Effect of combined administration of Acyl-CoA: Cholesterol acyltransferase 1 inhibitor and glucagon-like peptide 1 receptor agonist on a rodent model of diet-induced obesity.

A glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide was approved for the treatment of obesity by the Food and Drug Administration. However, it can cause gastrointestinal events at high doses, limiting its broader use. Combining drugs with multiple mechanisms of action could enhance the weight-reducing effects while minimizing side effects. To this end, we investigated the combined effects of semaglutide and avasimibe, an acyl-CoA:cholesterol acyltransferase 1 (ACAT1) inhibitor, on weight reduction in diet-induced obesity mice. Two cohorts of mice were used: In cohort 1, mice were fed a high-fat (HF) diet for 12 weeks and then randomly assigned to the vehicle, avasimibe [10 mg/kg body weight (BW)], semaglutide (0.4 mg/kg BW), or combination groups. The drugs were administered via subcutaneous (sc) injections on a daily basis. In cohort 2, mice were fed an HF diet for 8 weeks and randomly assigned to the same four groups, but avasimibe was administered at a dose of 20 mg/kg BW, and the drugs were administered every 3 days. In cohort 1, semaglutide initially reduced food intake initially, but this effect was diminished with prolonged administration. Avasimibe, on the other hand, did not affect food intake but prevented weight gain to a lesser extent than semaglutide. Importantly, the combination treatment resulted in the greatest percentage of body weight reduction, along with lower plasma glucose and leptin levels compared to the semaglutide single-treatment group. Cohort 2 confirmed that the superior weight loss in the combination group compared to the other three groups was largely due to a significant reduction in fat mass. Histological analysis of inguinal adipose tissue showed smaller adipocyte size across all treatment groups compared to the vehicle group, with no significant differences among the treatment groups. Collectively, these findings suggest combining semaglutide and avasimibe could be an effective approach to weight management.

Canary Seed (Phalaris canariensis L.) Peptides Prevent Obesity and Glucose Intolerance in Mice Fed a Western Diet.

Previous research showed that canary seed (Phalaris canariensis L.) peptides (CSP) possess robust in vitro antiobesity properties via inhibition of pancreatic lipase (PL). Nevertheless, no studies have yet explored their antiobesity properties in vivo. Consequently, we investigated the effects of CSP in C57BL/6J mice under a Western diet (WD). Mice were assigned into groups and fed a normal diet (ND) or a WD accompanied by an oral dose of CSP (250 or 500 mg/kg/day), orlistat (40 mg/kg/day), or distilled water. The results showed that consuming CSP can provide metabolic benefits, including preventing weight gain by up to 20%, increasing glucose tolerance, and reducing insulin, leptin, and LDL/VLDL levels in plasma. Conversely, total ghrelin was unaffected by CSP-500, but decreased by CSP-250, and amplified by orlistat. Surprisingly, CSP-250 was more effective in preventing weight gain and promoting satiety than CSP-500. Parallel to this, protein absorption in CSP-500 was decreased, supported by a rise in fecal crude protein (+3.5%). Similarly, fecal fat was increased by orlistat (38%) and was unaffected by CSP-250 (3.0%) and CSP (3.0%), comparatively to WD (2.5%). Despite this, both CSP treatments were equally effective in decreasing hepatic steatosis and avoiding hyperlipidemia. Furthermore, the enzymatic analysis showed that CSP-PL complexes dissociated faster (15 min) than orlistat-PL complexes (41 min). Lastly, CSP did not affect expression of hepatic lipid oxidation genes ACO and PPAR-α, but reduced the expression of the hydrolase gene LPL, and lipogenesis related genes FAS and ACC. Taken together, these results suggest that CSP antiobesity mechanism relies on lipid metabolism retardation to increase fat transit time and subsequently suppress hunger.

Global landscape of protein complexes in postprandial-state livers from diet-induced obese and lean mice.

