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Triterpenoids from functional mushroom Ganoderma resinaceum and the novel role of Resinacein S in enhancing the activity of brown/beige adipocytes
Abstract
As the major biologically active constituents in Ganoderma species, Ganoderma triterpenoids (GTs) also showed potential anti-obesity effect in recent reports. To further elucidate the anti-obesity effect of GTs, four new compounds Ganoderenses H–K (1–4) and four known compounds (5–8) from Ganoderma resinaceum were determined by extensive spectroscopic analysis. The absolute configurations of Ganoderenses H (1), I (2), and Resinacein S (Res S; 5) were confirmed for the first time by X-ray crystallographic analysis. Then the effects of these triterpenoids on brown/beige adipocytes were further analyzed in vitro. Our results may be summarized as follows: (1) Res S reduced lipid droplets size by regulating lipid metabolism, but not affect the differentiation of C3H10T1/2 cells. (2) Res S increased the expression of brown and beige adipocytes markers and enhanced the activity of brown and beige adipocytes (e.g., increased β-oxidation and pro-lipolytic activities et al.) in differentiated C3H10T1/2 cells. (3) Res S induced mitochondrial biogenesis and increased mitochondrial OCR in differentiated C3H10T1/2 cells. In conclusion, Res S is potential for activating the function of brown and beige adipocytes, thus having potential therapeutic implications for obesity and associated metabolic diseases.
... What's more, one of the triterpenoids, Resinacein S has been found to induce beige and brown phenotypes, which may be relevant to the activation of AMPK/PGC1α signaling pathway to inhibit and treat obesity and relevant diseases. At the molecular level, Resinacein S treatment could significantly induce the expression of genes and/or proteins related to thermogenesis, fatty acid oxidation and lipolysis (6). Resinacein S, as one of the major triterpenoids from G. resinaceum, provides a therapeutic strategy for lipid metabolic diseases such as NAFLD, but whether Resinacein S treatment could provide protective aspects against NAFLD remains unknown. ...
... Fruiting bodies of G. resinaceum were collected from Vientiane, Laos, identified by Peigui Liu and a voucher specimen (accession number: KGR-201606) was deposited at the State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, China (6). ...
... as Ucp1 and Pgc1α, fatty acid oxidation related genes such as Pparα and Cpt1α, lipolysis related genes such as Hsl and Atgl, and mitochondriogenesis-related genes. Resinacein S may be involved in activation of AMPK/PGC1α signaling pathway (6). Now we obtained eight Resinacein S targeting genes with potential therapeutic effects against NAFLD through RNA seq analysis and PPI network analysis. ...
Background
Ganoderma lucidum is reportedly the best source of traditional natural bioactive constituents. Ganoderma triterpenoids (GTs) have been verified as an alternative adjuvant for treating leukemia, cancer, hepatitis and diabetes. One of the major triterpenoids, Resinacein S, has been found to regulate lipid metabolism and mitochondrial biogenesis. Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that has become a major public health problem. Given the regulatory effects on lipid metabolism of Resinacein S, we sought to explore potential protective effects against NAFLD.
Methods
Resinacein S was extracted and isolated from G. lucidum. And mice were fed with high fat diet with or without Resinacein S to detect hepatic steatosis. According to Network Pharmacology and RNA-seq, we analyzed the hub genes of Resinacein S against NAFLD disease.
Results
Our results can be summarized as follows: (1) The structure of Resinacein S was elucidated using NMR and MS methods. (2) Resinacein S treatment could significantly attenuate high-fat diet (HFD)-induced hepatic steatosis and hepatic lipid accumulation in mouse. (3) GO terms, KEGG pathways and the PPI network of Resinacein S induced Differentially Expressed Genes (DEGs) demonstrated the key target genes of Resinacein S against NAFLD. (4) The hub proteins in PPI network analysis could be used for NAFLD diagnosis and treatment as drug targets.
Conclusion
Resinacein S can significantly change the lipid metabolism in liver cells and yield a protective effect against steatosis and liver injury. Intersected proteins between NAFLD related genes and Resinacein S-induced DEGs, especially the hub protein in PPI network analysis, can be used to characterize targets of Resinacein S against NAFLD.
... Yang et al. (2018) first isolated four compounds including one new meroterpenoid, ganoresinains F, and then (Yang et al. 2019a, b) isolated and identified three triterpenoid compounds, one new resinacein T, and two known lanostane triterpenoids, 3β,7β,15α,24-tetrahydroxy-11,23-dioxo-lanost-8-en-26-oic acid and resinacein O. Chen et al. (2019) identified 55 triterpenoids including 21 unknown compounds. Huang et al. (2020b) isolated of A − F type triterpenoids from the fruiting body of G. resinaceum, four new compounds (resinacein U, V, W and X) and eight known compounds (resinacein T, resinacein I, 3β,7βdihydroxy-11,15,23-trioxo-lanost-8,16-dien-26-oic acid, ganoderense A, resinacein G, 3β,7β-dihydroxy-11,15,23-trioxo-lanost-8,16-dien-26-oic acid methyl ester, resinacein S and resinacein C). Shi et al. (2019) determined C 28 steroids and identified eight novel, unidentified ergostane-type steroids, and 21 known analogues were isolated from the fruiting body of G. resinaceum. ...
... Ganoderma triterpenoids are one of the major secondary metabolites determined in Ganoderma species, and are deemed to be one of the main functional constituents in G. resinaceum (Peng et al. 2013;Huang et al. 2020b;Karaman et al. 2022). Some of the first isolated lanostane triterpenoids from G. resinaceum are 3-epipachymic acid and 3-oxo-5α-lanosta-8,24-dien-21-oic acid with significant cytotoxic activity with on Hep-2 cells (Niu et al. 2007). ...
Ganoderma adspersum (Schulzer) Donk; Ganoderma applanatum (Pers.) Pat.; Ganoderma lucidum (Curtis) P. Karst.; Ganoderma resinaceum Boud. - GANODERMATACEAE
Yusufjon Gafforov, Aisha Umar, Soumya Ghosh, Michal Tomšovský, Mustafa Yamaç, Milena Rašeta, Manzura Yarasheva, Wan Abd Al Qadr Imad Wan-Mohtar et Sylvie Rapior.
Ganoderma adspersum (Schulzer) Donk; Ganoderma applanatum (Pers.) Pat.; Ganoderma lucidum (Curtis) P. Karst.; Ganoderma resinaceum Boud. - GANODERMATACEAE. Pages 1135-1169. doi:10.1007/978-3-031-23031-8_111 ; hal-04373752v1 ; hal-04385086v1
... G. resinaceum has long been used for enhancing health and treating liver diseases (Peng et al. 2013;Rašeta et al. 2020b), hyperglycemia, and immune-regulation in Traditional Chinese Medicine (Chen et al. 2017a(Chen et al. , 2018aShi et al. 2020) but also exhibited antimicrobial, antiproliferative, anti-obesity, AO, anti-AChE, antihypertensive, anti-tyrosinase, α-amylase, and α-glucosidase activity (Zengin et al. 2015;Chen et al. 2018a, b;Huang et al. 2020b;Kozarski et al. 2020;Rašeta et al. 2020a, b). ...
... Ganoderma TRIs (GTs) are one of the major BAM in Ganoderma species, and are deemed to be the main functional constituents in G. resinaceum (Peng et al. 2013;Li et al. 2016;Chen et al. 2018a, b;Yang et al. 2019a;Huang et al. 2020a) (Fig. 8.2). Resinacein S, as one of the major lanostane-type TRIs from G. resinaceum, with increased intake provides a potential method for enhancing the activity of brown and beige adipocyte, thus providing a therapeutic strategy for preventing and treating obesity and related diseases (Huang et al. 2020b), while some others showed antidiabetic and hepatoprotective effects (Chen et al. 2018a;Shi et al. 2020). ...
