Anti-obesity and anti-diabetic bioactive peptides: A comprehensive review of their sources, properties, and techno-functional challenges.

The scourge of obesity arising from obesogens and poor dieting still ravages our planet as half of the global population may be overweight and obese by 2035. This metabolic disorder is intertwined with type 2 diabetes (T2D), both of which warrant alternative therapeutic options other than clinically approved drugs like orlistat with their tendency of abuse and side effects. In this review, we comprehensively describe the global obesity problem and its connection to T2D. Obesity, overconsumption of fats, the mechanism of fat digestion, obesogenic gut microbiota, inhibition of fat digestion, and natural anti-obesity compounds are discussed. Similar discussions are made for diabetes with regard to glucose regulation, the diabetic gut microbiota, and insulinotropic compounds. The sources and production of anti-obesity bioactive peptides (AOBPs) and anti-diabetic bioactive peptides (ADBPs) are also described while explaining their structure-function relationships, gastrointestinal behaviors, and action mechanisms. Finally, the techno-functional applications of AOBPs and ADBPs are highlighted.

Anti-Obesity Therapeutic Targets Studied In Silico and In Vivo: A Systematic Review.

In the age of information technology and the additional computational search tools and software available, this systematic review aimed to identify potential therapeutic targets for obesity, evaluated in silico and subsequently validated in vivo. The systematic review was initially guided by the research question "What therapeutic targets have been used in in silico analysis for the treatment of obesity?" and structured based on the acronym PECo (P, problem; E, exposure; Co, context). The systematic review protocol was formulated and registered in PROSPERO (CRD42022353808) in accordance with the Preferred Reporting Items Checklist for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and the PRISMA was followed for the systematic review. The studies were selected according to the eligibility criteria, aligned with PECo, in the following databases: PubMed, ScienceDirect, Scopus, Web of Science, BVS, and EMBASE. The search strategy yielded 1142 articles, from which, based on the evaluation criteria, 12 were included in the systematic review. Only seven these articles allowed the identification of both in silico and in vivo reassessed therapeutic targets. Among these targets, five were exclusively experimental, one was exclusively theoretical, and one of the targets presented an experimental portion and a portion obtained by modeling. The predominant methodology used was molecular docking and the most studied target was Human Pancreatic Lipase (HPL) (n = 4). The lack of methodological details resulted in more than 50% of the papers being categorized with an "unclear risk of bias" across eight out of the eleven evaluated criteria. From the current systematic review, it seems evident that integrating in silico methodologies into studies of potential drug targets for the exploration of new therapeutic agents provides an important tool, given the ongoing challenges in controlling obesity.

Heat-killed Lactiplantibacillus plantarum Shinshu N-07 exerts antiobesity effects in western diet-induced obese mice.

AIMS: The aim of this study was to evaluate the antiobesity effects of heat-killed Lactiplantibacillus plantarum Shinshu N-07 (N-07) isolated from fermented Brassica rapa L. METHODS AND RESULTS: Male mice were divided into three groups (n = 10/group); normal diet, western diet (WD), or WD + N-07 (N-07) group and administered each diet for 56 days. The N-07 group showed significant suppression of body weight gain and epididymal fat, perirenal fat, and liver weights compared with the WD group. Higher levels of fecal total cholesterol, triglyceride (TG), and free fatty acid (FFA) were observed in the N-07 group than in the WD group. The mRNA expression of the cholesterol transporter ATP-binding cassette transporter G5 (ABCG5) was significantly increased in the small intestine of N-07-fed mice compared with WD-fed mice. Moreover, N-07 supplementation significantly increased the mRNA expression of ABCG5 and ABCG8 in Caco-2 cells. Furthermore, the TG- and FFA-removal ability of N-07 was confirmed to evaluate its soybean oil- and oleic acid-binding capacities in in vitro experiments. CONCLUSIONS: The antiobesity effects of N-07 might be due to its ability to promote lipid excretion by regulating cholesterol transporter expression and lipid-binding ability.

