Actein ameliorates diet-induced obesity through the activation of AMPK-mediated white fat browning.

BACKGROUND: Targeting white adipose tissue (WAT) browning to increase systemic energy expenditure is a promising therapeutic strategy to combat obesity. Actein from Actaea cimicifuga L. has recently been reported to ameliorate high fat-induced hepatic steatosis. However, the effect of actein on diet-induced obesity merits more and further investigation. PURPOSE: We aimed to examine the anti-obesity potential of actein and unravel its actions on WAT browning. METHODS: The effect of actein on diet-induced obesity was evaluated using a high-fat diet model in C57BL/6 mice. Systemic energy expenditure of mice was measured with a combined indirect calorimetry system. Quantitative real-time PCR analyses were performed to investigate the mRNA levels of genes involved in thermogenesis, browning, and lipolysis. The protein levels were assessed by Western blot. Moreover, WAT explants and a transwell co-culture system consisting of SVFs and adipocytes were constructed to study the mechanisms of actein on promoting WAT browning and lipolysis. RESULTS: At a dosage of 5 mg/kg/d, actein not only protected mice against diet-induced obesity and insulin resistance, but also reversed pre-established obesity and glucose intolerance in mice. Meanwhile, actein facilitated systemic energy expenditure by activating WAT lipolysis and browning. Further, mechanistic studies revealed that actein indirectly induced epididymal adipocyte lipolysis and directly promoted a white-to-beige conversion of subcutaneous adipocytes by activating the AMPK signaling. CONCLUSION: Actein ameliorated diet-induced obesity and was discovered as a natural lead compound directly targeting white-to-beige conversion of subcutaneous adipocytes, suggesting the potential of developing new therapies for obesity and associated metabolic disorders.

Cordycepin Ameliorates High Fat Diet-Induced Obesity by Modulating Endogenous Metabolism and Gut Microbiota Dysbiosis.

BACKGROUND: Numerous metabolic illnesses have obesity as a risk factor. The composition of the gut microbiota and endogenous metabolism are important factors in the onset and progression of obesity. Recent research indicates that cordycepin (CRD), derived from fungi, exhibits anti-inflammatory and antioxidant properties, showing potential in combating obesity. However, further investigation is required to delineate its precise impacts on endogenous metabolism and gut microbiota. METHODS: In this work, male C57BL/6J mice were used as models of obesity caused by a high-fat diet (HFD) and given CRD. Mice's colon, liver, and adipose tissues were stained with H&E. Serum metabolome analysis and 16S rRNA sequencing elucidated the effects of CRD on HFD-induced obese mice and identified potential mediators for its anti-obesity effects. RESULTS: CRD intervention alleviated HFD-induced intestinal inflammation, improved blood glucose levels, and reduced fat accumulation. Furthermore, CRD supplementation demonstrated the ability to modulate endogenous metabolic disorders by regulating the levels of key metabolites, including DL-2-aminooctanoic acid, inositol, and 6-deoxyfagomine. CRD influenced the abundance of important microbiota such as Parasutterella, Alloprevotella, Prevotellaceae_NK3B31_group, Alistipes, unclassified_Clostridia_vadinBB60_group, and unclassified_Muribaculaceae, ultimately leading to the modulation of endogenous metabolism and the amelioration of gut microbiota disorders. CONCLUSIONS: According to our research, CRD therapies show promise in regulating fat accumulation and stabilizing blood glucose levels. Furthermore, through the modulation of gut microbiota composition and key metabolites, CRD interventions have the dual capacity to prevent and ameliorate obesity.

Targeted Nano-Based Systems for the Anti-Obesity Agent's Delivery.

