Interleukin-38 alleviates hepatic steatosis through AMPK/autophagy-mediated suppression of endoplasmic reticulum stress in obesity models.

Interleukin-38 (IL-38), recently recognized as a cytokine with anti-inflammatory properties that mitigate type 2 diabetes, has been associated with indicators of insulin resistance and nonalcoholic fatty liver disease (NAFLD). This study investigated the impact of IL-38 on hepatic lipid metabolism and endoplasmic reticulum (ER) stress. We assessed protein expression levels using Western blot analysis, while monodansylcadaverine staining was employed to detect autophagosomes in hepatocytes. Oil red O staining was utilized to examine lipid deposition. The study revealed elevated serum IL-38 levels in high-fat diet (HFD)-fed mice and IL-38 secretion from mouse keratinocytes. IL-38 treatment attenuated lipogenic lipid accumulation and ER stress markers in hepatocytes exposed to palmitate. Furthermore, IL-38 treatment increased AMP-activated protein kinase (AMPK) phosphorylation and autophagy. The effects of IL-38 on lipogenic lipid deposition and ER stress were nullified in cultured hepatocytes by suppressing AMPK through small interfering (si) RNA or 3-methyladenine (3MA). In animal studies, IL-38 administration mitigated hepatic steatosis by suppressing the expression of lipogenic proteins and ER stress markers while reversing AMPK phosphorylation and autophagy markers in the livers of HFD-fed mice. Additionally, AMPK siRNA, but not 3MA, mitigated IL-38-enhanced fatty acid oxidation in hepatocytes. In summary, IL-38 alleviates hepatic steatosis through AMPK/autophagy signaling-dependent attenuation of ER stress and enhancement of fatty acid oxidation via the AMPK pathway, suggesting a therapeutic strategy for treating NAFLD.

IL-38 alleviates atherogenic responses via SIRT6/HO-1 signaling: A promising strategy against obesity-related atherosclerosis.

Interleukin-38 (IL-38), a member of the IL-1 family, is known for its anti-inflammatory properties mediated through ligand signaling in various disease models. It plays a significant role in atherosclerosis development, forming a theoretical basis for therapeutic strategies. However, the direct effects of IL-38 on atherogenic responses in the vascular endothelium and monocytes remain unclear. In this investigation, IL-38 treatment reduced THP-1 monocyte adhesion to HUVECs, decreased the expression of vascular adhesion molecules, and mitigated inflammation in the presence of palmitate. IL-38 treatment upregulated SIRT6 expression and enhanced autophagy markers such as LC3 conversion and p62 degradation. The effects of IL-38 were nullified by siRNA-mediated suppression of SIRT6 or heme oxygenase-1 (HO-1) in HUVECs and palmitate-treated THP-1 cells. These findings reveal that IL-38 mitigates inflammation through the SIRT6/HO-1 pathway, offering a potential therapeutic approach for addressing obesity-related atherosclerosis.

Interleukin-27 as a novel player in alleviating hepatic steatosis: Mechanistic insights from an in vitro analysis.

Interleukin-27 (IL-27) is a recently discovered cytokine that has been implicated in inflammatory and metabolic conditions, such as atherosclerosis and insulin resistance. However, the mechanisms by which IL-27 attenuates hepatic lipid accumulation in hyperlipidemic conditions and counteracts endoplasmic reticulum (ER) stress, a known risk factor for impaired hepatic lipid metabolism, have not been elucidated. This in vitro study was designed to examine the effect of IL-27 on hepatic lipid metabolism. The study included the evaluation of lipogenesis-associated proteins and ER stress markers by Western blotting, the determination of hepatic lipid accumulation by Oil Red O staining, and the examination of autophagosome formation by MDC staining. The results showed that IL-27 treatment reduced lipogenic lipid deposition and the expression of ER stress markers in cultured hepatocytes exposed to palmitate. Moreover, treatment with IL-27 suppressed CD36 expression and enhanced fatty acid oxidation in palmitate-treated hepatocytes. The effects of IL-27 on hyperlipidemic hepatocytes were attenuated when adenosine monophosphate-activated protein kinase (AMPK) or 3-methyladenine (3 MA) were inhibited by small interfering RNA (siRNA). These results suggest that IL-27 attenuates hepatic ER stress and fatty acid uptake and stimulates fatty acid oxidation via AMPK/autophagy signaling, thereby alleviating hepatic steatosis. In conclusion, this study identified IL-27 as a promising therapeutic target for nonalcoholic fatty liver disease (NAFLD).

