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Abstract Skeletal muscle atrophy occurs in several pathological conditions. Among other reasons, high-dose or long-term administration of glucocorticoids increases circulating glucocorticoid levels and causes muscle atrophy. The purpose of this study was to investigate whether Lithospermum erythrorhizon and Lonicera japonica complex extract (LELJ) has a beneficial effect on dexamethasone (Dexa)-induced muscle atrophy. In Dexa-induced myotube atrophy, treatment with LELJ increased myotube diameter, decreased the expression of muscle atrophy markers, and increased the expression of myosin heavy chain (MHC) isoforms. Supplementation with LELJ improved muscle function and performance in mice with Dexa-induced muscle atrophy as demonstrated by grip strength and running tests. Additionally, it increased skeletal muscle mass, size, and expression of MHC isoforms and protein synthesis-related markers. Furthermore, it reduced the upregulated protein levels of skeletal muscle atrophy markers in Dexa-treated mice. Supplementation with LELJ reversed Dexa-induced translocation of the glucocorticoid receptor and forkhead box O3 from the cytosol to the nucleus in skeletal muscles. LELJ also ameliorated age-related muscle loss by extending lifespan and increasing locomotor capacity in Caenorhabditis elegans. We identified loganin and lithospermic acid as bioactive compounds of LELJ and found that treatment with these agents increased myotube diameter, MHC isoform, and puromycin protein levels, and decreased atrophy markers in Dexa-treated myotubes. The current findings underscore how LELJ can prevent Dexa-induced skeletal muscle atrophy, attributing the effects to loganin and lithospermic acid.

The potential anti-obesity effects of sea cucumber extract have been reported. However, the individual saponins responsible for these effects are yet to be isolated and characterized. This study aimed to identify the most effective sea cucumber body part for inhibiting lipid accumulation in adipocytes and to elucidate the compounds responsible for this effect using nuclear magnetic resonance (NMR) techniques. Sea cucumber ovary 80 % ethanol extract (SCOE) demonstrated remarkable efficacy in inhibiting adipocyte differentiation compared to other sea cucumber body parts with 50 % or 80 % ethanol extracts. SCOE anti-obesity effect was evaluated in C57BL/6 mice fed a high-fat diet, which revealed significant reductions in body weight, serum lipids, adipose tissue, and liver weight. Using column chromatography, eight saponins were isolated from the SCOE, four of which exhibited potent inhibitory effects on adipocyte differentiation. Of these, three active saponins, holotoxins A, B, and D1, were newly identified. These findings highlight the potential of SCOE and its saponins as effective anti-obesity agents.

Abstract Background Muscle atrophy is characterized by decreased muscle mass, function, and strength. Synthetic glucocorticoids, including dexamethasone (Dexa), are commonly used to treat autoimmune diseases. However, prolonged exposure of Dexa with high dose exerts severe side effects, including muscle atrophy. The purpose of this study was to investigate whether Gromwell root extract (GW) can prevent Dexa-induced muscle atrophy in C2C12 cells and mice and to characterize the composition of GW to identify bioactive compounds. Methods For in vitro experiments, GW (0.5 and 1 µg/mL) or lithospermic acid (LA, 5 and 10 µM) was added to C2C12 myotubes on day 4 of differentiation and incubated for 24 h, along with 50 µM Dexa. For in vivo experiment, four-week-old male C57BL/6 mice were randomly divided into the four following groups (n = 7/group): Con group, Dexa group, GW0.1 group, and GW0.2 group. Mice were fed experimental diets of AIN-93 M with or without 0.1 or 0.2% GW for 4 weeks. Subsequently, muscle atrophy was induced by administering an intraperitoneal injection of Dexa at a dose of 15 mg/kg/day for 38 days, in conjunction with dietary intake. Results In Dexa-induced myotube atrophy, treatment with GW increased myotube diameter, reduced the expression of muscle atrophy markers, and enhanced the expression of myosin heavy chain (MHC) isoforms in C2C12 cells. Supplementation with the GW improved muscle function and performance in mice with Dexa-induced muscle atrophy, evidenced in the grip strength and running tests. The GW group showed increased lean body mass, skeletal muscle mass, size, and myosin heavy chain isoform expression, along with reduced skeletal muscle atrophy markers in Dexa-injected mice. Supplementation with GW increased protein synthesis and decreased protein degradation through the Akt/mammalian target of rapamycin and glucocorticoid receptor/forkhead box O3 signaling pathways, respectively. We identified LA as a potential bioactive component of the GW. LA treatment increased myotube diameter and decreased the expression of muscle atrophy markers in Dexa-induced C2C12 cells. Conclusions These findings underscore the potential of the GW in preventing Dexa-induced skeletal muscle atrophy and highlight the contribution of LA to its effects.