Obesity is a global health concern and a chronic disease that is accompanied by excessive fat storage in adipose and nonadipose tissues. An increase in the body-mass index (BMI) is directly proportional to the 2- to 3.9-fold increase in all-cause mortality in obesity. If left untreated for a longer period, obesity-related metabolic, cardiovascular, inflammatory, and malignant diseases reduce life expectancy. Currently, most of the anti-obesity drugs have failed and fallen into disrepute, either due to their ineffectiveness or adverse effects. In this review, depending on their enhanced pharmacokinetic and biodistribution profiles, whether nanocarriers alter the basic properties and bioactivity of anti-obesity drugs used in clinical practice are debated. First, nanocarriers can improve the safety of still-used anti-obesity drugs by lowering their systemic toxicity through increasing targeting efficacy and preventing drug carrier toxicity. Second, when the micro-ribonucleic acids (miRNAs), which are aberrantly expressed in obesity and obesity-related diseases, are encapsulated into nanoparticles, they are effective in multiple obesity-related metabolic pathways and gene networks. Finally, a synergistic anti-obesity effect with low dose and low toxicity can be obtained with the combinatory therapy applied by encapsulating the anti-obesity drug and gene in the same nanocarrier delivery vehicle.

The endocannabinoid system in appetite regulation and treatment of obesity.

The endocannabinoid system (ECS) is a complex cell-signaling system that is responsible for maintaining homeostasis by modulating various regulatory reactions in response to internal and environmental changes. The influence of ECS on appetite regulation has been a subject of much recent research, however, the full extent of its impact remains unknown. Current evidence links human obesity to ECS activation, increased endocannabinoid levels in both central and peripheral tissues, along with cannabinoid receptor type 1 (CBR1) up-regulation. These findings imply the potential pharmacological use of the ECS in the treatment of obesity. Here, we present various pathophysiological processes in obesity involving the ECS, highlighting different pharmacological options for modulating endocannabinoid activity to treat obesity. However, the potential of those pharmacological possibilities remains under investigation and requires further research.

The discovery and development of GLP-1 based drugs that have revolutionized the treatment of obesity.

The 2024 Lasker~DeBakey Clinical Medical Research Award has been given to Joel Habener and Svetlana Mojsov for their discovery of a new hormone GLP-1(7-37) and to Lotte Knudsen for her role in developing sustained acting versions of this hormone as a treatment for obesity. Each of the three had a distinct set of skills that made this advance possible; Habener is an endocrinologist and molecular biologist, Mojsov is a peptide chemist, and Knudsen is a pharmaceutical scientist. Their collective efforts have done what few thought possible-the development of highly effective medicines for reducing weight. Their research has also solved a mystery that began more than a century ago.

Anti-obesity and immunomodulatory effects of Allium hookeri leaves cultivated with artificial light of different intensities on immune-depressed obese mice.

This study was conducted to evaluate the effects of Allium hookeri (AH) leaves cultivated with different light-emitting diode (LED) intensities (L: low, 100 µmol/m2/s; M: medium, 150 µmol/m2/s; H: high, 200 µmol/m2/s). Alliin concentration increased as light intensity increased in AH and showed the highest level at LED-H condition. The anti-obesity and immunomodulatory properties of AH were evaluated in a cyclophosphamide (CPA)-induced immunosuppressed obese animal model. C57BL/6 J mice were randomly divided into control (CON), high-fat diet (HFD) control (CON-H), negative control (NC), positive control (PC, ß-glucan, 50 mg/kg body weight (BW)), AH L, M, and H groups. The three kinds of AH extracts were orally administered to the mice at 300 mg/kg BW for 2 weeks. Except for CON and CON-H, all the other groups were intraperitoneally treated with CPA. Epididymal and abdominal fat weight decreased as LED intensity increased while spleen weight increased in the AH groups. Serum glucose decreased as LED intensity increased in the AH groups and H group showed the lowest level. Triglycerides, total, and LDL-cholesterol levels decreased while HDL-cholesterol level increased in the AH groups compared to the NC group. Moreover, AH effectively reduced serum ALT and AST levels and increased the total white blood cell count, particularly elevating lymphocyte and monocyte levels. Furthermore, NK cell activity was higher in the AH groups. These findings suggest that AH cultivated at optimal LED intensity could be used as a novel biomedicine and in pharmacotherapy to treat related diseases to improve public health without any toxicity.