Anti-Obesity and Anti-Diabetic Effects of Ostericum koreanum (Ganghwal) Extract.

"Ganghwal" is a widely used herbal medicine in Republic of Korea, but it has not been reported as a treatment strategy for obesity and diabetes within adipocytes. In this study, we determined that Ostericum koreanum extract (OKE) exerts an anti-obesity effect by inhibiting adipogenesis and an anti-diabetic effect by increasing the expression of genes related to glucose uptake in adipocytes and inhibiting α-glucosidase activity. 3T3-L1 preadipocytes were differentiated for 8 days in methylisobutylxanthine, dexamethasone, and insulin medium, and the effect of OKE was confirmed by the addition of 50 and 100 µg/mL of OKE during the differentiation process. This resulted in a reduction in lipid accumulation and the expression of PPARγ (Peroxisome proliferator-activated receptor γ) and C/EBPα (CCAAT enhancer binding protein α). Significant activation of AMPK (AMP-activated protein kinase), increased expression of GLUT4 (Glucose Transporter Type 4), and inhibition of α-glucosidase activity were also observed. These findings provide the basis for the anti-obesity and anti-diabetic effects of OKE. In addition, OKE has a significant antioxidant effect. This study presents OKE as a potential natural product-derived material for the treatment of patients with metabolic diseases such as obesity- and obesity-induced diabetes.

Effect of Salvia hispanica (Chia seeds) and Foeniculum vulgare (Fennel seeds) against weight-loss and lipid profile in obese human subjects.

Increased levels of bad cholesterol in the body result in increasing blood pressure and weight gain. The rate of mortality in people, especially who are obese, is increasing due to absence of organic sources of fiber in their diets. Chia and fennel seeds are rich sources of fiber. The objective of this study was to evaluate the combined effect of Salvia hispanica (Chia seeds) and Foeniculum vulgare (Fennel seeds) against weight-loss and lipid profile in obese human subjects. The research was conducted on obese people aged 25 to 40 years at the Jinnah Hospital Lahore. The study design was randomized control trial (RCT). The sample size was calculated and was divided in-to two groups. With the duration of study being 3 months, pre-testing of all the participants was done. Group 1 was control group, given placebo treatment and Group 2 was an intervention group and given chia and fennel seeds. Post-testing was done and data were analyzed. Results showed that chia and fennel seeds have significant effect (p <0.05) on BMI and lipid profile hence, both are beneficial for lowering body weight and improving LDL, HDL, serum triglycerides and total cholesterol levels.

Formation, physicochemical properties, and biological activities of theabrownins.

Theabrownins (TBs) are heterogeneous mixtures of water-soluble brown tea pigments, and important constituents to evaluate the quality of dark tea. TBs have numerous hydroxyl and carboxyl groups and are formed by the oxidative polymerization of tea polyphenols. Many biological activities attributed to TBs, including antioxidant, anti-obesity, and lipid-regulating, have been demonstrated. This review summarizes the research progress made on the formation mechanism and physicochemical properties of TBs. It also discusses their protective effects against various diseases and associated potential molecular mechanisms. Additionally, it examines the signaling pathways mediating the bioactivities of TBs and highlights the difficulties and challenges of TBs research as well as their research prospects and applications.

Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons.

Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here, we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine's food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.

Anorexigenic neuropeptides as anti-obesity and neuroprotective agents: exploring the neuroprotective effects of anorexigenic neuropeptides.