AbstractThe beneficial effects of Akkermansia muciniphila (Akk) on gut health and inflammation reduction have been demonstrated; however, scientific evidence of hair growth enhancement by Akk has not been reported. Therefore, this study was undertaken to investigate the effect of Akk on improving testosterone‐mediated hair growth inhibition. Hair growth inhibition was induced through subcutaneous injection of testosterone into the shaved dorsal skin of C57BL/6 male mice. Live and pasteurized Akk were orally administered at a concentration of 1 × 108 colony‐forming unit. After 5 weeks, hair length and skin tissues were analyzed. The live and pasteurized Akk significantly stimulated hair growth, countering the inhibitory effect of testosterone compared to the testosterone‐alone group. Hematoxylin and eosin staining revealed a significant increase in hair follicle size in the Akk‐treated group. An increase in β‐catenin levels, which are associated with hair growth and cell cycle progression, was also observed. Moreover, the Akk‐treated group exhibited increased levels of fibroblast growth factors, including Fgf7, Igf1, Fgf7, Fgf10, and Fgf21. However, no significant difference was observed between the live and pasteurized Akk groups. These results underscore the potential of live and pasteurized Akk in improving testosterone‐mediated hair growth inhibition.

Abstract The DNA damage response is essential for preserving genome integrity and eliminating damaged cells. Although cellular metabolism plays a central role in cell fate decision between proliferation, survival, or death, the metabolic response to DNA damage remains largely obscure. Here, this work shows that DNA damage induces fatty acid oxidation (FAO), which is required for DNA damage‐induced cell death. Mechanistically, FAO induction increases cellular acetyl‐CoA levels and promotes N‐alpha‐acetylation of caspase‐2, leading to cell death. Whereas chemotherapy increases FAO related genes through peroxisome proliferator‐activated receptor α (PPARα), accelerated hypoxia‐inducible factor‐1α stabilization by tumor cells in obese mice impedes the upregulation of FAO, which contributes to its chemoresistance. Finally, this work finds that improving FAO by PPARα activation ameliorates obesity‐driven chemoresistance and enhances the outcomes of chemotherapy in obese mice. These findings reveal the shift toward FAO induction is an important metabolic response to DNA damage and may provide effective therapeutic strategies for cancer patients with obesity.

Dark tea (DT), a tea post-fermented by the Eurotium cristatum fungus, is known to attenuate oxidative damage and chronic inflammation. It also extends the lifespan of Caenorhabditis elegans fed a high-sugar diet. However, its impact on age-related muscle loss in mice is unclear. We divided 65-week-old male C57BL/6 mice into three groups: old control received the AIN-93 M diet, while the 0.15DT and 0.3DT groups had 0.15 % and 0.3 % DT for 9 weeks. As a result, DT improved grip strength, treadmill performance, muscle weight, and size in aged mice. It reduced cellular senescence, muscle atrophy markers, and angiopoietin-like 2 expression, while increasing sirtuin 1 protein levels in aged mice. Additionally, DT lowered malondialdehyde content and pro-inflammatory cytokine levels and enhanced total antioxidant capacity and enzymes, ultimately attenuating mitochondrial dysfunction in skeletal muscle. Therefore, our results suggest DT attenuates age-related muscle atrophy by alleviating oxidative stress, mitochondrial dysfunction, and inflammation.

The plant Justicia procumbens is traditionally used in Asia to treat fever, cough, and pain. Previous studies have reported its anticancer and anti-asthmatic properties. However, its potential for preventing androgenic alopecia (AGA) has not yet been reported. AGA is a widespread hair loss condition primarily caused by male hormones. In this study, we examined the hair loss-preventing effects of an aqueous extract of J. procumbens (JPAE) using human hair follicle dermal papilla cell (HFDPC) and a mouse model of testosterone-induced AGA. JPAE treatment increased HFDPC proliferation by activating the Wnt/β-catenin signaling pathway. Additionally, JPAE increased the expression of Wnt targets, such as cyclin D1 and VEGF, by promoting the translocation of β-catenin to the nucleus. Administration of JPAE reduced hair loss, increased hair thickness, and enhanced hair shine in an AGA mouse model. Furthermore, it increased the expression of p-GSK-3β and β-catenin in the dorsal skin of the mice. These findings imply that JPAE promotes the proliferation of HFDPC and prevents hair loss in an AGA mouse model. JPAE can therefore be used as a functional food and natural treatment option for AGA to prevent hair loss.

Red paprika (RP) is rich in carotenoids and capsanthin (CS) is its main carotenoid. We determined whether whole RP and CS can ameliorate obesogenic sarcopenia.C2C12 myotubes were co-treated with 500 μM of palmitic acid (PA) and 1 and 5 μg/mL RP or 0.5 and 1.0 μM CS for 24 h. Both RP and CS effectively attenuated PA-induced myotube atrophy. Male obese C57BL/6 mice (n = 40) were fed high-fat diets containing 5 and 10% RP or 0.025% CS for 10 weeks. Supplementation with RP and CS increased lean body mass, muscle performance, mtDNA content, and mitochondrial oxidative phosphorylation, while it decreased intracellular lipid accumulation in muscle tissue. Moreover, both RP and CS increased myosin heavy chains and decreased atrogens expression, which are associated with the activation of mTORC1 signaling. These results demonstrated that RP and CS protect against obesogenic sarcopenia by improving mitochondrial function.