Obesity is associated with a spectrum of nonalcoholic fatty liver disease (NAFLD) which is characterized by steatosis. Prolonged fat deposition aggravates liver dysfunctions leading to an advanced form of NAFLD such as steatohepatitis and cirrhosis. As liver function in the postprandial state is critical for macronutrient metabolism and energy homeostasis, we sought to determine the differences in protein complex profiles in lean and fatty livers in the postprandial state. Protein complex profiling is of interest as proteins often do not function alone and the information on the interactions may reveal novel etiology of NAFLD, which is currently limited compared with proteome profiles or RNA-sequencing profiles. To this end, we fractionated liver lysates using size-exclusion chromatography (SEC) and analyzed each fraction using untargeted LC-MS/MS. We identified 1172 proteins that were discovered in lean and fatty livers, and their elution profiles were compared. We found that the majority of liver proteins were present as putative complexes. Also, the fatty liver protein elution profile showed great conservations as lean liver despite the metabolic disease state. Yet, we discovered a few proteins that showed different elution patterns in the fatty liver, including Acadm, Aldh1a7, Aldh1a1, Akr1a1, Eif3l, Fkbp2, G6pdx, Gm20441, Hao1, Pcna, Pkm, Ppif, Prdx4, Stmn1, Tagln, Tubb4b, Ubqln2, and Usp14, which may be involved in high fat diet-induced alterations of protein oligomerization and hepatic functions. Overall, our protein complex profiling could expand our understanding of hepatic abnormalities that cannot be uncovered by simple quantitation of protein expression.

Emergence of Edible Plant-Derived Nanovesicles as Functional Food Components and Nanocarriers for Therapeutics Delivery: Potentials in Human Health and Disease.

Extracellular vesicles (EVs) are a highly heterogeneous population of membranous particles that are secreted by almost all types of cells across different domains of life, including plants. In recent years, studies on plant-derived nanovesicles (PDNVs) showed that they could modulate metabolic reactions of the recipient cells, affecting (patho)physiology with health benefits in a trans-kingdom manner. In addition to its bioactivity, PDNV has advantages over conventional nanocarriers, making its application promising for therapeutics delivery. Here, we discuss the characteristics of PDNV and highlight up-to-date pre-clinical and clinical evidence, focusing on therapeutic application.

Oxidative Stress Protection by Canary Seed (Phalaris canariensis L.) Peptides in Caco-2 Cells and Caenorhabditis elegans.

During oxidative stress, degenerative diseases such as atherosclerosis, Alzheimer's, and certain cancers are likely to develop. Recent research on canary seed (Phalaris canariensis) peptides has demonstrated the high in vitro antioxidant potential. Thus, this study aimed to assess the cellular and in vivo antioxidant capacity of a low-molecular-weight (<3 kDa) canary seed peptide fraction (CSPF) using Caco-2 cells and the Caenorhabditis elegans model. The results show that the CSPF had no cytotoxicity effect on Caco-2 cells at any tested concentration (0.3−2.5 mg/mL). Additionally, the cellular antioxidant activity (CAA) of the CSPF was concentration-dependent, and the highest activity achieved was 80% by the CSPF at 2.5 mg/mL. Similarly, incubation with the CSPF significantly mitigated the acute and chronic oxidative damage, extending the lifespan of the nematodes by 88 and 61%, respectively. Furthermore, it was demonstrated that the CSPF reduced the accumulation of reactive oxygen species (ROS) to safe levels after sub-lethal doses of pro-oxidant paraquat. Quantitative real-time PCR revealed that the CSPF increased the expression of oxidative-stress-response-related gene GST-4. Overall, these results show that the CSPFs relied on GST-4 upregulation and scavenging of free radicals to confer oxidative stress protection and suggest that a CSPF can be used as a natural antioxidant in foods for health applications.

Piceatannol, a Dietary Polyphenol, Alleviates Adipose Tissue Loss in Pre-Clinical Model of Cancer-Associated Cachexia via Lipolysis Inhibition.