Since 1975, the incidence of obesity has increased to epidemic proportions, and the number of patients with obesity has quadrupled. Obesity is a major risk factor for developing other serious diseases, such as type 2 diabetes mellitus, hypertension, and cardiovascular diseases. Recent epidemiologic studies have defined obesity as a risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and other types of dementia. Despite all these serious comorbidities associated with obesity, there is still a lack of effective antiobesity treatment. Promising candidates for the treatment of obesity are anorexigenic neuropeptides, which are peptides produced by neurons in brain areas implicated in food intake regulation, such as the hypothalamus or the brainstem. These peptides efficiently reduce food intake and body weight. Moreover, because of the proven interconnection between obesity and the risk of developing AD, the potential neuroprotective effects of these two agents in animal models of neurodegeneration have been examined. The objective of this review was to explore anorexigenic neuropeptides produced and acting within the brain, emphasizing their potential not only for the treatment of obesity but also for the treatment of neurodegenerative disorders.

Narirutin-Rich Celluclast Extract from Mandarin (Citrus unshiu) Peel Alleviates High-Fat Diet-Induced Obesity and Promotes Energy Metabolism in C57BL/6 Mice.

Mandarin peel, a main by-product from the processing of citrus juice, has been highlighted for its various bioactivities and functional ingredients. Our previous study proved the inhibitory effects of Celluclast extract from mandarin peel (MPCE) on lipid accumulation and differentiation in 3T3-L1 adipocytes. Therefore, the current study aimed to evaluate the anti-obesity effect of MPCE in high-fat diet (HFD)-induced obese mice. The high-performance liquid chromatography (HPLC) analysis exhibited that narirutin and hesperidin are the main active components of MPCE. Our current results showed that MPCE supplementation decreased adiposity by reducing body and organ weights in HFD-induced obese mice. MPCE also reduced triglyceride (TG), alanine transaminase (ALT), aspartate transaminase (AST), and leptin contents in the serum of HFD-fed mice. Moreover, MPCE significantly inhibited hepatic lipid accumulation by regulating the expression levels of proteins associated with lipid metabolism, including sterol regulatory element-binding protein (SREBP1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). Furthermore, MPCE administration significantly inhibited both adipogenesis and lipogenesis, with modulation of energy metabolism by activating 5' adenosine monophosphate-activated protein kinase (AMPK) and lipolytic enzymes such as hormone-sensitive lipase (HSL) in the white adipose tissue (WAT). Altogether, our findings indicate that MPCE improves HFD-induced obesity and can be used as a curative agent in pharmaceuticals and nutraceuticals to alleviate obesity and related disorders.

Identification of phenolic compounds from fermented Moringa oleifera Lam. leaf supplemented with Fuzhuan brick tea and their volatile composition and anti-obesity activity.

As a nutritious plant with valuable potential, the Moringa oleifera Lam. (MOL) leaf addition on Fuzhuan brick tea (FBT) for the co-fermentation (MOL-FBT) was an industry innovation and a new route to make full use of MOL leaf. After optimization of the extraction conditions, the best conditions for the polyphenols extraction method from MOL-FBT (MFP) were 60°C for 40 min (1:80, V/W) using response surface methodology. A total of 30 phenolics were identified and quantified. Most of the polyphenols were increased after adding MOL leaf for co-fermentation compared to FBT polyphenols. In particular, caffeic acids were found only in MFP. Moreover, the MFP received high value in taste, aroma, and color. In total, 62 volatile flavor compounds, consisting of 3 acids, 5 alcohols, 15 aldehydes, 4 esters, 20 hydrocarbons, 10 ketones, and 5 others, were identified in MFP. In addition, MFP inhibited 3T3-L1 preadipocyte differentiation in a dose-dependent manner and decreased lipid accumulation via the peroxisome proliferator-activated receptor gamma (PPARγ)/CCAAT/enhancer binding protein alpha (CEBPα)/cluster of differentiation 36 (CD36) axis and induced a brown adipocyte-like phenotype. In vivo experiments were further conducted to confirm the in vitro results. MFP regulated lipid accumulation, glucose/insulin tolerance, improved liver and kidney function, and inhibited the secretion of pro-inflammatory factors by the PPARγ/CEBPα/CD36 axis and alleviated inflammation in high fat and high fructose diet-induced obese mice. In summary, MFP possesses high-quality properties and anti-obesity effects, as well as the great potential to be used as a novel functional food product.