Alopecia, regardless of gender, exacerbates psychological stress in those affected. The rising prevalence of alopecia has fueled a research interest in preventing hair loss. This study investigates the potential of millet seed oil (MSO) in promoting the proliferation of hair follicle dermal papilla cells (HFDPC) and stimulating hair growth in animals with testosterone-dependent hair growth inhibition as part of a study on dietary treatments to improve hair growth. MSO-treated HFDPC significantly increased cell proliferation and phosphorylation of AKT, S6K1, and GSK3β proteins. This induces β-catenin, a downstream transcription factor, to translocate to the nucleus and increase the expression of factors related to cell growth. In a C57BL/6 mice model in which hair growth was inhibited by subcutaneous testosterone injection after shaving the dorsal skin, oral administration of MSO stimulated hair growth in the subject mice by increasing the size and number of hair follicles. These results suggest that MSO is a potent agent that may help prevent or treat androgenetic alopecia by promoting hair growth.

Abstract Background Although mounting evidence indicates that insulin resistance (IR) co‐occurs with mitochondrial dysfunction in skeletal muscle, there is no clear causal link between mitochondrial dysfunction and IR pathogenesis. In this study, the exact role of mitochondria in IR development was determined. Methods Six‐week‐old C57BL/6 mice were fed a high‐fat diet for 2 weeks to induce acute IR or for 24 weeks to induce chronic IR (n = 8 per group). To characterize mitochondrial function, we measured citrate synthase activity, ATP content, mitochondrial DNA (mtDNA) content, and oxygen consumption rate in gastrocnemius and liver tissues. We intraperitoneally administered mitochondrial division inhibitor 1 (mdivi‐1) to mice with acute IR and measured mitochondrial adaptive responses such as mitophagy, mitochondrial unfolded protein response (UPRmt), and oxidative stress (n = 6 per group). Results Acute IR occurred coincidently with impaired mitochondrial function, including reduced citrate synthase activity (−37.8%, P

We investigated the effects of 6-gingerol on adiposity and obesity-induced inflammation by focusing on the regulation of adipogenesis and adipokines in white adipose tissue (WAT) of diet-induced obese mice. C57BL/6 mice were fed a high-fat diet (HFD) containing 0.05% 6-gingerol for 8 weeks. 6-Gingerol supplementation significantly reduced body weight, WAT mass, serum triglyceride, leptin and insulin levels, and HOMA-IR in HFD-fed mice. Additionally, the size of adipocytes in epididymal fat pads was reduced in HFD-fed mice by 6-gingerol supplementation. 6-Gingerol reduced the mRNA and protein levels of adipogenesis-related transcription factors, such as SREBP-1, PPARγ, and C/EBPα in WAT. Furthermore, 6-gingerol suppressed the expression of lipogenesis-related genes, such as fatty acid synthase and CD36 in WAT. Adiponectin expression was significantly increased, whereas inflammatory adipokines (leptin, resistin, TNF-α, MCP-1, and PAI-1) and the macrophage marker F4/80 were significantly reduced in the WAT of HFD-fed mice by 6-gingerol supplementation. In conclusion, 6-gingerol effectively contributed to the alleviation of adiposity and inflammation in WAT, which is associated with the regulation of adipokines in diet-induced obese mice.

Skeletal muscle atrophy is characterized by reduced muscle function and size. Oxidative stress contributes to muscle atrophy but can be treated with antioxidants. This study investigated the antioxidant activity of a castor oil plant leaf (Ricinus communis L.) extract (RC) and its effects on muscle atrophy. Rutin was identified as the major compound among the thirty compounds identified in RC via LC-MS/MS and was found to inhibit dexamethasone (DEX)-induced muscle atrophy and mitochondrial oxidative stress. Rutin-rich RC showed DPPH and ABTS radical scavenging activities and efficiently reduced the DEX-induced myotube atrophy and mitochondrial oxidative damage in C2C12 cells. RC supplementation prevented the loss of muscle function and muscle mass in DEX-administered mice and ameliorated DEX-induced oxidative stress via Nrf2 signaling. Taken together, both RC and rutin ameliorated muscle atrophy and helped in maintaining redox homeostasis; hence, rutin-rich RC could be a promising functional food that is beneficial for muscle health.