Cancer-associated cachexia (CAC) is the nutrition-independent loss of lean muscle and adipose tissues, and results in reduced chemotherapy effectiveness and increased mortality. Preventing adipose loss is considered a key target in the early stages of cachexia. Lipolysis is considered the central driver of adipose loss in CAC. We recently found that piceatannol, but not its analogue resveratrol, exhibits an inhibitory effect on lipolysis. The objective of this study was to investigate the role of piceatannol in cancer-associated lipolysis and cachexia-induced weight loss. Cancer cell-induced lipolysis in adipocytes was stimulated using cancer-conditioned media (CCM) or co-culture with human pancreatic cancer cells and the cachexia-associated cytokines TNF-α and interleukin-6 in 3T3-L1 adipocytes. C26 colon carcinoma-bearing mice were modeled using CAC in vivo. Piceatannol reduced cancer-associated lipolysis by at least 50% in both CCM and cytokine-induced lipolysis in vitro. Further gene and protein analysis confirmed that piceatannol modulated the stability of lipolytic proteins. Moreover, piceatannol protected tumor-bearing mice against weight-loss in early stages of CAC largely through preserving adipose tissue, with no effect on survival. This study demonstrates the use of a dietary compound to preserve adipose in models of early stage CAC and provides groundwork for further investigation of piceatannol or piceatannol-rich foods as alternative medicine in the preservation of body fat mass and future CAC therapy.

Multi-Omics Approach Reveals Dysregulation of Protein Phosphorylation Correlated with Lipid Metabolism in Mouse Non-Alcoholic Fatty Liver.

Obesity caused by overnutrition is a major risk factor for non-alcoholic fatty liver disease (NAFLD). Several lipid intermediates such as fatty acids, glycerophospholipids and sphingolipids are implicated in NAFLD, but detailed characterization of lipids and their functional links to proteome and phosphoproteome remain to be elucidated. To characterize this complex molecular relationship, we used a multi-omics approach by conducting comparative proteomic, phoshoproteomic and lipidomic analyses of high fat (HFD) and low fat (LFD) diet fed mice livers. We quantified 2447 proteins and 1339 phosphoproteins containing 1650 class I phosphosites, of which 669 phosphosites were significantly different between HFD and LFD mice livers. We detected alterations of proteins associated with cellular metabolic processes such as small molecule catabolic process, monocarboxylic acid, long- and medium-chain fatty acid, and ketone body metabolic processes, and peroxisome organization. We observed a significant downregulation of protein phosphorylation in HFD fed mice liver in general. Untargeted lipidomics identified upregulation of triacylglycerols, glycerolipids and ether glycerophosphocholines and downregulation of glycerophospholipids, such as lysoglycerophospholipids, as well as ceramides and acylcarnitines. Analysis of differentially regulated phosphosites revealed phosphorylation dependent deregulation of insulin signaling as well as lipogenic and lipolytic pathways during HFD induced obesity. Thus, this study reveals a molecular connection between decreased protein phosphorylation and lipolysis, as well as lipid-mediated signaling in diet-induced obesity.

Piceatannol antagonizes lipolysis by promoting autophagy-lysosome-dependent degradation of lipolytic protein clusters in adipocytes.

Overly elevated circulating non-esterified fatty acids (NEFAs) is an emerging health concern of obesity-associated energy disorders. However, methods to reduce circulating NEFAs remain elusive. The present study determined the effect of piceatannol, a naturally occurring stilbene, on adipocyte lipolysis and its underlying mechanism. Differentiated 3T3-L1 adipocytes, brown adipocytes and isolated white adipose tissue were treated with various concentrations of piceatannol for 1.5-h both in the basal and stimulated lipolysis conditions. Piceatannol significantly inhibited NEFAs and glycerol release with a concomitant reduction of ATGL, CGI-58 and PLIN1 expression in adipocytes. Using a series of inhibitor assays, piceatannol-induced degradation of these proteins was found to be mediated by upregulation of the autophagy-lysosome pathway. Moreover, we demonstrated that piceatannol is capable of stimulating autophagy in vitro. Importantly, piceatannol administration tended to lower fasting-induced serum glycerol levels in healthy mice. Furthermore, piceatannol administration lowered lipolysis, central adiposity and hyperinsulinemia in diet-induced obese mice. Our study provides profound evidence of a novel inhibitory role of piceatannol in lipolysis through autophagy-lysosome-dependent degradation of the key lipolytic proteins in adipocytes. This study offers a mechanistic foundation for investigating the potential of piceatannol-containing foods in reducing lipolysis and its associated metabolic disorders.

Pharmacological inhibition of acyl-coenzyme A:cholesterol acyltransferase alleviates obesity and insulin resistance in diet-induced obese mice by regulating food intake.

