HFD-induced Obese Mice Research Articles

Hepatic Runx1t1 improves body fat index after endurance exercise in obese mice

Endurance exercise could attenuate obesity induced by high fat diet (HFD). Thus, the purpose of this study was to explore the crucial targets that play key roles in the improvement of body fat index (BFI) in obese mice by endurance exercise. Firstly, we constructed murine obesity models: High fat diet control (HFD) group, HFD exercise (HFE) group, normal chow diet control (NC) group, and normal chow diet exercise (NE) group. Next, we identified the BFI improvement related genes using differential gene analysis, and investigated these genes’ functional pathways using functional enrichment analysis. The qRT-PCR and western blot assays were used to determine the gene expression and protein expression, respectively. Gene set enrichment analysis was used to explore the potential pathways associated with endurance exercise in obese mice and Mitochondrial respiratory control ratio (RCR) assay was applied to determine the RCR in the liver tissues of mice. We discovered that endurance exercise remarkably reduced the body weights and BFI of HFD-induced obese mice. Runx1t1 was related to the improvement of BFI by endurance exercise in HFD-induced obese mice. Runx1t1 mRNA and protein levels in liver tissues were observably decreased in HFD mice compared to mice in HFE, NC and NE groups. Moreover, Glucagon signaling pathway that was associated with mitochondrial function was significantly activated in HFE mice. The Runx1t1 expression exhibited an observable negative correlation with Acaca in HFD mice. Moreover, the mitochondrial RCR level was significantly increased in HFE mice than that in HFD mice. In HFD-induced obese mice, Runx1t1 was implicated in the improvement of BFI via endurance exercise. Endurance exercise could improve mitochondrial dysfunction in obese mice by activating the Runx1t1.

Early macrophage-mediated Bdnf expression in white adipose tissue during high-fat diet feeding

The expression of brain-derived neurotrophic factor (BDNF) is observed not only in the brain, but also in peripheral tissues including white adipose tissues (WATs). Here, we showed that the mRNA expression of Bdnf in inguinal WAT (iWAT) and epididymal WAT (eWAT) increased within 2 weeks of feeding mice with a high-fat diet (HFD). In mice on a 2-week HFD, the induction of Bdnf expression in WATs was significantly correlated with increases in body weight, suggesting that Bdnf expression may increase at an early stage of obesity. The mRNA expression of hypoxia-inducible factor 1α and platelet-derived growth factor, which are involved in neovascularization and the subsequent expansion of adipose tissues, increased in the iWAT of mice on the 2-week HFD. We also found that the expression of macrophage marker F4/80 in iWAT increased under the HFD. Interestingly, HFD-induced Bdnf expression in iWAT was not observed when macrophages were removed by the administration of clodronate liposomes. Accordingly, mice receiving clodronate liposomes also exhibited a significant reduction in the HFD-induced increase in body weight. In conclusion, increased body weight in HFD-induced obese model mice was accompanied by the induction of Bdnf expression in iWAT and was probably mediated by macrophages. Our findings imply a novel function for BDNF in iWAT at an early stage of obesity.

6-Gingerol, an active ingredient of ginger, reshapes gut microbiota and serum metabolites in HFD-induced obese mice

6-Gingerol, an active ingredient of ginger, reshapes gut microbiota and serum metabolites in HFD-induced obese mice

Electroacupuncture activates angiogenesis by regulating the PI3K/Pten/Thbs1 signaling pathway to promote the browning of adipose tissue in HFD-induced obese mice

This study investigated the effect of electroacupuncture (EA) on the browning of white adipose tissue (WAT) via angiogenesis and its potential mechanism in obese mice. Four-week-old male C56BL/6 mice were randomly divided into a high-fat diet (HFD) and a normal chow diet (ND) group. After 12 weeks, HFD mice were randomly divided into two groups to receive or not receive EA for 3 weeks. After EA treatment, body weight, adipocyte size, serum glucose (GLU), triacylglycerol (TG), cholesterol (CHO), leptin (Lep), monocyte chemoattractant protein-1 (MCP-1), WAT browning-related genes, angiogenesis-related genes, and the PI3K/Pten/Thbs1 signaling pathway were evaluated. The results indicated that EA significantly reduced body weight, adipocyte size, and serum concentrations of GLU, TG, CHO, Lep and MCP-1 and promoted WAT browning. Angiogenesis and the PI3K/Pten/Thbs1 signaling pathway were all activated by EA intervention. The expression levels were consistent with the results of RNA-seq and confirmed via qRTPCR and WB. Our study showed that EA may activate angiogenesis via the PI3K/Pten/Thbs1 signaling pathway in WAT, thereby promoting the browning and thermogenesis of adipose tissue.