Background & Aims: The development of nonalcoholic fatty liver disease (NAFLD) can be modulated by microRNAs (miRNA). Dietary polyphenols modulate the expression of miRNA such as miR-467b-3p in the liver. In addition, 6-gingerol (6-G), the functional polyphenol of ginger, has been reported to ameliorate hepatic steatosis; however, the exact mechanism involved and the role of miRNA remain elusive. In this study, we assessed the role of miR-467b-3p in the pathogenesis of hepatic steatosis and the regulation of miR-467b-3p by 6-G through the hepatocyte nuclear factor 4α (HNF4α). Methods: miR-467b-3p expression was measured in free fatty acid (FFA)-treated hepatocytes or liver from high-fat diet (HFD)-fed mice. Gain- or loss-of-function of miR-467b-3p was induced using miR-467b-3p–specific miRNA mimic or miRNA inhibitor, respectively. 6-G was exposed to FFA-treated cells and HFD-fed mice. The HNF4α/miR-467b-3p/GPAT1 axis was measured in mouse and human fatty liver tissues. Results: We found that miR-467b-3p was down-regulated in liver tissues from HFD-fed mice and in FFA-treated Hepa1-6 cells. Overexpression of miR-467b-3p decreased intracellular lipid accumulation in FFA-treated hepatocytes and mitigated hepatic steatosis in HFD-fed mice via negative regulation of glycerol-3-phosphate acyltransferase-1 (GPAT1). In addition, miR-467b-3p up-regulation by 6-G was observed. 6-G inhibited FFA-induced lipid accumulation and mitigated hepatic steatosis. Moreover, it increased the transcriptional activity of HNF4α, resulting in the increase of miR-467b-3p and subsequent decrease of GPAT1. HNF4α/miR-467b-3p/GPAT1 signaling also was observed in human samples with hepatic steatosis. Conclusions: Our findings establish a novel mechanism by which 6-G improves NAFLD. This suggests that targeting of the HNF4α/miR-467b-3p/GPAT1 cascade may be used as a potential therapeutic strategy to control NAFLD.

Chrysanthemum zawadskii Herbich (CZH) is used in traditional medicine to treat inflammatory diseases and diabetes. However, the effects of CZH on muscle wasting remains to be studied. Here, we investigated the effect of CZH on dexamethasone (DEX), a synthetic glucocorticoid, induced muscle atrophy. To examine the effect of CZH on muscle atrophy, C2C12 myotubes were co-treated with DEX and CZH for 24 h. The treatment with CZH prevented DEX-induced myotube atrophy in a dose-dependent manner. CZH inhibited the DEX-induced decrease of the MHC isoforms and the upregulation of atrogin-1 and MuRF1 in C2C12 differentiated cells. C57BL/6 mice were supplemented with 0.1 % CZH for 8 weeks, with DEX-induced muscle atrophy stimulated in the last 3 weeks. In the mice, CZH supplementation effectively reversed DEX-induced skeletal muscle atrophy and increased the exercise capacity of the mice through the inhibition of glucocorticoid receptor translocation. Additionally, we observed that DEX-evoked impaired proteostasis was ameliorated via the Akt/mTOR pathway. CZH also prevented the DEX-induced decrease in the mitochondrial respiration. HPLC analysis demonstrated the highest concentration of acacetin-7-O-β-d-rutinoside (AR) among 4 compounds. Moreover, AR, a functional compound of CZH, prevented DEX-evoked muscle atrophy. Thus, we suggest that CZH could be a potential therapeutic candidate against muscle atrophy and AR is the main functional compound of CZH.

Nonalcoholic fatty liver disease (NAFLD) is a common risk factor for metabolic syndrome that increases the risk of future cardiovascular disease, stroke, and diabetes. Recently, autophagy has been proposed as a means to prevent NAFLD. We investigated whether substances with autophagy-inducing activity alleviate NAFLD. The Valeriana fauriei (V. fauriei) was selected as a potential autophagy inducer among various natural materials using a Cyto-ID autophagy detection kit. V. fauriei 70 % ethanol extract (VFE) increased LC3II levels in the presence of the lysosomal inhibitor and reduced the GFP/mCherry puncta ratio, suggesting that VFE enhanced autophagy. VFE reduced oleic acid (OA)-induced lipid accumulation and increased the number of autophagosome in hepatocytes. Autophagy induction by VFE is due to inhibition of mTORC1 activity. VFE supplementation reduced fatty liver by downregulating lipogenesis-related genes and increased the autophagy, as revealed by TEM and IHC analysis in the fatty liver. We identified iridoids as main compounds of VFE; didrovaltrate (DI), valeriotriate B (VAL B), valeriotetrate C (VAL C), valtrate (VAL), and valechlorine (VC) were shown to enhance autophagy. These compounds also reduced OA-induced lipid accumulation in an Atg5-dependent manner. Taken together, VFE and its iridoids might be effective in alleviating fatty liver by acting as autophagy enhancers to break down LDs.