CTRP4 ameliorates inflammation, thereby attenuating the interaction between HUVECs and THP-1 monocytes through SIRT6/Nrf2 signaling.

CTRP4, identified as an adipokine, has demonstrated notable anti-inflammatory and anti-obesity effects in various disease models. Consequently, our research sought to explore the impact of CTRP4 on inflammation and the interaction between endothelial cells and monocytes in hyperlipidemic conditions. Using Western blotting, we assessed the expression levels of various proteins in HUVECs and THP-1 monocytes. Our study findings indicate that treatment with CTRP4 effectively mitigated the attachment of THP-1 monocytes to HUVECs. Furthermore, it reduced the expression of adhesion molecules and inflammation indicators in experimental cells exposed to hyperlipidemic conditions. Notably, CTRP4 treatment led to an increase in SIRT6 expression and the nuclear translocation of Nrf2. Interestingly, when SIRT6 or Nrf2 was silenced using siRNA, the positive effects of CTRP4 in HUVECs and THP-1 cells were nullified. Our results suggest that CTRP4 exhibits anti-inflammatory properties, thereby improving the interaction between endothelial cells and monocytes through the SIRT6/Nrf2-dependent pathway. This study provides insights into CTRP4 as a potential therapeutic target for mitigating obesity-related atherosclerosis.

Interleukin 38 improves insulin resistance in hyperlipidemic skeletal muscle cells via PPARδ/SIRT1-mediated suppression of STAT3 signaling and oxidative stress.

The cytokine interleukin-38 (IL-38), a recently discovered member of the IL-1 family, has been shown to regulate inflammation and improve hepatic endoplasmic reticulum stress and lipid metabolism in individuals with obesity. However, its impact on insulin signaling in skeletal muscle cells and the underlying mechanisms remain unclear. In vitro obesity models were established using palmitate treatment, and Western blot analysis was performed to assess target proteins. Commercial kits were used to measure glucose uptake in cultured myocytes. Our study showed that IL-38 treatment alleviated the impairment of insulin signaling, including IRS-1 and Akt phosphorylation, and increased glucose uptake in palmitate-treated C2C12 myocytes. Increased levels of STAT3-mediated signaling and oxidative stress were observed in these cells following palmitate treatment, and these effects were reversed by IL-38 treatment. In addition, IL-38 treatment upregulated the expression of PPARδ, SIRT1 and antioxidants. Knockdown of PPARδ or SIRT1 using appropriate siRNAs abrogated the effects of IL-38 on insulin signaling, oxidative stress, and the STAT3-dependent pathway. These results suggest that IL-38 alleviates insulin resistance by inhibiting STAT3-mediated signaling and oxidative stress in skeletal muscle cells through PPARδ/SIRT1. This study provides fundamental evidence to support the potential use of IL-38 as a safe therapeutic agent for the treatment of insulin resistance and type 2 diabetes.

Uvaol ameliorates lipid deposition in hyperlipidemic hepatocytes by suppressing protein-tyrosine phosphatase 1B/ER stress signaling.

Uvaol (UV), a pentacyclic triterpene found in olives and virgin olive oil, is known for its anti-inflammatory and antioxidant effects in various disease models. While olive oil is reported to reduce obesity and insulin resistance, the specific impact of UV on liver lipid metabolism and its molecular mechanisms are not fully understood. In this study, hepatic lipid accumulation was measured using oil red O staining, and protein expression levels in liver cells were assessed via Western blot analysis. Apoptosis was evaluated through cell viability and caspase 3 activity assays. UV treatment reduced lipid accumulation, fatty acid uptake, apoptosis, and ER stress in palmitate-treated liver cells. Additionally, UV enhanced fatty acid oxidation. Mechanistically, increased SIRT6 expression and autophagy were observed in UV-treated cells. SIRT6-targeted siRNA or 3-methyladenine blocked the effects of UV in hyperlipidemic cells. In conclusion, UV improves SIRT6/autophagy signaling, reducing lipid deposition and apoptosis in liver cells under high lipid conditions. This in vitro study provides strong evidence for potential therapeutic strategies for hepatic steatosis.