BACKGROUND/OBJECTIVES: Acyl-coenzyme A:cholesterol acyltransferases (ACATs) catalyze the formation of cholesteryl ester (CE) from free cholesterol to regulate intracellular cholesterol homeostasis. Despite the well-documented role of ACATs in hypercholesterolemia and their emerging role in cancer and Alzheimer's disease, the role of ACATs in adipose lipid metabolism and obesity is poorly understood. Herein, we investigated the therapeutic potential of pharmacological inhibition of ACATs in obesity. METHODS: We administrated avasimibe, an ACAT inhibitor, or vehicle to high-fat diet-induced obese (DIO) mice via intraperitoneal injection and evaluated adiposity, food intake, energy expenditure, and glucose homeostasis. Moreover, we examined the effect of avasimibe on the expressions of the genes in adipogenesis, lipogenesis, inflammation and adipose pathology in adipose tissue by real-time PCR. We also performed a pair feeding study to determine the mechanism for body weight lowering effect of avasimibe. RESULTS: Avasimibe treatment markedly decreased body weight, body fat content and food intake with increased energy expenditure in DIO mice. Avasimibe treatment significantly lowered blood levels of glucose and insulin, and improved glucose tolerance in obese mice. The beneficial effects of avasimibe were associated with lower levels of adipocyte-specific genes in adipose tissue and the suppression of food intake. Using a pair-feeding study, we further demonstrated that avasimibe-promoted weight loss is attributed mainly to the reduction of food intake. CONCLUSIONS: These results indicate that avasimibe ameliorates obesity and its-related insulin resistance in DIO mice through, at least in part, suppression of food intake.

Methylglyoxal influences development of Caenorhabditis elegans via lin-41-dependent pathway.

Methylglyoxal is a highly reactive dicarbonyl compound. It can be obtained either endogenously through biological enzymatic/non-enzymatic pathways or exogenously via the uptake of certain foods and beverages, such as Manuka honey. Studies about its biological properties are quite controversial, though the majority reported a positive association between methylglyoxal and certain pathologies. In this report, we tested if methylglyoxal can alter the development of animals using Caenorhabditis elegans as the in vivo model. Treatment of methylglyoxal at 0.1 and 1 mmol/L for 2 days significantly inhibited the development of Caenorhabditis elegans, particularly targeting the transition from L3 stage. Pharyngeal pumping rate, the food intake marker was also significantly reduced by methylglyoxal at both 0.1 and 1 mmol/L. Additionally, treatment of 0.1 mmol/L methylglyoxal increased, while 1 mmol/L methylglyoxal decreased the nematodes' average moving speed. The effect of methylglyoxal on development was in part due to the modulation of lin-41, which encodes a homolog of human TRIM71. The mutation of lin-41 could alleviate or abolish the effects of methylglyoxal on growth rate, body size, pumping rate and locomotive activity. In summary, these results suggested that methylglyoxal influenced the development of Caenorhabditis elegans, which is in part via the lin-41-dependent pathway.

Azelaic Acid Promotes Caenorhabditis elegans Longevity at Low Temperature Via an Increase in Fatty Acid Desaturation.

PURPOSE: Azelaic acid (AzA) is a dicarboxylic acid naturally occurring in various grains having anti-inflammatory and anti-oxidation properties. Recently, AzA is shown to reduce high-fat diet-induced adiposity in animals. However, its physiological role in lipid metabolism and aging in various environmental stresses is unknown. METHODS AND RESULTS: Using C. elegans as an invertebrate animal model, we demonstrate that AzA suppresses fat accumulation with no effect on lifespan at normal temperatures. Moreover, AzA promotes lifespan at low temperatures by elevation of unsaturated long-chain fatty acids and expression of genes in fatty acid desaturation. We further find that genes encoding fatty acid desaturases such as fat-1, fat-5, fat-6, and fat-7 are crucial for the lifespan-extending effect of AzA at low temperature. CONCLUSIONS: Taken together, our results suggest that AzA promotes adaption to low temperature in C. elegans via shifting fatty acid profile to unsaturated long-chain fatty acids.

Transcriptome analysis reveals the genetic basis of skeletal muscle glycolytic potential based on a pig model.