Peptides Evaluated In Silico, In Vitro, and In Vivo as Therapeutic Tools for Obesity: A Systematic Review.

Bioinformatics has emerged as a valuable tool for screening drugs and understanding their effects. This systematic review aimed to evaluate whether in silico studies using anti-obesity peptides targeting therapeutic pathways for obesity, when subsequently evaluated in vitro and in vivo, demonstrated effects consistent with those predicted in the computational analysis. The review was framed by the question: "What peptides or proteins have been used to treat obesity in in silico studies?" and structured according to the acronym PECo. The systematic review protocol was developed and registered in PROSPERO (CRD42022355540) in accordance with the PRISMA-P, and all stages of the review adhered to these guidelines. Studies were sourced from the following databases: PubMed, ScienceDirect, Scopus, Web of Science, Virtual Heath Library, and EMBASE. The search strategies resulted in 1015 articles, of which, based on the exclusion and inclusion criteria, 7 were included in this systematic review. The anti-obesity peptides identified originated from various sources including bovine alpha-lactalbumin from cocoa seed (Theobroma cacao L.), chia seed (Salvia hispanica L.), rice bran (Oryza sativa), sesame (Sesamum indicum L.), sea buckthorn seed flour (Hippophae rhamnoides), and adzuki beans (Vigna angularis). All articles underwent in vitro and in vivo reassessment and used molecular docking methodology in their in silico studies. Among the studies included in the review, 46.15% were classified as having an "uncertain risk of bias" in six of the thirteen criteria evaluated. The primary target investigated was pancreatic lipase (n = 5), with all peptides targeting this enzyme demonstrating inhibition, a finding supported both in vitro and in vivo. Additionally, other peptides were identified as PPARγ and PPARα agonists (n = 2). Notably, all peptides exhibited different mechanisms of action in lipid metabolism and adipogenesis. The findings of this systematic review underscore the effectiveness of computational simulation as a screening tool, providing crucial insights and guiding in vitro and in vivo investigations for the discovery of novel anti-obesity peptides.

L-Fucose-Rich Sulfated Glycans from Edible Brown Seaweed: A Promising Functional Food for Obesity and Energy Expenditure Improvement.

The global obesity epidemic, exacerbated by the sedentary lifestyle fostered by the COVID-19 pandemic, presents a growing socioeconomic burden due to decreased physical activity and increased morbidity. Current obesity treatments show promise, but they often come with expensive medications, frequent injections, and potential side effects, with limited success in improving obesity through increased energy expenditure. This study explores the potential of a refined sulfated polysaccharide (SPSL), derived from the brown seaweed Scytosiphon lomentaria (SL), as a safe and effective anti-obesity treatment by promoting energy expenditure. Chemical characterization revealed that SPSL, rich in sulfate and L-fucose content, comprises nine distinct sulfated glycan structures. In vitro analysis demonstrated potent anti-lipogenic properties in adipocytes, mediated by the downregulation of key adipogenic modulators, including 5' adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor γ (PPARγ) pathways. Inhibiting AMPK attenuated the anti-adipogenic effects of SPSL, confirming its involvement in the mechanism of action. Furthermore, in vivo studies using zebrafish models showed that SPSL increased energy expenditure and reduced lipid accumulation. These findings collectively highlight the therapeutic potential of SPSL as a functional food ingredient for mitigating obesity-related metabolic dysregulation by promoting energy expenditure. Further mechanistic and preclinical investigations are warranted to fully elucidate its mode of action and evaluate its efficacy in obesity management, potentially offering a novel, natural therapeutic avenue for this global health concern.

Selected Mesoamerican Crops - Anti-Obesity Potential and Health Promotion. A Review.