Brown adipose tissue-derived Nrg4 alleviates non-alcoholic fatty liver disease in mice

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, seriously affecting human health. Carnosine, which widely exists in the skeletal muscle of marine migratory fish, birds, and chickens, is a non-protein histidine dipeptide with anti-inflammatory properties. To investigate whether carnosine can alleviate high-fat diet (HFD)-induced NAFLD. Mice were fed a HFD and orally administered with carnosine at doses of 60, 120, and 240 mg/kg/day for 16 weeks. Its lipid content, liver oxidative damage, neuregulin 4 (Nrg4), lipid-associated protein, and inflammation-related protein content in mice were measured and its brown fat morphology were observed by microscope. Results showed that carnosine significantly inhibited mice body weight gain (reduced by 28.90%, 25.43%, and 42.34%, respectively), liver oxidative damage, and lipid metabolism and decreased its serum interleukin-1β (IL-1β) content in HFD-induced obese mice (P < 0.05).Western blot analysis showed that carnosine could activate brown adipose tissue and upregulate Nrg4 to inhibit sterol regulatory element binding protein-1 (SREBP-1) expression and the NOD-like receptor thermal protein domain associated protein 3/ nuclear factor kappa-B (NLRP3/NF-κB) pathway. These results indicated that carnosine could lessen the effects of a HFD on NAFLD in mice.

Fumigaclavine C ameliorates liver steatosis by attenuating hepatic de novo lipogenesis via modulation of the RhoA/ROCK signaling pathway

BackgroundNon-alcoholic fatty liver disease (NAFLD) has been well defined as a common chronic liver metabolism disorder. Statins as a first-line therapeutic treatment had some side effects. Here, we found that Fumigaclavine C (FC) was collected from endophytic Aspergillus terreus via the root of Rhizophora stylosa (Rhizophoraceae), had potential anti-adipogenic and hepatoprotective effects both in vitro and in vivo without obvious adverse side effects. However, the mechanisms of the prevention and management of FC for hepatic steatosis are incompletely delineated.MethodsThe pharmacodynamic effects of FC were measured in high-fat diet (HFD)-induced obese mice. Liver index and blood biochemical were examined. Histopathological examination in the liver was performed by hematoxylin & eosin or oil red O. The levels of serum TG, TC, LDL-c, HDL-c, FFA, T-bili, ALT, AST, creatinine, and creatine kinase were estimated via diagnostic assay kits. The levels of hepatic lipid metabolism-related genes were detected via qRT-PCR. The expression levels of hepatic de novo lipogenesis were quantitated with Western blot analysis. ResultsFC-treatment markedly reduced hepatic lipid accumulation in HFD-induced obese mice. FC significantly attenuated the hepatic lipid metabolism and ameliorated liver injury without obvious adverse side effects. Moreover, FC also could dose-dependently modulate the expressions of lipid metabolism-related transcription genes. Mechanically, FC notably suppressed sterol response element binding protein-1c mediated de novo lipogenesis via interfering with the RhoA/ROCK signaling pathway by decreasing the levels of geranylgeranyl diphosphate and farnesyl diphosphate.ConclusionsThese findings suggested that FC could improve hepatic steatosis through inhibiting de novo lipogenesis via modulating the RhoA/ROCK signaling pathway.

Complementary effects of dapagliflozin and lobeglitazone on metabolism in a diet-induced obese mouse model

Thiazolidinedione, an insulin sensitizer, has beneficial effects on glucose metabolism; however, there are concerns regarding weight gain and heart failure. Sodium-glucose co-transporter 2 (SGLT2) inhibitors can reduce body weight, increase diuresis, and play a protective role in heart failure. We examined the complementary effects of dapagliflozin, an SGLT2 inhibitor, and lobeglitazone, a thiazolidinedione, in high-fat diet (HFD)-induced obese mice. We treated HFD-induced obese mice with vehicle, dapagliflozin, lobeglitazone, and their combination for 12 weeks. Oral glucose tolerance and insulin tolerance tests were performed after 12-week treatment, and body composition was measured by dual-energy X-ray absorptiometry before and after treatment. We analyzed oxygen consumption rate (OCR) using 3T3-L1 cells after treatment of β-hydroxybutyrate and/or lobeglitazone. Treatment with a combination of dapagliflozin and lobeglitazone resulted in a significant decrease in postprandial hyperglycemia compared with dapagliflozin monotherapy, but not compared with lobeglitazone monotherapy. The addition of dapagliflozin to lobeglitazone treatment did not attenuate weight gain compared with lobeglitazone monotherapy in this study. However, this combination prevented the increase of organ weight of liver and heart, and OCR in 3T3-L1 cells was increased after treatment with a combination of β-hydroxybutyrate and lobeglitazone compared to lobeglitazone monotherapy. We confirmed the beneficial effect of lobeglitazone on glucose metabolism; however, we did not find any beneficial effect of dapagliflozin on body weight in HFD-induced obese mice. However, the protective effects of dapagliflozin and lobeglitazone combined therapy on the liver, heart, energy consumption, and β-cell senescence are worth investigating in clinical trials.