Glycolytic potential (GP) calculated based on glucose, glycogen, glucose-6-phosphate, and lactate contents is a critical factor for multiple meat quality characteristics. However, the genetic basis of glycolytic metabolism is still unclear. In this study, we constructed six RNA-Seq libraries using longissimus dorsi (LD) muscles from pigs divergent for GP phenotypic values and generated the whole genome-wide gene expression profiles. Furthermore, we identified 25,880 known and 220 novel genes from these skeletal muscle libraries, and 222 differentially expressed genes (DEGs) between the higher and lower GP groups. Notably, we found that the Lactate dehydrogenase B (LDHB) and Fructose-2, 6-biphosphatase 3 (PFKFB3) expression levels were higher in the higher GP group than the lower GP group, and positively correlated with GP and lactic acid (LA), and reversely correlated with pH value at 45 min postmortem (pH45min). Besides, LDHB and PFKFB3 expression were positively correlated with drip loss measured at 48 h postmortem (DL48h) and drip loss measured at 24 h postmortem (DL24h). Collectively, we identified a serial of DEGs as the potential key candidate genes affecting GP and found that LDHB and PFKFB3 are closely related to GP and GP-related traits. Our results lay a solid basis for in-depth studies of the regulatory mechanisms on GP and GP-related traits in pigs.

Piceatannol attenuates fat accumulation and oxidative stress in steatosis-induced HepG2 cells.

Non-alcoholic fatty liver disease (NAFLD), which affects over 20% of the adult population, is the most common liver disease worldwide and can progress to inflammatory hepatitis, cirrhosis and liver cancer. The need to alleviate NAFLD is imperative, but there are limited pharmacological therapies available. Based on previous reports that piceatannol, a stilbenoid metabolite of resveratrol, exhibits anti-obesity, antioxidant and anti-inflammatory effects, the goal of this study was to determine the efficacy of piceatannol on prevention and/or treatment of NAFLD. The results showed that piceatannol significantly decreased fat accumulation and suppressed lipogenesis and fatty acids (FAs) uptake by decreasing sterol regulatory element-binding protein 1 (SREBP1) and cluster of differentiation 36 (CD36) in steatosis-induced HepG2 hepatocytes. Piceatannol treatment also promoted FAs ß-oxidation by increasing farnesoid X receptor (FXR), peroxisome proliferator-activated receptor α (PPARα), and carnitine palmitoyltransferase 1α (CPT1α) under steatosis conditions. Moreover, piceatannol significantly suppressed FA-induced oxidative stress and inhibited phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinases 1/2 (ERK1/2). Overall, it is suggested that piceatannol reduced fat accumulation in steatosis-induced HepG2 cells by suppressing lipogenesis (SREBP1 and ACC) and FA uptake (CD36), and promoting FAs oxidation (FXR, PPARα and CPT1α).

Exploring the lncRNAs Related to Skeletal Muscle Fiber Types and Meat Quality Traits in Pigs.

The alteration in skeletal muscle fiber is a critical factor affecting livestock meat quality traits and human metabolic diseases. Long non-coding RNAs (lncRNAs) are a diverse class of non-coding RNAs with a length of more than 200 nucleotides. However, the mechanisms underlying the regulation of lncRNAs in skeletal muscle fibers remain elusive. To understand the genetic basis of lncRNA-regulated skeletal muscle fiber development, we performed a transcriptome analysis to identify the key lncRNAs affecting skeletal muscle fiber and meat quality traits on a pig model. We generated the lncRNA expression profiles of fast-twitch Biceps femoris (Bf) and slow-twitch Soleus (Sol) muscles and identified the differentially expressed (DE) lncRNAs using RNA-seq and performed bioinformatics analyses. This allowed us to identify 4581 lncRNA genes among six RNA libraries and 92 DE lncRNAs between Bf and Sol which are the key candidates for the conversion of skeletal muscle fiber types. Moreover, we detected the expression patterns of lncRNA MSTRG.42019 in different tissues and skeletal muscles of various development stages. In addition, we performed a correlation analyses between the expression of DE lncRNA MSTRG.42019 and meat quality traits. Notably, we found that DE lncRNA MSTRG.42019 was highly expressed in skeletal muscle and its expression was significantly higher in Sol than in Bf, with a positive correlation with the expression of Myosin heavy chain 7 (MYH7) (r = 0.6597, p = 0.0016) and a negative correlation with meat quality traits glycolytic potential (r = -0.5447, p = 0.0130), as well as drip loss (r = -0.5085, p = 0.0221). Moreover, we constructed the lncRNA MSTRG.42019-mRNAs regulatory network for a better understanding of a possible mechanism regulating skeletal muscle fiber formation. Our data provide the groundwork for studying the lncRNA regulatory mechanisms of skeletal muscle fiber conversion, and given the importance of skeletal muscle fiber types in muscle-related diseases, our data may provide insight into the treatment of muscular diseases in humans.