DEL-1: a promising treatment for AMD-associated ER stress in retinal pigment epithelial cells.

BACKGROUND: Age-related macular degeneration (AMD) is an irreversible eye disease that can cause blurred vision. Regular exercise has been suggested as a therapeutic strategy for treating AMD, but how exercise improves AMD is not yet understood. This study investigated the protective effects of developmental endothelial locus-1 (DEL-1), a myokine upregulated during exercise, on endoplasmic reticulum (ER) stress-induced injury in retinal pigment epithelial cells. METHODS: We evaluated the levels of AMPK phosphorylation, autophagy markers, and ER stress markers in DEL-1-treated human retinal pigment epithelial cells (hRPE) using Western blotting. We also performed cell viability, caspase 3 activity assays, and autophagosome staining. RESULTS: Our findings showed that treatment with recombinant DEL-1 dose-dependently reduced the impairment of cell viability and caspase 3 activity in tunicamycin-treated hRPE cells. DEL-1 treatment also alleviated tunicamycin-induced ER stress markers and VEGF expression. Moreover, AMPK phosphorylation and autophagy markers were increased in hRPE cells in the presence of DEL-1. However, the effects of DEL-1 on ER stress, VEGF expression, and apoptosis in tunicamycin-treated hRPE cells were reduced by AMPK siRNA or 3-methyladenine (3-MA), an autophagy inhibitor. CONCLUSIONS: Our study suggests that DEL-1, a myokine, may have potential as a treatment strategy for AMD by attenuating ER stress-induced injury in retinal pigment epithelial cells.

Adipokine gremlin-1 promotes hepatic steatosis via upregulation of ER stress by suppressing autophagy-mediated signaling.

Gremlin-1 (GR1) is a novel adipokine that is highly expressed in human adipocytes and has been shown to inhibit the BMP2/4-TGFb signaling pathway. It has an effect on insulin sensitivity. Elevated levels of Gremlin have been shown to lead to insulin resistance in skeletal muscle, adipocytes, and hepatocytes. In this study, we investigated the effect of GR1 on hepatic lipid metabolism under hyperlipidemic conditions and explored the molecular mechanisms associated with GR1 by in vitro and in vivo studies. We found that palmitate increased GR1 expression in visceral adipocytes. Recombinant GR1 increased lipid accumulation, lipogenesis, and ER stress markers in cultured primary hepatocytes. Treatment with GR1 increased EGFR expression and mTOR phosphorylation and reduced autophagy markers. EGFR or rapamycin siRNA reduced the effects of GR1 on lipogenic lipid deposition and ER stress in cultured hepatocytes. Administration of GR1 via the tail vein induced lipogenic proteins and ER stress while suppressing autophagy in the livers of experimental mice. Suppression of GR1 by in vivo transfection reduced the effects of a high-fat diet on hepatic lipid metabolism, ER stress, and autophagy in mice. These results suggest that the adipokine GR1 promotes hepatic ER stress due to the impairment of autophagy, ultimately causing hepatic steatosis in the obese state. The current study demonstrated that targeting GR1 may be a potential therapeutic approach for treating metabolic diseases, including metabolic-associated fatty liver disease (MAFLD).

CTRP4 attenuates apoptosis and epithelial-mesenchymal transition markers in podocytes through an AMPK/autophagy-dependent pathway.