The dairy-derived peptide Miltin exerts anti-obesity effects by increasing adipocyte thermogenesis.

Growing research has highlighted that the consumption of dairy products improves the metabolic health in obese individuals by functioning as regulatory modulators. However, the molecular basis of this effect remains largely unknown. Herein, we report a dairy-derived peptide, which we named Miltin, that activates the thermogenesis of brown adipocytes and increases white adipocyte browning. Previously, Miltin was merely identified for its antioxidant capacity, although it is commonly present in different dairy products. In this study, we revealed the effect of Miltin in modulating adipose thermogenesis and further explored its potential in treating obesity through in vivo and in vitro strategies. The administration of Miltin in mice fed with a high-fat diet resulted in enhanced thermogenesis, improved glucose homeostasis, and reduced body mass and lipid accumulation, indicating the anti-obesity effect of Miltin. Genomic analysis revealed that Miltin modulates thermogenesis by inducing the activation of the MAPK signaling pathway by preferentially interacting with GADD45γ to promote its stability. Together, our findings indicate that Miltin's role in initiating the thermogenesis of adipocytes makes it a potential anti-obesity therapy for future development.

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

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

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

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

Mulberry leaf and its effects against obesity: A systematic review of phytochemistry, molecular mechanisms and applications.

BACKGROUND: Obesity and hyperlipidemia can induce a variety of diseases, and have become major health problems worldwide. How to effectively prevent and control obesity has become one of the hot-spots of contemporary research. Mulberry leaf is the dried leaf of Morus alba L., which is approved by the Ministry of Health as a "homology of medicine and food", rich in diverse active constituents and with a variety of health effects including anti-obesity and anti-hyperlipidemia activities. PURPOSE: The review attempts to summarize and provide the molecular basis, mechanism, safety and products for further exploration and application of mulberry leaf on the treatment on the control of weight gain and obesity. METHODS: This review is conducted by using ScienceDirect, PubMed, CNKI and Web of Science databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Based on the research progress of domestic and foreign scholars, the effective phytochemicals, molecular mechanisms and product applications of mulberry leaf in the prevention and treatment of obesity and related metabolic diseases were summarized. CONCLUSION: Mulberry leaf has excellent medicinal and health care value in obesity treatment. However, its pharmacodynamic substance basis and molecular mechanisms need to be further studied.

Natural H2S-donors: A new pharmacological opportunity for the management of overweight and obesity.

The prevalence of overweight and obesity has progressively increased in the last few years, becoming a real threat to healthcare systems. To date, the clinical management of body weight gain is an unmet medical need, as there are few approved anti-obesity drugs and most require an extensive monitoring and vigilance due to risk of adverse effects and poor patient adherence/persistence. Growing evidence has shown that the gasotransmitter hydrogen sulfide (H2S) and, therefore, H2S-donors could have a central role in the prevention and treatment of overweight/obesity. The main natural sources of H2S-donors are plants from the Alliaceae (garlic and onion), Brassicaceae (e.g., broccoli, cabbage, and wasabi), and Moringaceae botanical families. In particular, polysulfides and isothiocyanates, which slowly release H2S, derive from the hydrolysis of alliin from Alliaceae and glucosinolates from Brassicaceae/Moringaceae, respectively. In this review, we describe the emerging role of endogenous H2S in regulating adipose tissue function and the potential efficacy of natural H2S-donors in animal models of overweight/obesity, with a final focus on the preliminary results from clinical trials. We conclude that organosulfur-containing plants and their extracts could be used before or in combination with conventional anti-obesity agents to improve treatment efficacy and reduce inflammation in obesogenic conditions. However, further high-quality studies are needed to firmly establish their clinical efficacy.

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

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

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

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

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

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