Red paprika (Capsicum annuum L.) is a widely used natural food colorant and source of vital micronutrients. The main carotenoid in red paprika is capsanthin. In this study, the effects of red paprika and capsanthin on impaired lipid metabolism were investigated in diet-induced obese mice. Forty male mice were divided into 4 groups; normal diet (ND), high-fat diet (HD), HD with red paprika, and HD with capsanthin. After 8 weeks, the red paprika and capsanthin groups showed significantly reduced weight gain, and ameliorated hypertrophy of the liver and adipose tissues. Red paprika and capsanthin treatment also improved serum lipid profile and adipokine secretion, and ameliorated hepatic steatosis by suppressing hepatic lipogenesis, fatty acid oxidation, and gluconeogenesis. In epididymal adipose tissue, red paprika and capsanthin inhibited adipogenesis and decreased lipid droplet size. Taken together, red paprika and capsanthin could ameliorate the detrimental effects of diet-induced obesity by improving impaired lipid metabolism.

Background: Korean diet has received considerable attention because of the low prevalence of obesity and metabolic disorders in Korea. Although the Korean diet has been shown to have health benefits, these effects have been investigated by analyzing individual nutrients or food components. In this study, we used a dietary pattern approach to investigate the effect of the Korean diet on obesity and glucose homeostasis in mice fed a high-fat diet (HFD). Methods: C57BL/6 mice were fed the HFD for 7 weeks to induce obesity and then fed either the HFD or Korean diet for the next 7 weeks. The Korean diet was based on food frequency data obtained from the 4th Korean National Health and Nutrition Examination Survey and adjusted to have the same energy content as the HFD. Serum insulin and leptin were quantified by enzyme-linked immunosorbent assay, and glucose clearance was assessed using the oral glucose tolerance test. Lipogenic gene expression was determined by quantitative reverse transcription-polymerase chain reaction. Results: The Korean diet significantly decreased the HFD-induced body weight increase and body fat accumulation and improved serum lipid profiles. Hepatic mRNA levels of lipogenic genes were lower in Korean diet-fed mice, which also showed decreased fasting blood glucose, insulin, and leptin levels, and improved glucose clearance. The Korean diet also ameliorated HFD-induced islet hypertrophy and elevated pancreatic insulin level. Conclusions: Korean diet prevented obesity and ameliorated insulin resistance in mice fed a HFD. Therefore, Korean diet may be useful as a therapeutic diet to control metabolic disorders.

Abstract Transplantation of spermatogonial stem cells (SSCs) in experimental animal models has been used to study germ line stem cell biology and to produce transgenic animals. The species-specific recipient model preparation is important for the characterization of SSCs and the production of offspring. Here, we investigated the effects of surgically induced cryptorchidism in dog as a new recipient model for spermatogonial stem cell transplantation. Artificially unilateral or bilateral cryptorchidism was induced in ten mature male dogs by surgically returning the testis and epididymis to the abdominal cavity. The testes and epididymides were collected every week after the induction of artificial cryptorchidism (surgery) for one month. To determine the effect of surgical cryptorchidism, the seminiferous tubule diameter was measured and immunohistochemistry using PGP9.5 and GATA4 antibodies was analyzed. The diameters of the seminiferous tubules of abdominal testes were significantly reduced compared to those of the scrotal testes. Immunohistochemistry results showed that PGP9.5 positive undifferentiated spermatogonia were significantly reduced after surgical cryptorchidism induction, but there were no significant changes in GATA-4 positive sertoli cells. To evaluate the testis function recovery rate, orchiopexy was performed on two dogs after 30 days of bilateral cryptorchidism. In the orchiopexy group, SCP3 positive spermatocytes were detected, and spermatogenesis was recovered 8 weeks after orchiopexy. In this study, we provided optimum experimental conditions and time for surgical preparation of a recipient canine model for SSC transplantation. Additionally, our data will contribute to recipient preparation by using surgically induced cryptorchidism in non-rodent species.

Limonin, the most prevalent limonoid in citrus fruits, is widely used as a dietary supplement because of its biological activities. Although studies have shown that limonin inhibits bone resorption in osteoclasts and improves bone quality in orchidectomised rats, the anti-osteoporosis activity of limonin in ovariectomised (OVX) animal models is still unknown, and its exact molecular mechanisms remain undefined. Therefore, the effect of limonin on osteoblastogenesis in MC3T3-E1 cells and an OVX-induced osteoporosis rat model was investigated. Limonin stimulated alkaline phosphatase (ALP) activity, mineralisation, and increased osteoblast differentiation gene marker expression via extracellular signal-regulated kinase (ERK) and p38 signalling in osteoblastic MC3T3-E1 cells. In animals, limonin decreased OVX-induced body weight increase, affected the trabecular bone structure and biochemical properties, and facilitated bone mineral density and content regulation. These findings demonstrated that limonin has beneficial bone metabolism effects based on bone formation and might have potential as a functional food ingredients and a dietary supplement for osteoporosis.