Hyperglycemia, characterized by high blood glucose levels resulting from pancreatic beta cell dysfunction or impaired insulin signaling, is a contributing factor in the development of diabetic nephropathy. This study aimed to investigate the effects of C1q/TNF-related protein 4 (CTRP4), known for its anti-obesity and anti-inflammatory properties in various disease models, on podocyte apoptosis and endoplasmic reticulum (ER) stress in the presence of elevated glucose levels. The expression levels of various proteins in podocytes and adipocytes were evaluated by Western blotting. Autophagosomes in podocytes were stained by MDC. Chromatin condensation in podocytes was examined by Hoechst staining. The research revealed increased expression of CTRP4 in 3T3-L1 adipocytes and CIHP-1 podocytes exposed to high glucose (HG) conditions. Treatment with CTRP4 effectively mitigated HG-induced apoptosis and ER stress and normalized epithelial-to-mesenchymal transition (EMT) markers in CIHP-1 cells. Furthermore, elevated levels of AMPK phosphorylation and autophagy were observed in CIHP-1 cells treated with CTRP4. Silencing of AMPK or the use of 3-methyl adenine (3 MA) reduced the impacts of CTRP4 on apoptosis, EMT markers and ER stress in CIHP-1 cells. In conclusion, these findings suggest that CTRP4 alleviates ER stress in podocytes under hyperglycemic conditions, leading to the suppression of apoptosis and the restoration of EMT through AMPK/autophagy-mediated signaling. These insights provide valuable information for the development of therapeutic strategies for diabetic nephropathy.

Myokine musclin alleviates lipid accumulation in 3T3-L1 adipocytes through PKA/p38-mediated upregulation of lipolysis and suppression of lipogenesis.

Musclin (MUS), an exercise-responsive myokine, has been documented to attenuate inflammation and enhance physical endurance. However, the effects of MUS on differentiation and related molecular mechanisms in adipocytes have not yet been studied. In this study, we found that treatment with MUS attenuated lipid accumulation in fully differentiated 3T3-L1 cells. Furthermore, MUS treatment enhanced lipolysis assessed by glycerol release, and caused apoptosis, whereas it reduced the expression of lipogenic proteins, such as PPARγ and processed SREBP1. Treatment with MUS augmented phosphorylated PKA expression, whereas suppressed p38 phosphorylation in 3T3-L1 adipocytes. H89, a selective PKA inhibitor reduced the effects of MUS on lipogenic lipid accumulation as well as lipolysis except for apoptosis. These results suggest that MUS promotes lipolysis and suppresses lipogenesis through a PKA/p38-dependent pathway, thereby ameliorating lipid deposition in cultured adipocytes. The current study offers the potential of MUS as a therapeutic approach for treating obesity with few side effects.

Oroxylin-A alleviates hepatic lipid accumulation and apoptosis under hyperlipidemic conditions via AMPK/FGF21 signaling.

Oroxylin-A (OA) is an O-methylated flavone that has been demonstrated to have anti-inflammatory properties in various disease models. However, the roles of OA in hepatic lipid metabolism and the specific molecular mechanisms by which it exerts these effects are not yet fully understood. In the current study, we aimed to investigate the effects of OA on hepatic lipid deposition and apoptosis, which play a pivotal role in the development of nonalcoholic fatty liver disease (NAFLD) in obesity in vitro models. We found that treatment with OA attenuated lipid accumulation, the expression of lipogenesis-associated proteins and apoptosis in palmitate-treated primary mouse hepatocytes. OA treatment suppressed phosphorylated NFκB and IκB expression in as well as TNFα and MCP-1 release from hepatocytes treated with palmitate. Treatment of hepatocytes with OA augmented AMPK phosphorylation and FGF21 expression. siRNA of AMPK or FGF21 abolished the effects of OA on inflammation as well as lipid accumulation and apoptosis in hepatocytes under palmitate treatment conditions. In conclusion, OA improves inflammation through the AMPK/FGF21 pathway, thereby attenuating lipid accumulation and apoptosis in hepatocytes. This study may help identify new targets for developing treatments for NAFLD.

Musclin attenuates lipid deposition in hepatocytes through SIRT7/autophagy-mediated suppression of ER stress.