The aim of this chapter is to introduce the main problems in the study of wild growing medicinal mushroom species by presenting the research from the period 2005–2020, with special emphasis on autochthonous species of Serbia and the Balkan region. Four major problems have been discussed regarding identification of the species, their biodiversity, chemical characterization, and environmental contamination, since they represent a great source of bioactive compounds with various activities: antioxidative, antimicrobial, antidiabetic, and anti-AChE inhibition.The aim of this chapter is to introduce the main problems in the study of wild growing medicinal mushroom species by presenting the research from the period 2005–2020, with special emphasis on autochthonous species of Serbia and the Balkan region.Four major problems have been discussed regarding identification of the species, their biodiversity, chemical characterization, and environmental contamination, since they represent a great source of bioactive compounds with various activities: antioxidative, antimicrobial, antidiabetic, and anti-AChE inhibition. A proper taxonomic identification is the first step in the further research. The identification is difficult due to similarity of morphological characteristics, especially within species complexes such as Pleurotus
and Ganoderma
. Molecular identification through multi-gene phylogenetic analysis helped to resolve some of these issues while full genome sequencing enabled annotation of genes, as it was done with Schizophyllum commune
and Hericium erinaceus
.Chemical characterization of the secondary bioactive compounds mostly confirmed the existence of terpenoids, phenols, and sterols, while polysaccharides and immunomodulatory proteins including polysaccharide-peptide complexes have been identified recently. Although wild fungal strains represent powerful sources of medicinal substances, they can also pose a potential risk to human health through (hyper) accumulation of toxic elements (e.g. Hg, Pb, Cd, Ni, 238U, and 137Cs) from different substrates, not only in the polluted urban environments, but also in protected natural areas. Their use should be well reasoned and controlled along with their conservation and protection.KeywordsAntioxidantsCosmeceuticalsDiversityMolecular identificationToxic elements
... This medicinal fungus has been used for centuries to promote health, enhance immunity, and treat various ailments (Peng et al. 2013;Kou et al. 2022). Modern research has revealed that G. resinaceum contains a rich array of bioactive compounds, including polysaccharides, triterpenoids, and sterols, which are responsible for its diverse pharmacological effects Huang et al. 2020;Gauna et al. 2021). These compounds exhibit immunomodulatory, anti-inflammatory, and antitumor properties, making G. resinaceum a promising candidate for drug development Sipping et al. 2022). ...
The medical mushroom Ganoderma resinaceum Boud., 1889, is of great interest in pharmacy due to its diverse functional active ingredients. However, the mitochondrial genome of G. resinaceum remains unexplored. Here, we present the complete mitochondrial genome of G. resinaceum, which spans 67,458 bp and has a GC content of 25.65%. This genome encompasses 15 core protein-coding genes, 8 independent ORFs, 15 intronic ORFs, 27 tRNAs, and 2 rRNA genes. Through phylogenetic analysis using Bayesian inference (BI), we elucidated the evolutionary relationships among 34 Basidiomycota fungi, revealing distinct clades and indicating a close relationship between G. resinaceum and G. subamboinense.
... It has been reported to grow on a wide range of hosts such as Acer negundo, Platanus acerifolia, Acacia melanoxylon, Blepharocalyx salicifolius, Melia azedarach, Pinus sp., and Robinia pseudoacacia, but it was mentioned as a weak invasive specimen behaving as saprotrophic nature (Keypour and Asef, 2020). As one of these popular mushrooms, G. resinaceum is widely used for the treatment of hyperglycaemia, liver disease, hepatitis, and immunity disorders in China and Nigeria Shi et al., 2020;Huang et al., 2020). It has long been used for immunoregulation as well (Zhu, 1994). ...
Mushrooms have long been recognized for their remarkable health benefits, where the genus Ganoderma is considered as one of the most extensively studied groups of medicinal macrofungi. The taxon comprises over 130 species found worldwide, especially in Asia, many of which have been valued in traditional medicine. Despite such rich diversity and ethnic importance, majority of the research has primarily focused on Ganoderma lucidum; while numerous other potent members remain overlooked in the scientific community. Some of such matrices include Ganoderma atrum, G. australe, G. carnosum, G. colossus, G. curtisii, G. formosanum, G. leucocontextum, G. neo-japonicum, G. praelongum, G. pfeifferi, G. resinaceum, and G. sinense that have demonstrated significant medicinal attributes. These encompass antioxidant, antimicrobial, cytotoxic, anti-tumor, anticancer, anti-diabetic, cholesterol-lowering, immune-modulating, hepatoprotective properties and more. The present review aims to shed light on the therapeutic potential of these underappreciated Ganoderma spp. emphasizing need for more comprehensive research. Future investigations should thus be directed towards exploring their bioactive compounds, mechanisms of action, clinical studies, and potential applications in addressing various health conditions.
... The mycelial growth rate of G. resinaceum is faster than that of G. lingzhi, and triterpenoids are abundant and high in content [7][8][9]. G. resinaceum triterpenes have anti-inflammation, antioxidation, antiapoptosis, α-glucosidase inhibition and other biological activities and have potential therapeutic importance for neuro-related diseases, obesity and related metabolic diseases, diabetes, etc. [10][11][12]. Our previous experiments showed that G. lingzhi also had strong insecticidal properties and a high polysaccharide content, and G. resinaceum had a high yield. ...
Ganoderma lingzhi is an important medicinal fungus, and it is particularly important to select strains with high yields and active substance contents. In this study, protoplasts of G. lingzhi were thermally inactivated to destroy intracellular enzyme proteins and preserve DNA. The DNA of G. resinaceum was damaged by ultraviolet (UV) radiation, and other components of the protoplasm except DNA were preserved. Then, the protoplast was induced using polyethylene glycol (PEG) for fusion. The results showed that the optimal thermal inactivation conditions for G. lingzhi were 30 min in a 45 °C water bath, and the optimal UV inactivation conditions for G. resinaceum were 70 s of irradiation using a 20 W UV lamp at a vertical distance of 15 cm. Antagonistic tests, internal transcribed space (ITS) and mitochondrial DNA identification, intersimple sequence repeat (ISSR) molecular markers and morphology were used to distinguish the parents from the fusants. Four true fusants were obtained, and the yield was 2.5%. The fruiting body yield of the fusants was significantly higher than that of G. lingzhi, and the polysaccharide and triterpene contents of the RAD-64 fusant were significantly higher than those of G. lingzhi. The results presented in this paper show that protoplast fusion technology can effectively improve G. lingzhi varieties and support the breeding of new varieties.
... This is characterized by hypercytokinemia caused by the hyperactivation of macrophages 22 and associated with acute lung injury, ARDS, coagulopathy, multi-organ failures, and death. 23 The anti-inflammatory properties of G. lucidum have been well established. The solvent extracts of G. lucidum contain varieties of bioactive ingredients that have varying anti-inflammatory effects which primarily act on multiple stages of the inflammatory process. ...
The corona virus disease 2019 (COVID-19) caused by SARS-CoV-2 is characterized by acute respiratory distress syndrome (ARDS) facilitated by cytokine storm and other risk factors that increase susceptibility and complications leading to death. Emerging as a major global public health challenge, the disease has claimed more than 6 million lives and caused catastrophic global economic disruptions. However, there are concerns about the safety as well as the efficacy of drugs and vaccines presently used to control the pandemic, therefore necessitating intense global search for safe natural products that can effectively and safely combat it. This work reviews studies on lingzhi or reishi medicinal mushroom, Ganoderma lucidium and its properties that may potentially combat SARS-CoV-2 infection and the co-morbidities. Available evidence suggests that medicinal properties of the Ganoderma mushroom can combat the complications of SARS-CoV-2 infection and the co-morbidities that can aggravate the severity of the disease. Preclinical and clinical evaluation to establish dose, efficacy, and potential toxicity and possible use in the management of COVID-19 is recommended.
... This is characterized by hypercytokinemia caused by the hyperactivation of macrophages 22 and associated with acute lung injury, ARDS, coagulopathy, multi-organ failures, and death. 23 The anti-inflammatory properties of G. lucidum have been well established. The solvent extracts of G. lucidum contain varieties of bioactive ingredients that have varying anti-inflammatory effects which primarily act on multiple stages of the inflammatory process. ...
Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is characterized by acute respiratory distress syndrome (ARDS) facilitated by cytokine storm and other risk factors that increase susceptibility and complications leading to death. Emerging as a major global public health challenge, the disease has claimed more than 6 million lives and caused catastrophic global economic disruptions. However, there are concerns about the safety as well as the efficacy of drugs and vaccines presently used to control the pandemic, therefore necessitating intense global search for safe natural products that can effectively and safely combat it. This work reviews studies on lingzhi or reishi medicinal mushroom, Ganoderma lucidum and its properties that may potentially combat SARS-CoV-2 infection and the co-morbidities. Available evidence suggests that medicinal properties of the Ganoderma mushroom can combat the complications of SARS-CoV-2 infection and the co-morbidities that can aggravate the severity of the disease. Preclinical and clinical evaluation to establish dose, efficacy, and potential toxicity and possible use in the management of COVID-19 is recommended.
... This journal is © The Royal Society of Chemistry 2022 mor 48 and neuroprotective functions, 49,50 and also have the functions of protecting the liver, intestines, 51 and kidneys, 52 and regulating their related metabolism. 53 Ganoderma proteins have antioxidant, melanin inhibition and antibacterial functions, 54 and can protect DNA from hydroxyl radical damage. 55 Therefore, in the SSF product of G. resinaceum FQ23, various components form a complex effect, which may help endow G. resinaceum FQ23 with a wider range of physiological regulation functions. ...
Herein, a solid-state fermentation (SSF) system of Ganoderma resinaceum FQ23 with high-yield ergothioneine (EGT) was established, and the amelioration effect of the water extract from its fungal substance on anxiety-like insomnia mice was studied. The content of EGT in the G. resinaceum FQ23 SSF fungal substance increased to 1.146 ± 0.066 mg g-1 DW in the optimization tests. Besides EGT, the common functional components of the water extract from the G. resinaceum FQ23 SSF fungal substance (GSW) were determined, including triterpenoids, polysaccharides, phenols, proteins and amino acids. The animal experiments showed that GSW could alleviate the anxiety-like behavior, improve the antioxidant capacity and protect the organ structure of the anxiety-like insomnia mice. With an increase in the dose of GSW given to the anxiety-like insomnia mice, their serum 5-HT and GABA levels increased, HPA axis hormone levels significantly decreased, BDNF level notably increased, and the response level of the BDNF/CREB signaling pathway was significantly enhanced, indicating that GSW may improve neuroendocrine regulation and neuroprotection in anxiety-like insomnia mice. A 30-times dose of GSW had no acute toxicity in the normal mice. Therefore, the SSF fungal substance of G. resinaceum FQ23 is a potential dietary source for improving sleep. It can be used as a solid drink to help people who are poor sleepers and as a substitute for tea or coffee to help people who are like to drink tea or coffee and cannot sleep.
... Recently, natural products play a pivotal role in drug discovery, which also provide new clues to molecular mechanisms of diseases (7,8). A number of studies have demonstrated that natural compounds (e.g., indirubin, rutin) exert protective roles against the hepatic steatosis in vitro and in vivo (9,10). ...
Non-alcoholic fatty liver disease (NAFLD) has been considered to be one of the most common chronic liver diseases. However, no validated pharmacological therapies have been officially proved in clinic due to its complex pathogenesis. The purpose of this study was to examine the protective effects of Corilagin (referred to Cori) against NAFLD in mice under a high fat diet (HFD) condition. Mice were fed either a normal control diet (NCD) or HFD with or without Cori (5 or 10 mg/kg body weight) for 15 weeks. In our results, Cori treatment significantly attenuated HFD-induced hepatic steatosis, high NAFLD activity score (NAD) and liver injury. Consistently, Cori treatment remarkably alleviated HFD-induced hepatic lipid accumulation (e.g., triglycerides (TG) and total cholesterol (TC) contents in liver), and improved plasma lipid concentrations (e.g., plasma TG, TC, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c)). Moreover, Cori treatment ameliorated NAFLD associated metabolic disorders such as glucose intolerance and insulin resistance in HFD-fed mice. Additionally, Cori treatment dramatically changed HFD-induced liver gene expression profiles, and identified overlapped differentially expressed genes (DEGs) between NCD vs. HFD group and HFD vs. HCR (high fat diet plus treatment with Cori) group. With these DEGs, we observed a marked enrichment of Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, which were closely associated with the metabolic balance in liver. Particularly, we found several potential hub proteins against NAFLD development with analyses of protein-protein interaction (PPI) network and qPCR assays. Collectively, our results revealed the important protective effects of Cori against the progress of NAFLD, which was probably mediated through improving dysregulated lipid metabolism and insulin resistance in HFD-fed mice. Additionally, Cori-dependent overlapped DEGs might serve as a featured NAFLD-associated gene expression signature for the diagnosis, treatment, as well as drug discovery and development of NAFLD in the near future.
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 analysis 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 maxicum 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.
Lotus (Nelumbo nucifera Gaertn.) is an aquatic perennial crop planted worldwide and its leaf (also called “He-Ye”) has therapeutic effects on obesity. However, whether the underlying mechanism leads to increased energy expenditure by activation of brown adipocytes has not been clarified. Here, murine C3H10T1/2 mesenchymal stem cells (MSCs) were employed to investigate the effects of ethanol extracts from lotus leaf (LLE) on brown adipocytes formation and the underlying molecular mechanisms. The results showed LLE was rich in polyphenols (383.7 mg/g) and flavonoids (178.3 mg/g), with quercetin 3-O-glucuronide (Q3G) the most abundant (128.2 μg/mg). In LLE-treated C3H10T1/2 MSCs, the expressions of lipolytic factors (e.g., ATGL, HSL, and ABHD5) and brown regulators (e.g., Sirt1, PGC-1α, Cidea, and UCP1) were significantly upregulated compared to that in the untreated MSCs. Furthermore, LLE promoted mitochondrial biogenesis and fatty acid β-oxidation, as evidenced by increases in the expression of Tfam, Cox7A, CoxIV, Cox2, Pparα, and Adrb3. Likewise, enhanced browning and mitochondrial biogenesis were also observed in Q3G-stimulated cells. Importantly, LLE and Q3G induced phosphorylation of AMPK accompanied by a remarkable increase in the brown fat marker UCP1, while pretreatment with Compound C (an AMPK inhibitor) reversed these changes. Moreover, stimulating LLE or Q3G-treated cells with CL316243 (a beta3-AR agonist) increased p-AMPKα/AMPKα ratio and UCP1 protein expression, indicating β3-AR/AMPK signaling may involve in this process. Collectively, these observations suggested that LLE, especially the component Q3G, stimulates thermogenesis by activating brown adipocytes, which may involve the β3-AR/AMPK signaling pathway.
Obesity, usually indicated by a body mass index of more than 30 kg/m2, is a worsening global health issue. It leads to chronic diseases, including type II diabetes, hypertension, and cardiovascular diseases. Conventional treatments for obesity include physical activity and maintaining a negative energy balance. However, physical activity alone cannot determine body weight as several other factors play a role in the overall energy balance. Alternatively, weight loss may be achieved by medication and surgery. However, these options can be expensive or have side effects. Therefore, dietary factors, including dietary modifications, nutraceutical preparations, and functional foods have been investigated recently. For example, edible mushrooms have beneficial effects on human health. Polysaccharides (essentially β-D-glucans), chitinous substances, heteroglycans, proteoglycans, peptidoglycans, alkaloids, lactones, lectins, alkaloids, flavonoids, steroids, terpenoids, terpenes, phenols, nucleotides, glycoproteins, proteins, amino acids, antimicrobials, and minerals are the major bioactive compounds in these mushrooms. These bioactive compounds have chemo-preventive, anti-obesity, anti-diabetic, cardioprotective, and neuroprotective properties. Consumption of edible mushrooms reduces plasma triglyceride, total cholesterol, low-density lipoprotein, and plasma glucose levels. Polysaccharides from edible mushrooms suppress mRNA expression in 3T3-L1 adipocytes, contributing to their anti-obesity properties. Therefore, edible mushrooms or their active ingredients may help prevent obesity and other chronic ailments.