Although drug therapies are available for postmenopausal osteoporosis, these drugs are not free of side effects and long-term adherence to them are low. A safe and effective nutritional approach to counter postmenopausal osteoporosis is an important research goal. We fed ovariectomized (OVX) Sprague–Dawley rats a diet supplemented with 1% or 2% green tomato extract (GTE). After 12 weeks, micro-computed tomography scans revealed that GTE supplementation effectively prevented distal femur bone loss. This prevention was due to improved bone formation and suppressed bone resorption as observed by the regulation of osteoblast and osteoclast activities. GTE supplementation also improved bone formation through Bmp2-Smad 1/5/8-Runx2 signaling, while bone resorption was regulated by the receptor activator of nuclear factor kappa-B (RANKL)/osteoprogeterin (OPG) pathway. These results suggest that GTE supplementation prevents severe postmenopausal bone loss by maintaining the regulation of bone homeostasis in OVX rats. GTE as a diet supplement might be a potential novel alternative for the prevention of postmenopausal osteoporosis.

As obesity promotes ectopic fat accumulation in skeletal muscle, resulting in impaired skeletal muscle and mitochondria function, it is associated with skeletal muscle loss and dysfunction. This study investigated whether Chrysanthemi zawadskii var. latilobum (CZH) protected mice against obesity-induced skeletal muscle atrophy and the underlying molecular mechanisms. High-fat diet (HFD)-induced obese mice were orally administered either distilled water, low-dose CZH (125 mg/kg), or high-dose CZH (250 mg/kg) for 8 w. CZH reduced obesity-induced increases in inflammatory cytokines levels and skeletal muscle atrophy, which is induced by expression of atrophic genes such as muscle RING-finger protein 1 and muscle atrophy F-box. CZH also improved muscle function according to treadmill running results and increased the muscle fiber size in skeletal muscle. Furthermore, CZH upregulated mRNA and protein levels of protein arginine methyltransferases (PRMT)1 and PRMT7, which subsequently attenuated mitochondrial dysfunction in the skeletal muscle of obese mice. We also observed that CZH significantly decreased PRMT6 mRNA and protein expression, which resulted in decreased muscle atrophy. These results suggest that CZH ameliorated obesity-induced skeletal muscle atrophy in mice via regulation of PRMTs in skeletal muscle.

Shikonin, a natural plant pigment, is known to have anti-obesity activity and to improve insulin sensitivity. This study aimed to examine the effect of shikonin on hepatic steatosis, focusing on the AMP-activated protein kinase (AMPK) and energy expenditure in Hepa 1-6 cells and in high-fat fed mice. Shikonin increased AMPK phosphorylation in a dose- and time-dependent manner, and inhibition of AMPK with compound C inhibited this activation. In an oleic acid-induced steatosis model in hepatocytes, shikonin suppressed oleic acid-induced lipid accumulation, increased AMPK phosphorylation, suppressed the expression of lipogenic genes, and stimulated fatty acid oxidation-related genes. Shikonin administration for four weeks decreased body weight gain and the accumulation of lipid droplets in the liver of high-fat fed mice. Furthermore, shikonin promoted energy expenditure by activating fatty acid oxidation. In addition, shikonin increased the expression of PPARγ coactivator-1α (PGC-1α), carnitine palmitoyltransferase-1 (CPT1) and other mitochondrial function-related genes. These results suggest that shikonin attenuated a high fat diet-induced nonalcoholic fatty liver disease by stimulating fatty acid oxidation and energy expenditure via AMPK activation.

Withania somnifera (WS), commonly known as ashwagandha, possesses diverse biological functions. WS root has mainly been used as an herbal medicine to treat anxiety and was recently reported to have an anti-obesity effect, however, the mechanisms underlying its action remain to be explored. We hypothesized that WS exerts its anti-obesity effect by enhancing energy expenditure through improving the mitochondrial function of brown/beige adipocytes and skeletal muscle. Male C57BL/6J mice were fed a high-fat diet (HFD) containing 0.25% or 0.5% WS 70% ethanol extract (WSE) for 10 weeks. WSE (0.5%) supplementation significantly suppressed the increases in body weight and serum lipids, and lipid accumulation in the liver and adipose tissue induced by HFD. WSE supplementation increased oxygen consumption and enhanced mitochondrial activity in brown fat and skeletal muscle in the HFD-fed mice. In addition, it promoted browning of subcutaneous fat by increasing mitochondrial uncoupling protein 1 (UCP1) expression. Withaferin A (WFA), a major compound of WS, enhanced the differentiation of pre-adipocytes into beige adipocytes and oxygen consumption in C2C12 murine myoblasts. These results suggest that WSE ameliorates diet-induced obesity by enhancing energy expenditure via promoting mitochondrial function in adipose tissue and skeletal muscle, and WFA is a key regulator in this function.