IDH2 Deficiency Is Critical in Myogenesis and Fatty Acid Metabolism in Mice Skeletal Muscle.

Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) catalyzes the oxidative decarboxylation of isocitrate into α-ketoglutarate with concurrent reduction of NADP+ to NADPH. However, it is not fully understood how IDH2 is intertwined with muscle development and fatty acid metabolism. Here, we examined the effects of IDH2 knockout (KO) on skeletal muscle energy homeostasis. Calf skeletal muscle samples from 10-week-old male IDH2 KO and wild-type (WT; C57BL/6N) mice were harvested, and the ratio of skeletal muscle weight to body and the ratio of mitochondrial to nucleic DNA were measured. In addition, genes involved in myogenesis, mitochondria biogenesis, adipogenesis, and thermogenesis were compared. Results showed that the ratio of skeletal muscle weight to body weight was lower in IDH2 KO mice than those in WT mice. Of note, a noticeable shift in fiber size distribution was found in IDH2 KO mice. Additionally, there was a trend of a decrease in mitochondrial content in IDH2 KO mice than in WT mice (p = 0.09). Further, mRNA expressions for myogenesis and mitochondrial biogenesis were either decreased or showed a trend of decrease in IDH2 KO mice. Moreover, genes for adipogenesis pathway (Pparg, Znf423, and Fat1) were downregulated in IDH2 KO mice. Interestingly, mRNA and protein expression of uncoupling protein 1 (UCP1), a hallmark of thermogenesis, were remarkably increased in IDH2 KO mice. In line with the UCP1 expression, IDH2 KO mice showed higher rectal temperature than WT mice under cold stress. Taken together, IDH2 deficiency may affect myogenesis, possibly due to impairments of muscle generation and abnormal fatty acid oxidation as well as thermogenesis in muscle via upregulation of UCP1.

C. elegans ACAT regulates lipolysis and its related lifespan in fasting through modulation of the genes in lipolysis and insulin/IGF-1 signaling.

Overly active acyl-coenzyme A: cholesterol acyltransferases (ACATs) are known to contribute to the development of atherosclerosis, cancer cell proliferation and de novo lipogenesis. However, the role of ACAT in systemic lipid metabolism and its consequence of aging is unknown. Using avasimibe, a clinically proven ACAT inhibitor, and mboa-1 mutant strain, a homologous to mammalian ACAT, herein, we found that Ava treatment and mboa-1 mutant exhibited a decreased fat accumulation during feeding and increased lipolysis with extended lifespan of C. elegans during fasting. Our study highlights the essential role of ACAT inhibitor and mboa-1 in fat mobilization and the survival of C. elegans in fasting through the modulation of the genes involved in lipolysis and insulin/IGF-1 signaling.

Proteomic identification of aerobic glycolysis as a potential metabolic target for methylglyoxal in adipocytes.

Obesity is often accompanied by metabolic changes in adipocytes that are closely associated with metabolic disease. Although high sugar consumption contributes to obesity, it may also directly affect adipocytes by increasing the rate of glycolysis and formation of the glycolytic by-product methylglyoxal (MG). MG is a reactive dicarbonyl that irreversibly damages proteins and other cellular components. Although the accumulation of MG is clinically associated with hyperglycemia and diabetic complications, a better understanding of how proteins are regulated by MG is needed to evaluate its role in the pathogenesis of metabolic disease. Because adipocytes rely heavily on glycolysis for glucose disposal, we hypothesized that prolonged MG treatment at nontoxic concentrations would impact the landscape of proteins involved in glucose metabolism. To test this hypothesis, we treated 3T3-L1 adipocytes with MG (100 µmol/L) and used comparative proteomics to assess the effects. We identified 25 differentially expressed proteins in adipocytes treated with MG compared to the control. Our results suggested that MG induced metabolic changes typically associated with aerobic glycolysis, including a lowered expression of proteins involved in oxidative metabolism and increased expression of the glycolytic enzymes L-lactate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase. The detection of increased lactate secreted into the culture media of adipocytes treated with MG further supported these findings, as did gene expression analysis. In summary, these results indicate MG as a metabolic contributor to aerobic glycolysis in adipocytes, a potential adaptive response to increased glucose flux which over time could lead to permanent metabolic changes.

