectively ameliorated the signs and symptoms of CLD, resulting in significant decreases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, decreased overall fat and collagen deposition in the liver, decreased intrahepatic triglyceride (TG) concentrations, and normalized expression of genes related to β-oxidation of fatty acids, inflammation, and extracellular matrix (ECM) deposition. We also designed and synthesized a novel analog of A-33, termed MDL3, which inhibited both PDE4B and PDE5A and was more effective in ameliorating pathophysiological signs and symptoms of liver injury and inflammation. In addition, MDL3 re-sensitized obese mice to glucose and significantly inhibited the pathological remodeling of adipose tissue, which was not observed with A-33 administration. In conclusion, we synthesized and demonstrated that MDL3, a novel PDE4B and PDE5A inhibitor, presents a promising avenue of exploration for treating CLD.

Identification of an alternative ligand-binding pocket in peroxisome proliferator-activated receptor gamma and its correlated selective agonist for promoting beige adipocyte differentiation.

The pharmacological activation of peroxisome proliferator-activated receptor gamma (PPARγ) is a convenient and promising strategy for promoting beige adipocyte biogenesis to combat obesity-related metabolic disorders. However, thiazolidinediones (TZDs), the full agonists of PPARγ exhibit severe side effects in animal models and in clinical settings. Therefore, the development of efficient and safe PPARγ modulators for the treatment of metabolic diseases is emerging. In this study, using comprehensive methods, we report a previously unidentified ligand-binding pocket (LBP) in PPARγ and link it to beige adipocyte differentiation. Further virtual screening of 4097 natural compounds based on this novel LBP revealed that saikosaponin A (NJT-2), a terpenoid compound, can bind to PPARγ to induce coactivator recruitment and effectively activate PPARγ-mediated transcription of the beige adipocyte program. In a mouse model, NJT-2 administration efficiently promoted beige adipocyte biogenesis and improved obesity-associated metabolic dysfunction, with significantly fewer adverse effects than those observed with TZD. Our results not only provide an advanced molecular insight into the structural ligand-binding details in PPARγ, but also develop a linked selective and safe agonist for obesity treatment.

Heterogeneous metabolic changes of brown and white adipose tissues are associated with metabolic adaptations in periparturient mice.

Pregnancy requires metabolic adaptations in order to meet support fetal growth with nutrient availability. In this study, the influence of pregnancy on metabolically active organs (adipose tissues in particular) was investigated. Our results showed that maternal weight and adipose mass presented dynamic remodeling in the periparturient mice. Meanwhile, pregnancy mice displayed obvious glucose intolerance and insulin resistance in late pregnancy as compared to non-pregnancy, which were partially reversed at parturition. Further analyses revealed that different fat depots exhibited site-specific adaptions of morphology and functionality as pregnancy advanced. Brown and inguinal white adipose tissue (BAT and IngWAT) exhibited obviously decreased thermogenic activity; by contrast, gonadal white adipose tissue (GonWAT) displayed remarkably increased lipid mobilization. Notably, we found that mammary gland differentiation was enhanced in IngWAT, followed by BAT but not in GonWAT. These result indicated that brown and white adipose tissues might synergistically play a crucial role in maintaining the maximum of energy supply for mother and fetus, which facilitates the mammary duct luminal epithelium development as well as the growth and development of fetus. Accompanied with adipose adaptation, however, our results revealed that the liver and pancreas also displayed significant metabolic adaptability, which together tended to trigger the risk of maternal metabolic diseases. Importantly, pregnancy-dependent obesity in our mice model resembled the disturbed metabolic phenotypes of pregnant women such as hyperglyceridemia and hypercholesterolemia. Our findings in this study could provide valuable clues for better understanding the underlying mechanisms of metabolic maladaptation and facilitate the development of the prevention and treatment of metabolic diseases.

Screening of peptidyl arginine deiminase 4 inhibitors in traditional herbal medicines

Peptidyl arginine deiminase 4 (PAD4) is a promising target for the treatment of metabolic diseases associated with autoimmune and central nervous system disease. By now there are limited numbers of PAD4 inhibitors, and no one is ready for clinical use. This study aims to find efficient and specific PAD4 inhibitors from traditional herbal medicines and to investigate their inhibitory mechanisms. The inhibitory effects of forty-eight extracts from sixteen traditional herbal medicines which are widely used in traditional herbal medicines were investigated. Salvia miltiorrhiza was found to have the most potent PAD4 inhibitory activity. After that, a practical bioactivity-guided fractionation coupling with a chemical profiling strategy was used to identify the fractions from Salvia miltiorrhiza with strong PAD4 inhibition activity, and the major constituents in these bioactive fractions were characterized by LC-MS/MS. Seven compounds were found to have inhibition on PAD4 with IC50 values ranging from 33.52 μM to 667 μM, in which salvianolic acid A showed the most potent inhibitory activity, with an IC50 value of 33.52 μM. Inhibition kinetic analyses indicated that salvianolic acid A effectively inhibited PAD4 in a mixed inhibitory manner, and computer simulation analyses demonstrated that salvianolic acid A binds to PAD4 mainly using hydrogen bonding. Overall, our results suggest that salvianolic acid A from Salvia miltiorrhiza is a potent inhibitor of PAD4, and that salvianolic acid A can be used as a promising lead compound for the development of more potent PAD4 inhibitors.