Mesoamerica is the center of origin of a great number of food crops that nowadays are part of a healthy diet. Pre-Columbian civilizations utilized more than 90% of these foods as ingredient or in main dishes, as well as for remedies and religious ceremonies. Since several years ago, Mesoamerican foods have been recognized by their outstanding concentration of bioactive compounds, including, phenolic compounds, pigments, essential fatty acids, amino acids, peptides, carbohydrates and vitamins, which provide a great number of health benefits. As a result of their unique composition, these ancient crops have several positive effects, such as hypoglycemic, antioxidant, anti-obesity, anti-inflammatory, anti-ageing, neuroprotective, anti-diarrheal, and anti-hypercholesterolemic capacity. Hence, this review is focused mainly in the anti-obesity and antioxidant potential of some of the most cultivated, harvested, as well as commercialized and consumed, food crops native of Mesoamerica, like, nopal and its fruit (Opuntia ficus indica spp.), chia (Salvia hispanica L.), pumpkin (Cucurbita spp.) and cacao (Theobroma cacao).

Weighing in on the role of brown adipose tissue for treatment of obesity.

Brown adipose tissue (BAT) activation is an emerging target for obesity treatments due to its thermogenic properties stemming from its ability to shuttle energy through uncoupling protein 1 (Ucp1). Recent rodent studies show how BAT and white adipose tissue (WAT) activity can be modulated to increase the expression of thermogenic proteins. Consequently, these alterations enable organisms to endure cold-temperatures and elevate energy expenditure, thereby promoting weight loss. In humans, BAT is less abundant in obese subjects and impacts of thermogenesis are less pronounced, bringing into question whether energy expending properties of BAT seen in rodents can be translated to human models. Our review will discuss pharmacological, hormonal, bioactive, sex-specific and environmental activators and inhibitors of BAT to determine the potential for BAT to act as a therapeutic strategy. We aim to address the feasibility of utilizing BAT modulators for weight reduction in obese individuals, as recent studies suggest that BAT's contributions to energy expenditure along with Ucp1-dependent and -independent pathways may or may not rectify energy imbalance characteristic of obesity.

Molecular Mechanisms behind Obesity and Their Potential Exploitation in Current and Future Therapy.

Obesity is a chronic disease caused primarily by the imbalance between the amount of calories supplied to the body and energy expenditure. Not only does it deteriorate the quality of life, but most importantly it increases the risk of cardiovascular diseases and the development of type 2 diabetes mellitus, leading to reduced life expectancy. In this review, we would like to present the molecular pathomechanisms underlying obesity, which constitute the target points for the action of anti-obesity medications. These include the central nervous system, brain-gut-microbiome axis, gastrointestinal motility, and energy expenditure. A significant part of this article is dedicated to incretin-based drugs such as GLP-1 receptor agonists (e.g., liraglutide and semaglutide), as well as the brand new dual GLP-1 and GIP receptor agonist tirzepatide, all of which have become "block-buster" drugs due to their effectiveness in reducing body weight and beneficial effects on the patient's metabolic profile. Finally, this review article highlights newly designed molecules with the potential for future obesity management that are the subject of ongoing clinical trials.

Phytochemical screening, antioxidant, anti-diabetic, and anti-obesity activities, formulation, and characterization of a self-nanoemulsion system loaded with pomegranate (Punica granatum) seed oil.