Musclin, an exercise-responsive myokine, has the ability to attenuate inflammation, oxidative stress, and apoptosis in cardiomyocytes under pathogenic conditions. While the potential benefits of musclin in the cardiovascular system have been well documented, its effects on hepatic endoplasmic reticulum (ER) stress and lipid metabolism are not fully understood. The present study showed that musclin treatment reduced lipid accumulation and lipogenic protein expression in primary hepatocytes exposed to palmitate. Palmitate treatment led to an increase in markers of ER stress, which was reversed by musclin treatment. Musclin treatment increased SIRT7 expression and markers of autophagy in a dose-dependent manner. Small interfering (si) RNA of SIRT7 or 3-methyladenine (3 MA) reduced the effects of musclin on lipogenic lipid deposition in hepatocytes under hyperlipidemic conditions. These findings suggest that musclin can suppress palmitate-induced ER stress by upregulating SIRT7 and autophagy signaling, thereby alleviating lipid accumulation in primary hepatocytes. The current study provides a potential therapeutic strategy for the treatment of liver diseases characterized by lipid accumulation and ER stress, such as nonalcoholic fatty liver disease (NAFLD).

Sclerostin aggravates insulin signaling in skeletal muscle and hepatic steatosis via upregulation of ER stress by mTOR-mediated inhibition of autophagy under hyperlipidemic conditions.

Recently, sclerostin (SCL), a circulating glycoprotein, was proposed to be a novel myokine involved in developing metabolic disorders. The association between SCL levels and insulin resistance in skeletal muscle, liver, and adipose tissue was studied in individuals with aggravated glucose tolerance. Thus, we hypothesized that elevated circulating SCL might affect skeletal muscle insulin signaling and hepatic lipid metabolism, and aimed to investigate the effects of SCL on skeletal muscle insulin resistance and hepatic steatosis in obesity using in vitro and in vivo experimental models under hyperlipidemic conditions. In the current study, we found elevated SCL messenger RNA expression levels in myocytes in obese patients. In addition to a higher blood level, SCL was expressed at an elevated level in the skeletal muscle of mice fed a high-fat diet (HFD). Higher SCL release levels and expression were also noticed in palmitate-treated C2C12 myocytes. SCL suppression by in vivo transfection improves skeletal muscle insulin resistance and hepatic steatosis in HFD-fed mice. The treatment of C2C12 myocytes with recombinant SCL aggravated insulin signaling. Furthermore, treatment with SCL augmented lipogenic lipid deposition in human primary hepatocytes. Treatment with SCL upregulated mammalian target of rapamycin (mTOR) phosphorylation and suppressed autophagy markers, thereby causing endoplasmic reticulum (ER) stress. 4-Phenylbutyric acid, a pharmacological ER stress inhibitor, abolished the effects of SCL on insulin signaling in C2C12 myocytes and lipid accumulation in primary hepatocytes. In conclusion, SCL promotes skeletal muscle insulin resistance and hepatic steatosis by upregulating ER stress via the mTOR/autophagy-mediated pathway. The present study suggests that antagonizing SCL might be a novel therapeutic strategy for simultaneously managing insulin resistance and hepatic steatosis in obesity.

Abietic acid alleviates endoplasmic reticulum stress and lipid accumulation in human primary hepatocytes through the AMPK/ORP150 signaling.

Abietic acid (AA), the main component of pine resin that has been traditionally used as Asian medicine, has been reported to demonstrate anti-inflammatory activities. Despite this, little is known about the effects of AA on hepatic endoplasmic reticulum (ER) stress and lipid metabolism. This study investigated the impacts of AA on ER stress and steatosis in in vitro obesity models. We found that Treatment with AA reduced lipid deposition and lipogenesis-related proteins expression in human primary hepatocytes. Augmented expression of ER stress markers (phospho-eukaryotic initiation factor-2α (eIF2α) and C/EBP homologous protein (CHOP)) in palmitate-treated hepatocytes were reversed by AA treatment. Further, AA treatment increased the expression of phospho-AMPK and oxygen-regulated protein 150 (ORP150) in hepatocytes. siRNA-associated knockdown of AMPK or ORP150 expression reduced the effects of AA on not only hepatic ER stress but also lipogenesis and apoptosis. These results denote that AA attenuates lipid accumulation in hepatocytes in the presence of palmitate through the suppression of ER stress by AMPK/ORP150 signaling. AA could be a potential candidate for treating non-alcoholic fatty liver disease.

Inhibitory Effects of Verrucarin A on Tunicamycin-Induced ER Stress in FaO Rat Liver Cells.