Four pairs of novel meroterpenoid dimers, (±)-applandimeric acids A-D (1-4) with an unprecedented spiro[furo[3], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40]benzofuran-3,2'-indene] core were isolated from the fruiting bodies of Ganoderma applanatum. Their planar structures were unambiguously determined via extensive spectroscopic analysis. Their relative and absolute configurations were confirmed through calculated internuclear distance, coupling constant, ¹³C NMR with DP4+ analysis and electronic circular dichroism (ECD). Furthermore, the molecular docking-based method was used to evaluate their interaction with formyl peptide receptor 2 (FPR2) associated with inflammation. Interestingly, (±)-applandimeric acid D (4) can bond with FPR2 by some key hydrogen bonds. Furthermore, an in vitro bioassay verified that 4 can inhibit the expression of FPR2 with IC50 value of 7.93 μM. In addition, compared to the positive control LiCl (20 mM), 4 showed comparable anti-lipogenesis activity at the concentration of 20 μM. Meanwhile, 4 can suppress the protein levels of peroxisome proliferators-activated receptor-γ (PPAR-γ), CCAAT/enhancer-binding protein-β (C/EBP-β), adipocyte fatty acid-binding protein 4 (FABP4), and fatty acid synthase (FAS) through activating AMP-activated protein kinase (AMPK) signaling pathway. Thus, our findings indicate that compound 4 could be a lead compound to treat obesity and obesity-related diseases by inhibiting lipid accumulation in adipocyte and alleviating inflammation.
Previously, we have demonstrated the antiadipogenic benefits of Ganoderma triterpenoids (GTs), which indicated GTs have potential therapeutic implications for obesity. In this study, the EtOAc extract of Ganoderma applanatum was further phytochemically investigated for searching new antiadipogenic agents, which led to the isolation of a total of 15 highly oxygenated lanostane triterpenoids, including 9 new compounds (1−9) and 6 known analogues (10−15). Structurally, ganodapplanoic acids A and B (1, 2) are two rearranged 6/6/5/6-fused lanostane-type triterpenoids with an unusual C-13/C-15 oxygen bridge moiety. In addition, the EtOAc extract (GAE) and isolates (1−4,6−15) were assayed for their antiadipogenic effects in 3T3-L1 adipocytes. The results revealed that compound 9 effectively repressed adipogenesis through down-regulating the expression of major proteins (PPARγ, CEBPβ and FAS) involving differentiation and adipogenesis in 3T3-L1 adipocytes. Thus, the present study further demonstrated the antiadipogenic potential of GTs and provided a possible perspective for obesity treatment.
Ganoderma triterpenoids (GTs), a class of major active constituents in Ganoderma species, play an important role in the anti-obesity effect of Ganoderma fungi. In the study, seventeen new highly oxygenated lanostane triterpenoids, ganoapplanoids A-Q (1-17), together with five previously reported compounds (18-22), were isolated from the fruiting bodies of Ganoderma applanatum. Their structures were confirmed by comprehensive spectroscopic analyses, single-crystal X-ray diffraction and Mo2(OAc)4 induced CD cotton effect. Structurally, compound 6 represents the first example of 2-norlanostane triterpenoid possessing an unusual semiacetal moiety. Furthermore, isolates (1-5, 7-11, 13-22, 3a) were evaluated for regulatory effects on lipid accumulation by 3T3-L1 adipocytes model. Among them, compounds 11 and 17 exhibited significant potency in blunted adipogenesis activities dose-dependently. Meanwhile, compounds 11 and 17 reduced triglyceride (TG) and total cholesterol (TC) levels in the adipocytes. These results supported that the highly oxygenated lanostane triterpenoids from G. applanatum may serve as agents for inhibiting the lipid accumulation in adipocytes and the G. applanatum provided an important source for searching new drugs to treat obesity.
Background:
Obesity occurs when the body's energy intake is constantly greater than its energy consumption and the pharmacological enhancing the activity of brown adipose tissue (BAT) and (or) browning of white adipose tissue (WAT) has been considered promising strategies to treat obesity.
Methods:
In this study, we took a multi-pronged approach to screen UCP1 activators, including in silico predictions, in vitro assays, as well as in vivo experiments.
Results:
Base on Connectivity MAP (CMAP) screening, we obtained multiple drugs that possess a remarkably correlating gene expression pattern to that of enhancing activity in BAT and (or) sWAT signature. Particularly, we focused on a previously unreported drug-indirubin, a compound obtained from the Indigo plant, which is now mainly used for the treatment of chronic myelogenous leukemia (CML). In the current study, our results shown that indirubin could enhance the BAT activity, as evidenced by up-regulated Ucp1 expression and enhanced mitochondrial respiratory function in vitro cellular model. Furthermore, indirubin treatment restrained high-fat diet (HFD)-induced body weight gain, improved glucose homeostasis and ameliorated hepatic steatosis which were associated with the increase of energy expenditure in the mice model. Moreover, we revealed that indirubin treatment increased BAT activity by promoting thermogenesis and mitochondrial biogenesis in BAT and induced browning of subcutaneous inguinal white adipose tissue (sWAT) of mice under HFD. Besides, our results indicated that indirubin induced UCP1 expression in brown adipocytes, at least in part, via activation of PKA and p38MAPK signaling pathways.
Conclusions:
Our results clearly show that as an effective BAT (as well as beige cells) activator, indirubin may have a protective effect on the prevention and treatment of obesity and its complications.
Pu-erh tea has been extensively reported to possess lipid lowering effects but the underlying mechanisms remained unclear. Free fatty acids (FFAs) are generally correlated with the development of obesity, leading to increased risk for type 2 diabetes mellitus and cardiovascular diseases. To investigate whether Pu-erh tea treatment alters FA metabolism, we treated HFD induced obese mice with Pu-erh tea for 22 weeks and analyzed FFA profiles of experimental mice using a UPLC-QTOF-MS platform. Results showed remarkable changes in metabolic phenotypes and FFA compositions in mice treated with or without Pu-erh tea. HFD induced a marked obese phenotype in mice as revealed by significantly increased body weight, liver and adipose tissue weight, lipid levels in serum and liver, and these parameters were markedly reduced by Pu-erh tea treatment. Several FFA or FFA ratios, such as DGLA, palmitoleic acid, and OA/SA ratio, were significantly increased while the levels of SA/PA and AA/DGLA were significantly reduced in HFD-induced obese mice. Interestingly, these differential FFAs or FFA ratios were previous identified as key markers in human obese subjects, and their changes observed in the HFD group were reversed by Pu-erh tea treatment. Moreover, a panel of FFA markers including C20:3 n6/C18:3 n6 and C20:3 n6/C20:2 n6, C18:3 n6/C18:2 n6, C18:3 n3/C18:2 n6 and C24:1 n9/C22:1 n9, which were previously identified as biomarkers in predicting the remission of obesity and diabetes in human subjects who underwent metabolic surgery procedures, were reversed by Pu-erh tea intervention. Pu-erh tea significantly improved glucose homeostasis and insulin tolerance compared to the HFD group. Additionally, Pu-erh tea treatment significantly decreased FFA synthesis genes and increased the expression of genes involved in FFA uptake and β-oxidation including FATP2, FATP5, PPARα, CPT1α, and ACOX-1. These finding confirmed the beneficial effects of Pu-erh tea on regulating lipid and glucose metabolism, and further validated a panel of FFA markers with diagnostic and prognostic value for obesity and diabetes.
Adipose tissue possesses the remarkable capacity to control its size and function in response to a variety of internal and external cues, such as nutritional status and temperature. The regulatory circuits of fuel storage and oxidation in white adipocytes and thermogenic adipocytes (brown and beige adipocytes) play a central role in systemic energy homeostasis, whereas dysregulation of the pathways is closely associated with metabolic disorders and adipose tissue malfunction, including obesity, insulin resistance, chronic inflammation, mitochondrial dysfunction, and fibrosis. Recent studies have uncovered new regulatory elements that control the above parameters and provide new mechanistic opportunities to reprogram fat cell fate and function. In this Review, we provide an overview of the current understanding of adipocyte metabolism in physiology and disease and also discuss possible strategies to alter fuel utilization in fat cells to improve metabolic health.