Butein inhibits lipogenesis in Caenorhabditis elegans.

Butein, a flavonoid found in annatto seeds and lacquer trees, may be used for many health benefits, including the prevention of obesity. However, its anti-obesity effects are not completely understood; in particular, the effects of butein on the regulation of lipid metabolism have not been explained. Thus, the goal of the current study was to determine the effects of butein on lipid metabolism in Caenorhabditis elegans, which is a multi-organ nematode used as an animal model in obesity research. Butein at 70 µM reduced triglyceride content by 27% compared to the control without altering food intake and energy expenditure. The reduced triglyceride content by butein was associated with the downregulation of sbp-1, fasn-1, and fat-7, the lipogenesis-related homologs of sterol regulatory element-binding proteins, fatty acid synthase and stearoyl-CoA desaturase, respectively. Furthermore, fat-7 and skn-1, a homolog of nuclear respiratory factors, were identified as genetic requirements for butein's effects on triglyceride content in C. elegans. The effects of butein on sbp-1 and fasn-1 were dependent on skn-1, but the downregulation of fat-7 was independent of skn-1. These results suggest that the inhibitory effects of butein on lipogenesis are via SKN-1- and FAT-7-dependent pathways in C. elegans.

Antioxidant Capacity of Thistle (Cirsium japonicum) in Various Drying Methods and their Protection Effect on Neuronal PC12 Cells and Caenorhabditis elegans.

The aim of this study was, firstly, to evaluate the phenol profile of thistle (Cirsium japonicum, CJ) by High performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS), dried by different methods (90 °C hot-air, 70 °C hot-air, shade-, and freeze-drying). Secondly, we aimed to evaluate the relationship between phenolic compounds content and antioxidant properties. CJ contained chlorogenic acid, linarin, and pectolinarin. Total phenolic contents of CJ significantly decreased under hot-air-drying condition, especially chlorogenic acid contents in CJ have been reduced by 85% and 60% for 90 °C and 70 °C hot-air-drying, respectively. We evaluated the protective effect on adrenal pheochromocytoma (PC12) cells and Caenorhabditis elegans using shade-dried CJ, which has the largest phenolic contents and the strongest antioxidant property. CJ-treated PC 12 cells dose-dependently exhibited the protective effects against reactive oxygen species (ROS), while cell viability increases, lactate dehydrogenase release decreases, and ROS formation decreases. Furthermore, CJ has also shown protection against ROS in C. elegans. Consequently, CJ contributed to lifespan extension under ROS stress without influencing the physiological growth.

trans-Trismethoxy resveratrol decreased fat accumulation dependent on fat-6 and fat-7 in Caenorhabditis elegans.

trans-Trismethoxy resveratrol (TMR) is a methyl analog of resveratrol. It is found to exhibit enhanced biological effects compared to resveratrol, such as inhibition of cancer cell growth and pro-apoptotic activities. However, the role of TMR in lipid metabolism is not fully understood. In this study, we used Caenorhabditis elegans, an in vivo nematode model which has been widely applied in disease research, including research on obesity, to investigate the effect of TMR on lipid metabolism. Treatment with TMR (100 and 200 µM) for 4 days significantly reduced triglyceride accumulation (14% and 20% reduction over the control, respectively) of C. elegans, without affecting nematode growth, food intake and reproduction. Treatment with TMR significantly downregulated stearoyl-CoA desaturase genes, fat-6 and fat-7, accompanied by a decrease in the desaturation index of fatty acids, the ratio of oleic acid to stearic acid. These results suggest that TMR inhibits fat accumulation by downregulating stearoyl-CoA desaturase in C. elegans.