Endoplasmic reticulum (ER) stress is linked with development and maintenance of cancer, and serves as a therapeutic target for treatment of cancer. Verrucarin A, isolated from the broth of Fusarium sp. F060190, showed potential inhibitory activity on tunicamycin-induced ER stress in FaO rat liver cells. In addition, the compound decreased tunicamycin-induced GRP78 promoter activity in a dose dependent manner without inducing significant inhibition of luciferase activity and cell growth for 6 and 12 h. Moreover, the compound decreased the expression of GRP78, CHOP, XBP-1, and suppressed XBP-1, and reduced phosphorylation of IRE1α in FaO rat liver cells. This evidence suggests for the first time that verrucarin A inhibited tunicamycin-induced ER stress in FaO rat liver cells.

Therapeutic potential of ginsenoside compound K in managing tenocyte apoptosis and extracellular matrix damage in diabetic tendinopathy.

The prevalence of tendinopathy in patients with diabetes is well documented. Despite efforts to improve diabetes management, there is a lack of research on therapeutic agents targeting the core features of tendinopathy, namely, tenocyte apoptosis and extracellular matrix (ECM) damage. In this study, we investigated the potential of ginsenoside compound K (CK), known for its antidiabetic properties, to mitigate tenocyte apoptosis, inflammation, oxidative stress, and the metalloproteinase (MMP) system under hyperglycemic conditions. Our research also aimed to unravel the molecular mechanism underlying the effects of CK. The assessment of apoptosis involved observing intracellular chromatin condensation and measuring caspase 3 activity. To gauge oxidative stress, we examined cellular ROS levels and hydrogen peroxide and malondialdehyde concentrations. Western blotting was employed to determine the expression of various proteins. Our findings indicate that CK treatment effectively countered high glucose-induced apoptosis, inflammation, and oxidative stress in cultured tenocytes. Furthermore, CK normalized the expression of MMP-9, MMP-13, and TIMP-1. Notably, CK treatment boosted the expression of PPARγ and antioxidant enzymes. We conducted small interfering (si) RNA experiments targeting PPARγ, revealing its role in mediating CK's effects on tendinopathy features in hyperglycemic tenocytes. In conclusion, these in vitro results offer valuable insights into the potential therapeutic role of CK in managing tendinopathy among individuals with diabetes. By addressing crucial aspects of tendinopathy, CK presents itself as a promising avenue for future research and treatment development in this domain.

Musclin Mitigates the Attachment of HUVECs to THP-1 Monocytes in Hyperlipidemic Conditions through PPARα/HO-1-Mediated Attenuation of Inflammation.

Musclin, a myokine, undergoes modulation during exercise and has demonstrated anti-inflammatory effects in cardiomyocytes and glomeruli. However, its role in atherosclerotic responses remains unclear. This study aimed to explore the impact of musclin on inflammatory responses and the interaction between endothelial cells and monocytes under hyperlipidemic conditions. The attachment levels of THP-1 monocytes on cultured HUVECs were examined. Inflammation and the expression of cell adhesion molecules were also evaluated. To explore the molecular mechanisms of musclin, PPARα or heme oxygenase 1 (HO-1) siRNA transfection was performed in HUVECs. The results revealed that treatment with recombinant musclin effectively suppressed the attachment of palmitate-induced HUVECs to THP-1 cells and reduced the expression of cell adhesion proteins (ICAM-1, VCAM-1, and E-selectin) in HUVECs. Furthermore, musclin treatment ameliorated the expression of inflammation markers (phosphorylated NFκB and IκB) in both HUVECs and THP-1 monocytes, as well as the release of TNFα and MCP-1 from HUVECs and THP-1 monocytes. Notably, musclin treatment augmented the expression levels of PPARα and HO-1. However, when PPARα or HO-1 siRNA was employed, the beneficial effects of musclin on inflammation, cell attachment, and adhesion molecule expression were abolished. These findings indicate that musclin exerts anti-inflammatory effects via the PPARα/HO-1 pathway, thereby mitigating the interaction between endothelial cells and monocytes. This study provides evidence supporting the important role of musclin in ameliorating obesity-related arteriosclerosis and highlights its potential as a therapeutic agent for treating arteriosclerosis.