Understanding the molecular mechanisms regulating beige adipocyte formation may lead to the development of new therapies to combat obesity. Here, we report a miRNA-based autocrine regulatory pathway that controls differentiation of preadipocytes into beige adipocytes. We identify miR-327 as one of the most downregulated miRNAs targeting growth factors in the stromal-vascular fraction (SVF) under conditions that promote white adipose tissue (WAT) browning in mice. Gain- and loss-of-function experiments reveal that miR-327 targets FGF10 to prevent beige adipocyte differentiation. Pharmacological and physiological β-adrenergic stimulation upregulates FGF10 levels and promotes preadipocyte differentiation into beige adipocytes. In vivo local delivery of miR-327 to WATs significantly compromises the beige phenotype and thermogenesis. Contrarily, systemic inhibition of miR-327 in mice induces browning and increases whole-body metabolic rate under thermoneutral conditions. Our data provide mechanistic insight into an autocrine regulatory signaling loop that regulates beige adipocyte formation and suggests that the miR-327-FGF10-FGFR2 signaling axis may be a therapeutic targets for treatment of obesity and metabolic diseases.
Purpose of review:
New treatment approaches to weight loss and weight loss maintenance in humans are critical. Given its potential role in stimulating energy expenditure, brown adipose tissue (BAT) activation has become a trending topic as an anti-obesity treatment.
Recent findings:
Most studies on BAT stimulation have been conducted in rodents and used cold stimulation. To date, few human trials exist that tested the effect of cold exposure on BAT. Those studies show that BAT contributes a small amount to overall energy metabolism which is unlikely to cause weight loss. Nonetheless, improvements in glucose metabolism have been demonstrated in humans. While new pharmacological approaches demonstrate some contribution of BAT to overall energy expenditure, the potential cardiovascular risk (increased heart rate and blood pressure to sustain the extra energy expenditure) may preclude their use. There is no convincing evidence yet to indicate that BAT may be a viable pharmaceutical target for body weight loss or even weight loss maintenance. More research is needed to confirm the relevance of BAT and beige tissue to whole-body energy metabolism in humans.
Purpose:
Myricetin, a dietary flavonoid, is effective in the treatment of obesity and insulin resistance by increasing glucose transport and lipogenesis in adipocyte and diminishing systemic inflammation in obesity. However, it has not been revealed yet whether myricetin is associated with brown adipose tissue (BAT) activation that tightly mediates systemic energy metabolism. Therefore, this study assessed whether myricetin activated brown adipose tissue in db/db mouse.
Methods:
Myricetin (400 mg/kg) in distilled water was fed daily by oral gavage to leptin receptor-deficient db/db male mice at 4 weeks of age for 14 weeks. Body weight change, glucose intolerance test, blood lipid profile and BAT activation using PET-CT were assessed.
Results:
After myricetin treatment for 14 weeks, systemic insulin resistance and hepatic steatosis were significantly improved in db/db mice with body weight reduction and myricetin led to decreased adipocity, improved plasma lipid profiles and increased energy expenditure. Myricetin activated BAT by upregulating thermogenic protein expression and activating mitochondrial biogenesis, eventually increasing heat dissipation in skin after cold exposure. In iWAT, myricetin induced beige formation, increased thermogenic protein expression and activated mitochondrial biogenesis. Consistently, thermogenic gene expression was upregulated when myricetin was introduced in C3H10T1/2 cells during brown adipocytes differentiation. Moreover, the expression level of adiponectin was significantly increased in C3H10T1/2 cells, adipose tissues and plasma after myricetin treatment.
Conclusions:
These results highlight that myricetin prevents obesity and systemic insulin resistance by activating BAT and increasing adiponectin expression in BAT.
Mitochondrial homeostasis is regulated by a balance between mitochondrial biogenesis and degradation. Emerging evidence suggests that mitophagy, a selective form of autophagy that degrades mitochondria, plays a key role in the physiology and pathophysiology of mitochondria-enriched cells, such as brown and beige adipocytes. This review discusses findings regarding the roles of autophagy and mitophagy in cellular development, maintenance, and functions of metabolic organs, including adipose tissue, liver, and pancreas. A better understanding of the molecular links between mitophagy and energy metabolism will help to identify promising targets for the treatment of obesity and obesity-associated disorders.
Although ginseng has been shown to have an anti-obesity effect, anti-obesity-related mechanisms are complex and have not been completely elucidated. In the present study, we evaluated ginseng’s effects on food intake, the digestion and absorption systems, as well as liver, adipose tissue, and skeletal muscle in order to identify the mechanisms involved. A review of previous in vitro and in vivo studies revealed that ginseng and ginsenosides can increase energy expenditure by stimulating the adenosine monophosphate-activated kinase pathway and can reduce energy intake. Moreover, in high fat diet-induced obese and diabetic subjects, ginseng has shown a two-way adjustment effect on adipogenesis. Nevertheless, most of the previous studies into anti-obesity effects of ginseng have been animal based, and there is a paucity of evidence supporting the suggestion that ginseng can exert an anti-obesity effect in humans.
Obesity is regulated by genetic, endocrine, metabolic, neurological, pharmacological, environmental, and nutritional factors. [...].
Obesity and its associated metabolic syndrome continue to be a health epidemic in westernized societies and is catching up in the developing world. Despite such increases, little headway has been made to reverse adverse weight gain in the global population. Few medical options exist for the treatment of obesity which points to the necessity for exploration of anti-obesity therapies including pharmaceutical and nutraceutical compounds. Defects in brown adipose tissue, a major energy dissipating organ, has been identified in the obese and is hypothesized to contribute to the overall metabolic deficit observed in obesity. Not surprisingly, considerable attention has been placed on the discovery of methods to activate brown adipose tissue. A variety of plant-derived, natural compounds have shown promise to regulate brown adipose tissue activity and enhance the lipolytic and catabolic potential of white adipose tissue. Through activation of the sympathetic nervous system, thyroid hormone signaling, and transcriptional regulation of metabolism, natural compounds such as capsaicin and resveratrol may provide a relatively safe and effective option to upregulate energy expenditure. Through utilizing the energy dissipating potential of such nutraceutical compounds, the possibility exists to provide a therapeutic solution to correct the energy imbalance that underlines obesity.
Increasing energy expenditure through activation of brown adipose tissue (BAT) is a critical approach to treating obesity and diabetes. In this study, rutin, a natural compound extracted frommulberry and a drug used as a capillary stabilizer clinically formany yearswithout any side effects, regulated whole-body energymetabolism by enhancing BAT activity. Rutin treatment significantly reduced adiposity, increased energy expenditure, and improved glucose homeostasis in both genetically obese (Db/Db) and diet-induced obesity (DIO) mice. Rutin also induced brown-like adipocyte (beige) formation in subcutaneous adipose tissue in both obesity mouse models. Mechanistically, we found that rutin directly bound to and stabilized SIRT1, leading to hypoacetylation of peroxisome proliferator-activated receptor g coactivator-1a protein, which stimulated Tfam transactivation and eventually augmented the number of mitochondria and UCP1 activity in BAT. These findings reveal that rutin is a novel small molecule that activates BAT and may provide a novel therapeutic approach to the treatment of metabolic disorders.-Yuan, X.,Wei, G., You, Y.,Huang, Y., Lee,H. J.,Dong,M., Lin, J.,Hu, T., Zhang,H.,Zhang,C.,Zhou,H., Ye, R., Qi, X., Zhai, B., Huang, W., Liu, S., Xie, W., Liu, Q., Liu, X., Cui, C., Li, D., Zhan, J., Cheng, J., Yuan, Z., Jin, W. Rutin ameliorates obesity through brown fat activation. FASEB J. 31, 333-345 (2017). www.fasebj.org.
Our understanding of adipose tissue biology has progressed rapidly since the turn of the century. White adipose tissue has emerged as a key determinant of healthy metabolism and metabolic dysfunction. This realization is paralleled only by the confirmation that adult humans have heat-dissipating brown adipose tissue, an important contributor to energy balance and a possible therapeutic target for the treatment of metabolic disease. We propose that the development of successful strategies to target brown and white adipose tissues will depend on investigations that elucidate their developmental origins and cell-type-specific functional regulators.