Recent studies show that brown rice improves glucose intolerance and potentially the risk of diabetes, although the underlying molecular mechanisms remain unclear. One of the phytochemicals found in high concentration in brown rice is γ-oryzanol (Orz), a group of ferulic acid esters of phytosterols and triterpene alcohols. Here, we found that Orz stimulated differentiation of 3T3-L1 preadipocytes and increased the protein expression of adipogenic marker genes such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and CCAAT/enhanced binding protein alpha (C/EBPα). Moreover, Orz significantly increased the glucose uptake in insulin-resistant cells and translocation of glucose transporter type 4 (GLUT4) from the cytosol to the cell surface. To investigate the mechanism by which Orz stimulated cell differentiation, we examined its effects on cellular signaling of the mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth and proliferation. The Orz treatment increased mTORC1 kinase activity based on phosphorylation of 70-kDa ribosomal S6 kinase 1 (S6K1). The effect of Orz on adipocyte differentiation was dependent on mTORC1 activity because rapamycin blocks cell differentiation in Orz-treated cells. Collectively, our results indicate that Orz stimulates adipocyte differentiation, enhances glucose uptake, and may be associated with cellular signaling mediated by PPAR-γ and mTORC1.

This study was designed to evaluate the effect of ovariectomy on nutrikinetics of genistein metabolites. To characterize the time-dependent changes in genistein metabolite concentrations, we identified 13 genistein metabolites using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The nutrikinetics of the individual metabolites at different time points were analyzed. Nutrikinetic analysis showed that genistein, genistein 4'-glucuronide, genistein 7-glucuronide, 3-hydroxygenistein, and hippuric acid showed relatively high bioavailability in the sham group compared to that in the ovariectomy group, suggesting that ovariectomy likely results in lower genistein bioavailability. These results may be related to alteration of gut microbiota by ovariectomy. The relative abundance of species of the Parabacteroides, Dorea, and Butyricimonas genera, and Desulfovibrionaceae_unclassified, Lachnospiraceae_unclassified, and Rikenellaceae_unclassified families increased in the ovariectomy group while the relative abundance of 523_7_unclassified and Y52_unclassified_unclassified increased in the sham group. These results suggest that gut microbiota alteration by ovariectomy may affect genistein bioavailability.

We evaluated whether intake of an ethanolic extract of Taheebo (TBE) from Tabebuia avellanedae protects against body weight increase and fat accumulation in mice with high-fat diet (HFD)-induced obesity. Four-week old male C57BL/6 mice were fed a HFD (25% fat, w/w) for 11 weeks. The diet of control (HFD) mice was supplemented with vehicle (0.5% sodium carboxymethyl cellulose by gavage); the diet of experimental (TBE) mice was supplemented with TBE (150 mg/kg body weight/day by gavage). Mice administered TBE had significantly reduced body weight gain, fat accumulation in the liver, and fat pad weight, compared to HFD mice. Reduced hypertrophy of fat cells was also observed in TBE mice. Mice administered TBE also showed significantly lower serum levels of triglycerides, insulin, and leptin. Lipid profiles and levels of mRNAs and proteins related to lipid metabolism were determined in liver and white adipose tissue of the mice. Expression of mRNA and proteins related to lipogenesis were decreased in TBE-administered mice compared to mice fed HFD alone. These results suggest that TBE inhibits obesity and fat accumulation by regulation of gene expression related to lipid metabolism in HFD-induced obesity in mice.

Gliadin is a major protein component of gluten and causes gluten toxicity through intestinal stress. We previously showed that gliadin intake induces oxidative stress in the intestine and reduces fertility in a Caenorhabditis elegans model. To elucidate the possible link between intestinal stress and reproduction, changes in the intestine and germ cells of C. elegans after gliadin intake were examined at the molecular level. Gliadin intake increased reactive oxygen species (ROS) production in the intestine, decreased intestinal F-actin levels, and increased germ cell apoptosis. These gliadin-triggered effects were suppressed by antioxidant treatment. These results suggest that ROS production in the intestine induced by gliadin intake causes disruption of intestinal integrity and increases germ cell apoptosis. Gliadin-induced germ cell apoptosis (GIGA) was suppressed by depletion of cep-1, ced-13, egl-1, or mpk-1. However, HUS-1 was not activated, suggesting that GIGA is activated through the mitogen-activated protein kinase (MAPK) pathway and is CEP-1-dependent but is a separate pathway from that controlling the DNA damage response. Taken together, our results suggest that gliadin causes intestinal barrier disruption through ROS production and interacts with the germ cells to reduce fertility through GIGA.