Pomegranate (Punica granatum) is a tree of the Punicaceae family that is widespread all over the world and has several types and therapeutic uses. The current study aimed to investigate the phytochemical compounds by GC analysis and carried out physical characterization of the pomegranate seed oil and its self-nanoemulsifying system. Then antioxidant, anti-diabetic, and anti-lipase activities were investigated for both.The pomegranate seed oil was extracted, and its self-nanoemulsifying system was then prepared. Phytochemical compounds were analyzed by GC, and physical characterization was established of the pomegranate seed oil and its self-nanoemulsifying system. Then antioxidant, anti-diabetic, and anti-lipase activities were investigated for both.The GC-MS analysis revealed that punicic acid, ß-eleosteric acid, catalpic acid, α-eleosteric acid, and oleic acid were the most predominant compounds in pomegranate seed oil. Other active compounds like linoleic acid, palmitic acid, stearic acid, and α-linolenic acid were detected in trace percentages. The self-nanoemulsifying system was prepared using various concentrations of surfactant (Tween 80), co-surfactant (Span 80), and pomegranate seed oil. The selected formulation had a PDI of 0.229 ± 0.09 and a droplet size of 189.44 ± 2.1 nm. The free radical scavenging activity of pomegranate seed oil, the self-emulsifying system, and Trolox was conducted using DPPH. The oil-self-nanoemulsifying system showed potent antioxidant activity compared to Trolox. Also, pomegranate oil inhibited α-amylase with a weak IC50 value of 354.81 ± 2.3 µg/ml. The oil self-nanoemulsifying system showed potent activity compared to acarbose and had a weaker IC50 value (616.59 ± 2.1 µg/ml) and a potent IC50 value (43.65 ± 1.9 µg/ml) compared to orlistat.Pomegranate seed oil self-nanoemulsifying system could be applied in the future for the preparation of possible oral medications for the prevention and treatment of oxidative stress, diabetes, and obesity due to its high activity against free radical, amylase, and lipase enzymes compared to pomegranate seed oil itself and the references used. This study reveals that self-nanoemulsion systems can enhance oil drug formulations by improving pharmacokinetics and pharmacodynamics, acting as drug reservoirs, and facilitating efficient oil release.

Brown Algae Ecklonia cava Extract Modulates Adipogenesis and Browning in 3T3-L1 Preadipocytes through HO-1/Nrf2 Signaling.

This study explores the anti-obesity effects of the ethyl acetate extract of Ecklonia cava (EC-ETAC) on 3T3-L1 preadipocytes, focusing on its impact on adipogenesis, lipolysis, and adipose browning via the HO-1/Nrf2 pathway. Western blot analysis revealed that EC-ETAC significantly inhibited adipogenic transcription factors (PPARγ, C/EBPα, SREBP-1) and lipogenesis-related proteins (FAS, LPL). Concurrently, EC-ETAC enhanced lipolytic markers (p-AMPK, p-HSL) and adipose browning-related proteins (UCP-1, PGC-1α), indicating its role in promoting lipolysis and adipose browning. The inhibition of HO-1 by zinc protoporphyrin (ZnPP) significantly reversed these effects, underscoring the critical role of HO-1 in mediating the anti-obesity properties of EC-ETAC. Additionally, fluorescence measurements and Oil Red O staining confirmed the reduction of lipid accumulation and oxidative stress upon EC-ETAC treatment. These findings suggest that EC-ETAC exerts its anti-obesity effects by modulating the HO-1/Nrf2 pathway, which is crucial for regulating adipogenesis, lipolysis, and adipose browning. This study highlights the potential of EC-ETAC as a natural therapeutic agent for obesity management and supports further research into its clinical applications. By targeting the HO-1/Nrf2 pathway, EC-ETAC could offer a novel approach to enhancing energy expenditure and reducing fat mass, thereby improving metabolic health.

A Comparative Analysis on Impact of Extraction Methods on Carotenoids Composition, Antioxidants, Antidiabetes, and Antiobesity Properties in Seagrass Enhalus acoroides: In Silico and In Vitro Study.