CETP and SGLT2 inhibitor combination therapy increases glycemic control: a 2x2 factorial Mendelian randomization analysis.

Cholesteryl ester transfer protein (CETP) inhibitors, initially developed for treating hyperlipidemia, have shown promise in reducing the risk of new-onset diabetes during clinical trials. This positions CETP inhibitors as potential candidates for repurposing in metabolic disease treatment. Given their oral administration, they could complement existing oral medications like sodium-glucose cotransporter 2 (SGLT2) inhibitors, potentially delaying the need for injectable therapies such as insulin. We conducted a 2x2 factorial Mendelian Randomization analysis involving 233,765 participants from the UK Biobank. This study aimed to evaluate whether simultaneous genetic inhibition of CETP and SGLT2 enhances glycemic control compared to inhibiting each separately. Our findings indicate that dual genetic inhibition of CETP and SGLT2 significantly reduces glycated hemoglobin levels compared to controls and single-agent inhibition. Additionally, the combined inhibition is linked to a lower incidence of diabetes compared to both the control group and SGLT2 inhibition alone. These results suggest that combining CETP and SGLT2 inhibitor therapies may offer superior glycemic control over SGLT2 inhibitors alone. Future clinical trials should investigate the potential of repurposing CETP inhibitors for metabolic disease treatment, providing an oral therapeutic option that could benefit high-risk patients before they require injectable therapies like insulin or glucagon-like peptide-1 (GLP-1) receptor agonists.

Integrative analysis reveals the anti-obesity roles of Poria cocos polysaccharides through beneficial effects on gut microbiota

Obesity is a global health problem that is characterized with metabolic disorders. And new medicine for obesity is developed needfully. In this study, we investigated the beneficial anti-obesity effects of Poria Cocos polysaccharides (PCP) through modulation of fatty acid metabolism and gut microbiota in vivo. PCP, the functional nutrient components, have gained attention due to emerging pharmacological properties. Plant polysaccharides have also shown promising application for the treatment of metabolic diseases. However, the correlative mechanisms of PCP-exhibited anti-obesity effects via targeting fatty acid metabolism remain unclear. Therefore, we employed a network pharmacology approach combined with 16S ribosomal RNA (rRNA) sequencing to explore the anti-obesity actions, targets, and metabolic mechanisms exerted by PCP. By using public databases for comprehensive analysis, we identified 35 genes that were mutual with PCP, obesity, and fatty acid metabolism. These genes could play crucial roles in inflammation, adipogenesis, lipid metabolism, and insulin signaling regulation. Furthermore, current results demonstrated that PCP attenuated the activation of the inflammatory signaling pathway in adipose tissue caused by high-fat diet (HFD) in mice. PCP showed benefits in reducing the inflammatory processes and improving metabolic disturbance. Base on metagenomic sequencing report, PCP might restore the gut microbiota composition and diversity, thereby meliorating fatty acid metabolism and energy homeostasis. Further 16S rRNA findings revealed changes in gut microbial profiles, including altered Eisenbergiella, Dorea, Proteiniphilum and Lachnospira in response to PCP treatment. Overall, our study provides insights into the beneficial actions of PCP for exhibiting anti-obesity effects through improving fatty acid metabolism and gut microbiota homeostasis in vivo, suggesting that PCP may be a therapeutic strategy for obesity and metabolic disorders.

Quercetin Alleviates Insulin Resistance and Repairs Intestinal Barrier in db/db Mice by Modulating Gut Microbiota.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease which seriously affects public health. Gut microbiota remains a dynamic balance state in healthy individuals, and its disorder may affect health status and even results in metabolic diseases. Quercetin, a natural flavonoid, has been shown to have biological activities that can be used in the prevention and treatment of metabolic diseases. This study aimed to explore the mechanism of quercetin in alleviating T2DM based on gut microbiota. db/db mice were adopted as the model for T2DM in this study. After 10 weeks of administration, quercetin could significantly decrease the levels of body weight, fasting blood glucose (FBG), serum insulin (INS), the homeostasis model assessment of insulin resistance (HOMA-IR), monocyte chemoattractant protein-1 (MCP-1), D-lactic acid (D-LA), and lipopolysaccharide (LPS) in db/db mice. 16S rRNA gene sequencing and untargeted metabolomics analysis were performed to compare the differences of gut microbiota and metabolites among the groups. The results demonstrated that quercetin decreased the abundance of Proteobacteria, Bacteroides, Escherichia-Shigella and Escherichia_coli. Moreover, metabolomics analysis showed that the levels of L-Dopa and S-Adenosyl-L-methionine (SAM) were significantly increased, but 3-Methoxytyramine (3-MET), L-Aspartic acid, L-Glutamic acid, and Androstenedione were significantly decreased under quercetin intervention. Taken together, quercetin could exert its hypoglycemic effect, alleviate insulin resistance, repair the intestinal barrier, remodel the intestinal microbiota, and alter the metabolites of db/db mice.