The imbalance between energy intake and expenditure is the underlying cause of the current obesity and diabetes pandemics. Central to these pathologies is the fat depot: white adipose tissue (WAT) stores excess calories, and brown adipose tissue (BAT) consumes fuel for thermogenesis using tissue-specific uncoupling protein 1 (UCP1). BAT was once thought to have a functional role in rodents and human infants only, but it has been recently shown that in response to mild cold exposure, adult human BAT consumes more glucose per gram than any other tissue. In addition to this nonshivering thermogenesis, human BAT may also combat weight gain by becoming more active in the setting of increased whole-body energy intake. This phenomenon of BAT-mediated diet-induced thermogenesis has been observed in rodents and suggests that activation of human BAT could be used as a safe treatment for obesity and metabolic dysregulation. In this study, we isolated anatomically defined neck fat from adult human volunteers and compared its gene expression, differentiation capacity and basal oxygen consumption to different mouse adipose depots. Although the properties of human neck fat vary substantially between individuals, some human samples share many similarities with classical, also called constitutive, rodent BAT.
For centuries, mushrooms have been appreciated as sources of food nutrients and pharmacologically important compounds useful in medicine. Yet not all the medicinal properties of mushrooms have been exploited. The above statement is more pertinent to mushrooms that are indigenous to Nigeria. There are inadequate data on the identity and medicinal properties of these wild mushrooms. Information on the ethnomedicinal uses of some mushrooms such as Pleurotus tuber-regium used for headache, stomach pain fever, cold, constipation; Lentinus squarullosus for mumps, heart diseases; Termitomyces microcarpus for gonorrhea; Calvatia cyathiformis for leucorrhea, barreness; Ganoderma lucidum for treating arthritis, neoplasia; G. resinaceum used for hyperglycemia, liver diseases (hepatoprotector); G. applanatum used as antioxidant and for diabetes had been gathered through survey. The above information is mostly obtained from traditional herbalists who in most cases will not disclose their preparation compositions. A lot of these mushrooms are obtained only in the wild. Scientific documents of the identities and medicinal properties are still scanty. Preliminary studies on some species of Temitomyces, Lenzites and Lentinus species showed that they possess appreciable antimicrobial and antioxidant properties. Moreover, molecular characterization also reveals that they are not 100% homologous with existing sequences under the same name in GenBank. It is therefore pertinent that well structured studies on their ecology, identification and medicinal uses be carried out. This will make the full exploitation of the medicinal potentials of mushrooms indigenous to Nigeria realizable.
White and brown adipocytes are believed to occupy different sites in the body. We studied the anatomical features and quantitative histology of the fat depots in obesity and type 2 diabetes-prone C57BL/6J mice acclimated to warm or cold temperatures. Most of the fat tissue was contained in depots with discrete anatomical features, and most depots contained both white and brown adipocytes. Quantitative analysis showed that cold acclimation induced an increase in brown adipocytes and an almost equal reduction in white adipocytes; however, there were no significant differences in total adipocyte count or any signs of apoptosis or mitosis, in line with the hypothesis of the direct transformation of white into brown adipocytes. The brown adipocyte increase was accompanied by enhanced density of noradrenergic parenchymal nerve fibers, with a significant correlation between the density of these fibers and the number of brown adipocytes. Comparison with data from obesity-resistant Sv129 mice disclosed a significantly different brown adipocyte content in C57BL/6J mice, suggesting that this feature could underpin the propensity of the latter strain to develop obesity. However, the greater C57BL/6J browning capacity can hopefully be harnessed to curb obesity and type 2 diabetes in patients with constitutively low amounts of brown adipose tissue.
Obesity is a health hazard which is closely associated with various complications including insulin resistance, hypertension, dyslipidemia, atherosclerosis, type 2 diabetes and cancer. In spite of numerous preclinical and clinical interventions, the prevalence of obesity and its related disorders are on the rise demanding an urgent need for exploring novel therapeutic agents that can regulate adipogenesis. In the present study, we evaluated whether a dietary supplement ReishiMax (RM), containing triterpenes and polysaccharides extracted from medicinal mushroom Ganoderma lucidum, affects adipocyte differentiation and glucose uptake in 3T3-L1 cells.
3T3-L1 pre-adipocytes were differentiated into adipocytes and treated with RM (0-300 μg/ml). Adipocyte differentiation/lipid uptake was evaluated by oil red O staining and triglyceride and glycerol concentrations were determined. Gene expression was evaluated by semi-quantitative RT-PCR and Western blot analysis. Glucose uptake was determined with [³H]-glucose.
RM inhibited adipocyte differentiation through the suppresion of expression of adipogenic transcription factors peroxisome proliferator-activated receptor-γ (PPAR-γ), sterol regulatory element binding element protein-1c (SREBP-1c) and CCAAT/enhancer binding protein-α (C/EBP-α). RM also suppressed expression of enzymes and proteins responsible for lipid synthesis, transport and storage: fatty acid synthase (FAS), acyl-CoA synthetase-1 (ACS1), fatty acid binding protein-4 (FABP4), fatty acid transport protein-1 (FATP1) and perilipin. RM induced AMP-activated protein kinase (AMPK) and increased glucose uptake by adipocytes.
Our study suggests that RM can control adipocyte differentiation and glucose uptake. The health benefits of ReishiMax warrant further clinical studies.
Obesity is now so common within the world's population that it is beginning to replace undernutrition and infectious diseases as the most significant contributor to ill health. In particular, obesity is associated with diabetes mellitus, coronary heart disease, certain forms of cancer, and sleep-breathing disorders. Obesity is defined by a body-mass index (weight divided by square of the height) of 30 kg m(-2) or greater, but this does not take into account the morbidity and mortality associated with more modest degrees of overweight, nor the detrimental effect of intra-abdominal fat. The global epidemic of obesity results from a combination of genetic susceptibility, increased availability of high-energy foods and decreased requirement for physical activity in modern society. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals, but an epidemic that threatens global well being.
Adaptive nonshivering thermogenesis may have profound effects on energy balance and is therefore therefore is a potential mechanism for counteracting the development of obesity. The molecular basis for adaptive nonshivering thermogenesis has remained a challenge that sparked acute interest with the identification of proteins (UCP2, UCP3, etc.) with high-sequence similarity to the original uncoupling protein-1 (UCP1), which is localized only in brown adipose tissue. Using UCP1-ablated mice, we examined whether any adaptive nonshivering thermogenesis could be recruited by acclimation to cold. Remarkably, by successive acclimation, the UCP1-ablated mice could be made to subsist for several weeks at 4C during which they had to constantly produce heat at four times their resting levels. Despite these extreme requirements for adaptive nonshivering thermogenesis, however, no substitution of shivering by any adaptive nonshivering thermogenic process occurred. Thus, although the existence of, for example, muscular mechanisms for adaptive nonshivering thermogenesis has recurrently been implied, we did not find any indication of such thermogenesis. Not even during prolonged and enhanced demand for extra heat production was any endogenous hormone or neurotransmitter able to recruit any UCP1-independent adaptive nonshivering thermogenic process in muscle or in any other organ, and no proteins other than UCP1-not even UCP2 or UCP3-therefore have the ability to mediate adaptive nonshivering thermogenesis in the cold.
gACRP30, the globular subunit of adipocyte complement-related protein of 30 kDa (ACRP30), improves insulin sensitivity and increases fatty acid oxidation. The mechanism by which gACRP30 exerts these effects is unknown. Here, we examined if gACRP30 activates AMP-activated protein kinase (AMPK), an enzyme that has been shown to increase muscle fatty acid oxidation and insulin sensitivity. Incubation of rat extensor digitorum longus (EDL), a predominantly fast twitch muscle, with gACRP30 (2.5 micro g/ml) for 30 min led to 2-fold increases in AMPK activity and phosphorylation of both AMPK on Thr-172 and acetyl CoA carboxylase (ACC) on Ser-79. Accordingly, concentration of malonyl CoA was diminished by 30%. In addition, gACRP30 caused a 1.5-fold increase in 2-deoxyglucose uptake. Similar changes in malonyl CoA and ACC were observed in soleus muscle incubated with gACRP30 (2.5 micro g/ml), although no significant changes in AMPK activity or 2-deoxyglucose uptake were detected. When EDL was incubated with full-length hexameric ACRP30 (10 micro g/ml), AMPK activity and ACC phosphorylation were not altered. Administration of gACRP30 (75 micro g) to C57 BL6J mice in vivo led to increased AMPK activity and ACC phosphorylation and decreased malonyl CoA concentration in gastrocnemius muscle within 15-30 min. Both in vivo and in vitro, activation of AMPK was the first effect of gACRP30 and was transient, whereas alterations in malonyl CoA and ACC occurred later and were more sustained. Thus, gACRP30 most likely exerts its actions on muscle fatty acid oxidation by inactivating ACC via activation of AMPK and perhaps other signal transduction proteins.