Enhalus acoroides, a tropical seagrass, is known for its significant contribution to marine ecosystems and its potential health benefits due to bioactive compounds. This study aims to compare the carotenoid levels in E. acoroides using green extraction via ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE) and to evaluate the biological properties of these extracts against oxidative stress, diabetes, and obesity through in silico and in vitro analyses. E. acoroides samples were collected from Manado City, Indonesia, and subjected to UAE and MAE. The extracts were analyzed using UHPLC-ESI-MS/MS to identify carotenoids, including ß-carotene, lutein, lycopene, ß-cryptoxanthin, and zeaxanthin. In silico analysis was conducted to predict the compounds' bioactivity, toxicity, and drug-likeness using WAY2DRUG PASS and molecular docking with CB-Dock2. The compounds C3, C4, and C7 demonstrated notable interactions, with key metabolic proteins and microRNAs, further validating their potential therapeutic benefits. In vitro assays evaluated antioxidant activities using DPPH and FRAP assays, antidiabetic properties through α-glucosidase and α-amylase inhibition, and antiobesity effects via lipase inhibition and MTT assay with 3T3-L1 cells. Results indicated that both UAE and MAE extracts exhibited significant antioxidant, antidiabetic, and antiobesity activities. MAE extracts showed higher carotenoid content and greater biological activity compared to UAE extracts. These findings suggest that E. acoroides, mainly when extracted using MAE, has promising potential as a source of natural bioactive compounds for developing marine-based antioxidant, antidiabetic, and antiobesity agents. This study supplements existing literature by providing insights into the efficient extraction methods and the therapeutic potential of E. acoroides carotenoids.

Design, synthesis and structure-activity relationship of novel 2-pyrimidinylindole derivatives as orally available anti-obesity agents.

Due to the emerging global epidemic of obesity, developing safe and effective agents for anti-obesity is urgently needed. Our previous study found that 2-pyrimidinylindole derivative Wd3d exhibited potential anti-obesity activity. Herein, to further optimize the potential moiety, structural modifications were proceeded for two rounds in this study. Firstly, we designed, synthesized, and evaluated 36 new derivatives of 2-pyrimidinylindole scaffold with different substituents on the indole ring and pyrimidine ring to investigate their structure-activity relationship (SAR). Then, analogs with potent activity had the aldehyde group replaced with the acylhydrazone group to reduce cytotoxicity and improve metabolic stability. Detailed SAR studies and animal evaluation experiments led to the discovery of the compound 9ga, which significantly reduced TG accumulation with an EC50 value of 0.07 µM and showed relatively low cytotoxicity with an IC50 value of around 24 µM. Oral administration of 9ga effectively prevented the excessive growth of body weight and lessened fat mass as well as liver mass, decreased lipid accumulation in the liver and blood, and improved the heart injury parameter in the diet-induced obesity mouse model significantly better than Wd3d. A mechanism study showed that 9ga regulated the lipid metabolism during early adipogenesis by inhibiting PPARγ pathway. In conclusion, our study further highlights the anti-obesity potential of 2-pyrimidinylindole derivatives in diet-induced obesity.

Unveiling the anti-obesity potential of Kemuning (Murraya paniculata): A network pharmacology approach.

Obesity has become a global issue that affects the emergence of various chronic diseases such as diabetes mellitus, dysplasia, heart disorders, and cancer. In this study, an integration method was developed between the metabolite profile of the active compound of Murraya paniculata and the exploration of the targeting mechanism of adipose tissue using network pharmacology, molecular docking, molecular dynamics simulation, and in vitro tests. Network pharmacology results obtained with the skyline query technique using a block-nested loop (BNL) showed that histone acetyltransferase p300 (EP300), peroxisome proliferator-activated receptor gamma (PPARG), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) are potential targets for treating obesity. Enrichment analysis of these three proteins revealed their association with obesity, thermogenesis, energy metabolism, adipocytokines, fat cell differentiation, and glucose homeostasis. Metabolite profiling of M. paniculata leaves revealed sixteen active compounds, ten of which were selected for molecular docking based on drug-likeness and ADME results. Molecular docking results between PPARG and EP300 with the ten active compounds showed a binding affinity value of ≤ -5.0 kcal/mol in all dockings, indicating strong binding. The stability of the protein-ligand complex resulting from docking was examined using molecular dynamics simulations, and we observed the best average root mean square deviation (RMSD) of 0.99 Å for PPARG with trans-3-indoleacrylic acid, which was lower than with the native ligand BRL (2.02 Å). Furthermore, the RMSD was 2.70 Å for EP300 and the native ligand 99E, and the lowest RMSD with the ligand (1R,9S)-5-[(E)-2-(4-Chlorophenyl)vinyl]-11-(5-pyrimidinylcarbonyl)-7,11-diazatricyclo[7.3.1.02,7]trideca-2,4-dien-6-one was 3.33 Å. The in vitro tests to validate the potential of M. paniculata in treating obesity showed that there was a significant decrease in PPARG and EP300 gene expressions in 3T3-L1 mature adipocytes treated with M. paniculata ethanolic extract starting at concentrations 62.5 µg/ml and 15.625 µg/ml, respectively. These results indicate that M. paniculata can potentially treat obesity by disrupting adipocyte maturation and influencing intracellular lipid metabolism.