Inula japonica Thunb. (Asteraceae) is a flowering plant that grows mainly in Korea, Japan, and China and its flower extract has diverse biological effects such as anti-inflammatory and antioxidative activities. However, the effects on obesity and enhancement of endurance capacity have not been explored yet. This study aims to reveal the effects of I. japonica flower ethanol extract (IJE) on obesity and endurance capacity in high-fat diet (HFD) fed C57BL/6J mice and the mechanism. IJE inhibited lipid accumulation in 3T3-L1 adipocytes in vitro. Also, IJE-fed mice showed reduced body weight gain, hepatic lipid, and body fat mass, and increased muscle weight. IJE reduced lipid accumulation in the liver and adipose tissue by decreasing lipogenic and adipogenic gene expression. Additionally, consumption of low-dose IJE significantly enhanced endurance capacity via increasing AMP-activated protein kinase activity and mRNA levels of Myh7 and Myh2. Luteolin and 1β-hydroxyalantolactone (1β-HA), compounds of IJE, are involved in anti-adipogenesis in the 3T3-L cells and only luteolin increased the protein levels of MHC during C2C12 myoblast differentiation. Collectively, our results suggest that consumption of IJE not only helps to prevent obesity but also enhances endurance capacity reduced by HFD.

Abstract Sirtuin 1 (SIRT1) plays a critical role in the maintenance of metabolic homeostasis and promotes fat mobilization in white adipose tissue. However, regulation of SIRT1 during adipogenesis, particularly through microRNAs, remains unclear. We observed that miR‐146b expression was markedly increased during adipogenesis in 3T3‐L1 cells. Differentiation of 3T3‐L1 was induced by overexpression of miR‐146b. Conversely, inhibition of miR‐146b decreased adipocyte differentiation. Bioinformatics‐based studies suggested that SIRT1 is a target of miR‐146b. Further analysis confirmed that SIRT1 was negatively regulated by miR‐146b. We also observed that miR‐146b bound directly to the 3′‐untranslated region of SIRT1 and inhibited adipogenesis through SIRT1 downregulation. The miR‐146b/SIRT1 axis mediates adipogenesis through increased acetylation of forkhead box O1 (FOXO1). Expression of miR‐146b was increased and SIRT1 mRNA subsequently decreased in the adipose tissues of diet‐induced and genetically obese mice. Furthermore, in vivo knockdown of miR‐146b by a locked nucleic acid miR‐146b antagomir significantly reduced body weight and fat volume in accordance with upregulation of SIRT1 and subsequent acetylation of FOXO1. Therefore, the miR‐146b/SIRT1 pathway could be a potential target for obesity prevention and treatment.

Allyl-isothiocyanate (AITC) is an organosulfur phytochemical found in abundance in common cruciferous vegetables such as mustard, wasabi, and cabbage. Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function of AITC metabolites is still largely unknown. In this study, we evaluated the inhibitory effects of AITC metabolites on lipid accumulation in vitro and elucidated the pharmacokinetics and tissue distribution of AITC metabolites in rats. We found that AITC metabolites generally conjugate with glutathione (GSH) or N-acetylcysteine (NAC) and are distributed in most organs and tissues. Pharmacokinetic analysis showed a rapid uptake and complete metabolism of AITC following oral administration to rats. Although AITC has been reported to exhibit anti-tumor activity in bladder cancer, the potential bioactivity of its metabolites has not been explored. We found that GSH-AITC and NAC-AITC effectively inhibit adipogenic differentiation of 3T3-L1 preadipocytes and suppress expression of PPAR-γ, C/EBPα, and FAS, which are up-regulated during adipogenesis. GSH-AITC and NAC-AITC also suppressed oleic acid-induced lipid accumulation and lipogenesis in hepatocytes. Our findings suggest that AITC is almost completely metabolized in the liver and rapidly excreted in urine through the mercapturic acid pathway following administration in rats. AITC metabolites may exert anti-obesity effects through suppression of adipogenesis or lipogenesis.

Tyrosol is considered a potential antioxidant; however, little is known regarding the pharmacokinetics of its metabolites. To study the pharmacokinetics of tyrosol-derived metabolites after oral administration of a single dose of tyrosol, we attempted to identify tyrosol metabolites in rat plasma by using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Two tyrosol metabolites (M1 and M2) were detected in the plasma. M1 was identified as tyrosol-4-sulfate (T4S) with an [M − H]− ion at m/z 217. While M2 showed an [M − H]− ion at m/z 151.0, its metabolite was not identified. Pharmacokinetic analysis of T4S and M2 showed rapid uptake after oral administration of tyrosol within 1 h. The metabolites were rapidly distributed in most organs and tissues and eliminated within 4 h. The greatest T4S deposition by tissue weight was observed in the liver, followed by the kidney and spleen, while M2 was most concentrated in the kidney followed by the liver and spleen. These findings indicate that T4S and M2 were distributed mainly in tissues with an abundant blood supply and were rapidly excreted in urine.