Brown fat cells are specialized to dissipate energy and can counteract obesity; however, the transcriptional basis of their determination is largely unknown. We show here that the zinc-finger protein PRDM16 is highly enriched in brown fat cells compared to white fat cells. When expressed in white fat cell progenitors, PRDM16 activates a robust brown fat phenotype including induction of PGC-1alpha, UCP1, and type 2 deiodinase (Dio2) expression and a remarkable increase in uncoupled respiration. Transgenic expression of PRDM16 at physiological levels in white fat depots stimulates the formation of brown fat cells. Depletion of PRDM16 through shRNA expression in brown fat cells causes a near total loss of the brown characteristics. PRDM16 activates brown fat cell identity at least in part by simultaneously activating PGC-1alpha and PGC-1beta through direct protein binding. These data indicate that PRDM16 can control the determination of brown fat fate.
Mitochondrial dysfunction has been associated with the pathogenesis of a variety of neurodegenerative diseases. Sitagliptin is a dipeptidyl‐peptidase‐4 (DPP‐4) inhibitor that has been approved for the treatment of type 2 diabetes (T2DM). In the current study, we report that sitagliptin increased the expression of PGC‐1α, NRF1, and TFAM in human SH‐SY5Y neuronal cells. Notably, our data indicate that sitagliptin promoted mitochondrial biogenesis by increasing the amount of mtDNA, the levels of mitochondria‐related genes such as TOMM20, TOMM40, TIMM9, NDUFS3, ATP5C1, and the expression of oxidative phosphorylation subunits complex I and complex IV. Additionally, we found that sitagliptin induced a “gain of mitochondrial function” in SH‐SY5Y cells by increasing the mitochondrial respiratory rate and adenosine triphosphate (ATP) production. Significantly, our results demonstrate that sitagliptin activated the transcriptional factor CREB by inducing its phosphorylation at Ser133. Inhibition of CREB using its specific inhibitor H89 abolished the effects of sitagliptin on the expression of PGC‐1α, NRF1, and TFAM, as well as an increase in mtDNA amount and ATP production. These findings suggest that sitagliptin could become a potential agent for the treatment of neurological disorders.
Ganoderma is classified as a top‐grade traditional Chinese medicine for promoting human health by regulating “vital energy”. Its potency towards metabolism and energy homeostasis, particularly, the metabolic adaptations of adipocytes, needs to be re‐evaluated through an evidence‐based study. Here, the triterpenoid‐rich Ganoderma tsugae ethanol extract (GTEE) is found to contribute towards adipogenesis accompanied with elevated intracellular lipid metabolic flux. Additionally, proteomic profiling revealed that GTEE‐upregulates mitochondrial remodeling and chemical energy redox modifications, which display UCP1‐positive browning fat‐selective features and a NADH‐mediated adaptive mechanism. GTEE‐treatment of mice with diet‐induced obesity results in the amelioration of white adipocyte hypertrophy and the appearance of UCP1‐positive browning adipocytes. Our novel findings unravel that GTEE could promote intracellular metabolic flexibility and plasticity followed by the induction of adipocyte browning. This article is protected by copyright. All rights reserved.
Eighteen previously undescribed lanostane triterpenes and thirty known analogues were obtained from the fruiting bodies of Ganoderma resinaceum. Resinacein C was isolated from a natural source for the first time. The structures of all the above compounds were elucidated by extensive spectroscopic analysis and comparisons of their spectroscopic data with those reported in the literature. Furthermore, in an in vitro assay, Resinacein C, ganoderic acid Y, lucialdehyde C, 7-oxo-ganoderic acid Z3, 7-oxo-ganoderic acid Z, and lucidadiol showed strong inhibitory effects against α-glucosidase compared with the positive control drug acarbose. The structure-activity relationships of ganoderma triterpenes on α-glucosidase inhibition showed that the C-24/C-25 double bond is necessary for α-glucosidase inhibitory activity. Moreover, the carboxylic acid group at C-26 and the hydroxy group at C-15 play important roles in enhancing inhibitory effects of these triterpenes.
Working with isolated mitochondria is the gold standard approach to investigate the function of the electron transport chain in tissues, free from the influence of other cellular factors. In this chapter, we outline a detailed protocol to measure the rate of oxygen consumption (OCR) with the high-throughput analyzer Seahorse XF96. More importantly, this protocol wants to provide practical tips for handling many different samples at once, and take a real advantage of using a high-throughput system. As a proof of concept, we have isolated mitochondria from brain, heart, liver, muscle, kidney, and lung of a wild-type mouse, and measured basal respiration (State II), ADP-stimulated respiration (State III), non-ADP-stimulated respiration (State IVo), and FCCP-stimulated respiration (State IIIu) using respiratory substrates specific to the respiratory chain complex I (RCCI) and complex II (RCCII). Mitochondrial purification and Seahorse runs were performed in less than eight working hours.
The structures of eight novel triterpenoids, ganoderiol C (1), D (2), E (3), F (4), G (5), H (6), I (7), and ganolucidic acid E (8), isolated from the fruiting body of Ganoderma lucidum were determined by spectroscopic methods. In addition, the absolute configuration at C-23 of ganolucidic acid D (9) was determined from the CD spectrum of its p-imethylaminobenzoate derivative. © 1988, Japan Society for Bioscience, Biotechnology, and Agrochemistry. All rights reserved.
Five new lanostane-type triterpenoids, ganoderenses A − E (1 − 5), two new lanostane nor-triterpenoids, ganoderenses F and G (6 and 7), along with 13 known analogues (8 − 20) were isolated from the fruiting body of Ganoderma hainanense. Their structures were determined by combined chemical and spectral methods, and the absolute configurations of compounds 1 and 13 were confirmed by single crystal X-ray diffraction. All compounds were evaluated for inhibitory activity against thioredoxin reductase (TrxR), a potential target for cancer chemotherapy with redox balance and antioxidant functions, but were inactive.
The structures of eight novel triterpenoids, ganoderiol C (1), D (2), E (3), F (4), G (5), H (6), I (7), and ganolucidic acid E (8), isolated from the fruiting body of Ganoderma lucidum were determined by spectroscopic methods. In addition, the absolute configuration at C-23 of ganolucidic acid D (9) was determined from the CD spectrum of its p-dimethylaminobenzoate derivative.
Obesity and diabetes mellitus have reached epidemic proportions in the past few years. During 2011 to 2012, more than one-third of the US population was obese. Although recent trend data indicate that the epidemic has leveled off, prevalence of abdominal obesity continues to rise, especially among adults. As seen for obesity, the past few decades have seen a doubling of the diabetes mellitus incidence with an increasing number of type 2 diabetes mellitus cases being diagnosed in children. Significant racial and ethnic disparities exist in the prevalence and trends of obesity and diabetes mellitus. In general, in both adults and children, non-Hispanic blacks and Mexican Americans seem to be at a high risk than their non-Hispanic white counterparts. Secular changes in agricultural policies, diet, food environment, physical activity, and sleep have all contributed to the upward trends in the diabesity epidemic. Despite marginal improvements in physical activity and the US diet, the food environment has changed drastically to an obesogenic one with increased portion sizes and limited access to healthy food choices especially for disadvantaged populations. Interventions that improve the food environment are critical as both obesity and diabetes mellitus raise the risk of cardiovascular disease by ≈2-fold. Among those with type 2 diabetes mellitus, significant sex differences occur in the risk of cardiovascular disease such that diabetes mellitus completely eliminates or attenuates the advantages of being female. Given the substantial burden of obesity and diabetes mellitus, future research efforts should adopt a translational approach to find sustainable and holistic solutions in preventing these costly diseases.