Lycium chinense Mill Induces Anti-Obesity and Anti-Diabetic Effects In Vitro and In Vivo.

This study investigated the effects of Lycium chinense Mill (LCM) extract on obesity and diabetes, using both in vitro and high-fat diet (HFD)-induced obesity mouse models. We found that LCM notably enhanced glucagon-like peptide-1 (GLP-1) secretion in NCI-h716 cells from 411.4 ± 10.75 pg/mL to 411.4 ± 10.75 pg/mL compared to NT (78.0 ± 0.67 pg/mL) without causing cytotoxicity, implying the involvement of Protein Kinase A C (PKA C) and AMP-activated protein kinase (AMPK) in its action mechanism. LCM also decreased lipid droplets and lowered the expression of adipogenic and lipogenic indicators, such as Fatty Acid Synthase (FAS), Fatty Acid-Binding Protein 4 (FABP4), and Sterol Regulatory Element-Binding Protein 1c (SREBP1c), indicating the suppression of adipocyte differentiation and lipid accumulation. LCM administration to HFD mice resulted in significant weight loss (41.5 ± 3.3 g) compared to the HFD group (45.1 ± 1.8 g). In addition, improved glucose tolerance and serum lipid profiles demonstrated the ability to counteract obesity-related metabolic issues. Additionally, LCM exhibited hepatoprotective properties by reducing hepatic lipid accumulation and diminishing white adipose tissue mass and adipocyte size, thereby demonstrating its effectiveness against hepatic steatosis and adipocyte hypertrophy. These findings show that LCM can be efficiently used as a natural material to treat obesity and diabetes, providing a new approach for remedial and therapeutic purposes.

Intranasal delivery of glucagon-like peptide-1 to the brain for obesity treatment: opportunities and challenges.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), approved by the US FDA for obesity treatment, are typically administered subcutaneously, an invasive method leading to suboptimal patient adherence and peripheral side effects. Additionally, this route requires the drug to cross the restrictive blood-brain barrier (BBB), limiting its safety and effectiveness in weight management and cognitive addiction disorders. Delivering the drug intranasally could overcome these drawbacks. AREAS COVERED: This review summarizes GLP-1 RAs used as anti-obesity agents, focusing on the intranasal route as a potential pathway to deliver these biomolecules to the brain. It also discusses strategies to overcome challenges associated with nasal delivery. EXPERT OPINION: Nose-to-brain (N2B) pathways can address limitations of the subcutaneous route for GLP-1 RAs. However, peptide delivery to the brain is challenging due to nasal physiological barriers and the drug's physicochemical properties. Innovative approaches, such as cell permeation enhancers, mucoadhesive systems, and nanocarriers in nasal formulations, along with efficient drug delivery devices, show promising preclinical results. Despite this, successful preclinical data does not guarantee clinical effectiveness, highlighting the need for comprehensive clinical investigations to optimize formulations and fully utilize the nose-to-brain interface for peptide delivery.