Madecassoside modulates lipid metabolism in visceral adipocytes: exploring the browning, lipolysis, and lipogenesis mechanisms for potential obesity treatment.

OBJECTIVES: Madecassoside (MA) is a triterpene derived from Centella asiatica that has been recognized for its antioxidant and anti-inflammatory properties in various disease models. However, its direct impact on cultured white adipocytes and the underlying mechanisms, mainly through gene knockdown, have not been thoroughly explored. METHODS: Western blot analysis was utilized to assess the expression levels of various proteins, while oil red O staining was used to measure lipid deposition. The adipocyte shapes were confirmed using H&E staining. KEY FINDINGS: MA treatment enhanced browning and lipolysis in 3T3-L1 adipocytes and adipose tissue from experimental mice while suppressing lipogenesis. Furthermore, MA treatment increased the expression of PPARα and FGF21 in 3T3-L1 adipocytes as well as the secretion of FGF21 into the culture medium. Knockdown of PPARα or FGF21 using siRNA diminished the effects of MA on lipid metabolism in cultured adipocytes. CONCLUSIONS: These findings demonstrate that MA promotes thermogenic browning and lipolysis while inhibiting adipocyte lipogenesis, thus showing the potential for attenuating obesity. The study suggested that MA could be a viable therapeutic approach for treating obesity.

The Extract of Humulus japonicus Inhibits Lipogenesis and Promotes Lipolysis via PKA/p38 Signaling.

INTRODUCTION: Previous research has shown that an aqueous extract of Humulus japonicus (EH) can ameliorate hypertension, nonalcoholic fatty liver disease, and oxidative stress in adipocytes by activating the thermogenic pathway. However, the effects of an ethanol (30%) extract of EH on obesity are unknown. METHODS: Various protein expression levels in fully differentiated 3T3-L1 adipocytes were assessed by Western blotting. Lipid deposition in 3T3-L1 adipocytes was examined by oil red O staining. The MTT assay was used to evaluate adipocyte viability. Caspase 3 activity and glycerol release were determined using commercial assay kits. RESULTS: In this study, we discovered that EH treatment inhibited lipogenesis and promoted lipolysis in both differentiated 3T3-L1 adipocytes and adipose tissue of mice fed a high-fat diet. EH treatment also increased phosphorylated protein kinase A (PKA) levels while reducing p38 phosphorylation. When H89, a PKA inhibitor, was used, the effects of EH on lipogenic lipid accumulation and lipolysis in 3T3-L1 adipocytes were eliminated. Treatment with luteolin 7-O-ß-d-glucoside (LU), the major active compound in EH, also suppressed lipid deposition and p38 phosphorylation but enhanced lipolysis in 3T3-L1 adipocytes. These changes were abrogated by H89. CONCLUSION: These findings indicate that EH containing LU reduces lipogenesis and stimulates lipolysis via the PKA/p38 signaling pathway, leading to an improvement in obesity in mice. Therefore, our study suggested that EH could be a promising therapeutic agent for treating obesity.

Robust sound-guided image manipulation.

Recent successes suggest that an image can be manipulated by a text prompt, e.g., a landscape scene on a sunny day is manipulated into the same scene on a rainy day driven by a text input "raining". These approaches often utilize a StyleCLIP-based image generator, which leverages multi-modal (text and image) embedding space. However, we observe that such text inputs are often bottlenecked in providing and synthesizing rich semantic cues, e.g., differentiating heavy rain from rain with thunderstorms. To address this issue, we advocate leveraging an additional modality, sound, which has notable advantages in image manipulation as it can convey more diverse semantic cues (vivid emotions or dynamic expressions of the natural world) than texts. In this paper, we propose a novel approach that first extends the image-text joint embedding space with sound and applies a direct latent optimization method to manipulate a given image based on audio input, e.g., the sound of rain. Our extensive experiments show that our sound-guided image manipulation approach produces semantically and visually more plausible manipulation results than the state-of-the-art text and sound-guided image manipulation methods, which are further confirmed by our human evaluations. Our downstream task evaluations also show that our learned image-text-sound joint embedding space effectively encodes sound inputs. Examples are provided in our project page: https://kuai-lab.github.io/robust-demo/.