Obesity is a disease that has historically eluded effective medical therapy. Prior to 2012, phentermine and orlistat were the only medications available to treat obesity in the USA, with phentermine approved only for short-term use. However, as of 2015, the repertoire of pharmacological agents available to treat obesity has greatly expanded to include four new drugs: lorcaserin, phentermine/topiramate extended release (ER), naltrexone ER/wellbutrin ER and liraglutide. Each has a unique mechanism of action and all are intended for long-term use. These newer medications share a common strategy to promote weight loss in that they are designed to manipulate the control of hunger and satiety in the central nervous system. Interestingly, the majority of these new agents are combinations of older medications that have been used for conditions other than obesity. The amount of weight loss seen with these agents beyond placebo varies but generally falls in the range of 3-10% of starting weight and requires continual use of the drug in order for weight loss to be sustained. In addition, each drug has a unique side effect profile that should be carefully considered when selecting the best agent for a given individual. This article provides a review of these recently approved medications focusing on efficacy, side effect profiles and appropriate application to the individual patient.
The results of both prevention and reversal studies lead to the conclusion that transplanted BAT has a pivotal role in improving whole-organism energy expenditure and energy balance. The results presented in this study may also provide a basis for the development of novel treatment options for both obesity and diabetes.
One of the most promising areas in the therapeutics for metabolic diseases centers around activation of the pathways of energy expenditure. Brown adipose tissue is a particularly appealing target for increasing energy expenditure, given its amazing capacity to transform chemical energy into heat. In addition to classical brown adipose tissue, the last few years have seen great advances in our understanding of inducible thermogenic adipose tissue, also referred to as beige fat. A deeper understanding of the molecular processes involved in the development and function of these cell types may lead to new therapeutics for obesity, diabetes, and other metabolic diseases.
The first synthesis of ganodermanontriol, a bioactive lanostane triterpene from the medicinal mushroom Ganoderma lucidum, has been achieved in 15.3% yield over nine steps, along with its three stereoisomeric triols and ganoderol A. The key steps leading to this family of isomers involve the reconstruction of the trisubstituted alkene by stereoselective and chemoselective phosphonate reactions and the formation of the unusual Δ7,9(11)-diene core by the mild acidic opening of a lanosterone-derived epoxide. Ganodermanontriol showed promising activity on the inhibition and proliferation of breast cancer cells. The effect of ganodermanontriol and its isomers on cell proliferation was assayed; IC50 values of 5.8 and 9.7 μM on breast cancer cell lines MCF-7 and MDA-MB-231, respectively, were found for ganodermanontriol.
Adaptive thermogenesis is an important component of energy homeostasis and a metabolic defense against obesity. We have cloned a novel transcriptional coactivator of nuclear receptors, termed PGC-1, from a brown fat cDNA library. PGC-1 mRNA expression is dramatically elevated upon cold exposure of mice in both brown fat and skeletal muscle, key thermogenic tissues. PGC-1 greatly increases the transcriptional activity of PPARgamma and the thyroid hormone receptor on the uncoupling protein (UCP-1) promoter. Ectopic expression of PGC-1 in white adipose cells activates expression of UCP-1 and key mitochondrial enzymes of the respiratory chain, and increases the cellular content of mitochondrial DNA. These results indicate that PGC-1 plays a key role in linking nuclear receptors to the transcriptional program of adaptive thermogenesis.
Several lanostane triterpenes [butyl ganoderate A (1), butyl ganoderate B (2), butyl lucidenate N (3), and butyl lucidenate A (4)] bearing a butyl ester side chain from the fruiting bodies of Ganoderma lucidum exhibited considerable inhibitory effects on adipogenesis in 3T3-L1 cells. The inhibitory mechanism of 1 and 3 on adipogenesis in 3T3-L1 cells was investigated; we found that the mRNA and protein expression levels of SREBP-1c were reduced by treatment with 1 and 3 versus the untreated control. Furthermore, compounds 1 and 3 suppressed the mRNA expression levels of FAS and ACC. These results demonstrate that inhibition of adipogenesis in 3T3-L1 cells by treatment with 1 and 3 may be mediated in part through down-regulation of the adipogenic transcription factor SREBP-1c and its target genes, such as FAS and ACC.
Ganoderma lucidum (G. lucidum), a traditional Chinese medicine, has been used for the treatment of various diseases including cancer and atherosclerosis. In this study, the positive effect of G. lucidum on metabolic syndrome was investigated in more detail by the use of 3T3-L1 pre-adipocyte cells. Treatment of 3T3-L1 cells with G. lucidum extract (GE) significantly promoted adipocyte differentiation and adiponectin production in a dose-dependent manner, as assessed by Oil-Red O staining, quantitative RT-PCR and ELISA. Treatment with GW9662, an inhibitor for peroxisome proliferator-activated receptor-gamma (PPARgamma), significantly attenuated GE-dependent adipocyte differentiation and adiponectin gene expression, suggesting the involvement of PPARgamma. Moreover, a reporter gene assay using GAL4-PPAR fusion proteins revealed that GE enhances GAL4-PPARgamma and GAL4-PPARalpha activities. These results indicate the presence of natural compounds possessing PPARgamma and PPARalpha activating properties in G. lucidum.
Four new lanostane triterpenes, butyl ganoderate A (1), butyl ganoderate B (2), butyl lucidenate N (3), and butyl lucidenate A (4), were isolated from the fruiting bodies of Ganoderma lucidum together with 14 known compounds (5-18). The structures of the new triterpenes were established by extensive spectroscopic studies and chemical evidence. In addition, the inhibitory effect of isolated compounds on adipocyte differentiation in 3T3-L1 cells was examined. © 2010 American Chemical Society and American Society of Pharmacognosy.
Three new lanostanoid triterpenes named 3beta,7beta-di- hydroxy-11,15,23-trioxo-lanost-8,16-dien-26-oic acid (1), 3beta,7beta-dihydroxy-11,15,23-trioxo-lanost-8,16-dien-26-oic acid methyl ester (2), and 12beta-acetoxy-3beta,7beta-dihydroxy-11,15,23-trioxo-lanost-8,16-dien-26-oic acid (3) were isolated from the fruit bodies of Ganoderma lucidum. They all show a Delta(16, 17) double bond unprecedented in such types of lanostanoid triterpenes possessing the side chain at C-17. The complete NMR assignments for these compounds were carried out using (1)H, (13)C, DEPT, COSY, HSQC, HMBC, and ROESY NMR experiments.
Two new lanostane triterpenoids, 3-epipachymic acid (3alpha-acetoxy-16alpha-hydroxy-24-methylene-5alpha-lanost-8-en-21-oic acid, 1) and 3alpha-(3-hydroxy-5-methoxy-3-methyl-1,5-dioxopentyloxy)-24-methylene-5alpha-lanost-8-en-21-oic acid (2), together with a known compound, 3-oxo-5alpha-lanosta-8,24-dien-21-oic acid (3), were isolated from the fruiting body of Ganoderma resinaceum. The structure elucidation was accomplished by spectroscopic methods, especially NMR experiments. Compound 2 showed significant cytotoxic activity with IC(50) value of 2.5 microg/ml in Hep-2 cell line.
The prevalence of obesity, defined as a BMI of > or =30.0 kg/m2, has increased substantially over previous decades to about 20% in industrialized countries, and a further increase is expected in the future. Epidemiological studies have shown that obesity is a risk factor for: post-menopausal breast cancer; cancers of the endometrium, colon and kidney; malignant adenomas of the oesophagus. Obese subjects have an approximately 1.5-3.5-fold increased risk of developing these cancers compared with normal-weight subjects, and it has been estimated that between 15 and 45% of these cancers can be attributed to overweight (BMI 25.0-29.9 kg/m2) and obesity in Europe. More recent studies suggest that obesity may also increase the risk of other types of cancer, including pancreatic, hepatic and gallbladder cancer. The underlying mechanisms for the increased cancer risk as a result of obesity are unclear and may vary by cancer site and also depend on the distribution of body fat. Thus, abdominal obesity as defined by waist circumference or waist:hip ratio has been shown to be more strongly related to certain cancer types than obesity as defined by BMI. Possible mechanisms that relate obesity to cancer risk include insulin resistance and resultant chronic hyperinsulinaemia, increased production of insulin-like growth factors or increased bioavailability of steroid hormones. Recent research also suggests that adipose tissue-derived hormones and cytokines (adipokines), such as leptin, adiponectin and inflammatory markers, may reflect mechanisms linked to tumourigenesis.
Obesity as a medical problem
- Kopelman
- Y Huang
Y. Huang, et al.
Food Research International 136 (2020) 109303