Alisol B blocks the development of HFD-induced obesity by triggering the LKB1-AMPK signaling in subcutaneous adipose tissue

As a global epidemic disease, obesity causes dysfunction of glucose and lipid metabolism leading to persistently high morbidity and mortality. Given the difficulty to achieve and maintain weight loss through controlling diet and physical exercise, pharmacotherapy is considered an effective treatment for obesity. This investigation revealed that alisol B, a triterpene monomer isolated from the classical Chinese medicine Alisma orientale (Sam.) Juzep, functioned in suppressing adipogenesis and reducing the mass of subcutaneous adipose tissue, resulting in the reduction of weight gain, and improvements of hyperglycemia, hyperlipidemia, and insulin resistance in HFD-induced obese mice. In consistent to the results, alisol B also significantly inhibited adipocyte differentiation and maturation in vitro. Furthermore, our data revealed that the effects of alisol B on adipogenesis were mediated by LKB1-AMPK signaling pathway. In total, alisol B could be a potential lead compound which contributes to the improvement of obesity-related metabolic disorders.

Ophiopogonin D ameliorates non‑alcoholic fatty liver disease in high‑fat diet‑induced obese mice by improving lipid metabolism, oxidative stress and inflammatory response.

Lipid metabolic disorders, oxidative stress and inflammation in the liver are key steps in the progression of non-alcoholic fatty liver disease (NAFLD). Ophiopogonin D (OP-D), the main active ingredient of Ophiopogon japonicus, exhibits several pharmacological activities such as antioxidant and anti-inflammatory activities. Therefore, the current study aimed to explore the role of OP-D in NAFLD in a high-fat diet (HFD)-induced obesity mouse model. To investigate the effect of OP-D on NAFLD in vivo, a NAFLD mouse model was established following feeding mice with HFD, then the mice were randomly treated with HFD or HFD + OP-D for 4 weeks. Subsequently, primary mouse hepatocytes were isolated, and enzyme-linked immunosorbent assay, reverse transcription-quantitative PCR western blotting and immunofluorescence analysis were used for assessment to explore the direct effect of OP-D in vitro. The results of the present study indicated that OP-D could ameliorate NAFLD in HFD-induced obese mice by regulating lipid metabolism and antioxidant and anti-inflammatory responses. Additionally, OP-D treatment decreased lipogenesis and inflammation levels in vitro, suggesting that the NF-κB signaling pathway may be involved in the beneficial effects of OP-D on NAFLD.

Gluten worsens non-alcoholic fatty liver disease by affecting lipogenesis and fatty acid oxidation in diet-induced obese apolipoprotein E-deficient mice.

Obesity is closely associated with non-alcoholic fatty liver disease (NAFLD), characterized by hepatic fat accumulation and hepatocyte injury. Preclinical studies have shown exacerbated weight gain associated with an obesogenic gluten-containing diet. However, whether gluten affects obesity-induced hepatic lipid accumulation still remains unclear. We hypothesized that gluten intake could affect fatty liver development in high-fat diet (HFD)-induced obese mice. Thus, we aimed to investigate the impact of gluten intake on NAFLD in HFD-induced obese mice. Male apolipoprotein E-deficient (Apoe-/-) mice were fed with a HFD containing (GD) or not (GFD) vital wheat gluten (4.5%) for 10weeks. Blood and liver were collected for further analysis. We found that gluten exacerbated weight gain, hepatic fat deposition, and hyperglycemia without affecting the serum lipid profile. Livers of the GD group showed a larger area of fibrosis, associated with the expression of collagen and MMP9, and higher expression of apoptosis-related factors, p53, p21, and caspase-3. The expression of lipogenic factors, such as PPARγ and Acc1, was more elevated and factors related to beta-oxidation, such as PPARα and Cpt1, were lower in the GD group compared to the GFD. Further, gluten intake induced a more significant expression of Cd36, suggesting higher uptake of free fatty acids. Finally, we found lower protein expression of PGC1α followed by lower activation of AMPK. Our data show that gluten-containing high-fat diet exacerbated NAFLD by affecting lipogenesis and fatty acid oxidation in obese Apoe-/- mice through a mechanism involving lower activation of AMPK.

Anti-Obesity Effects of Hovenia Dulcis Branches in Mouse Adipocytes, 3t3-l1 Cells, and High-Fat Diet Obese Mice.

Hovenia dulcis has been reported to have various pharmacological activities, but most studies were done with its fruits. However, from an economic point of view, the use of discarded leaves and branches as by-products is very valuable. In this study, thein vitro andin vivo anti-obesity activities of Hovenia dulcis branch extract (HDB) were investigated to evaluate the applicability of HDB as an anti-obesity agent. In differentiated 3T3-L1 cells, HDB inhibited lipid droplet accumulation. And HDB downregulated CEBPα, PPARγ, and perilipin-1, and upregulated ATGL, p-HSL, HSL, p-AMPK, UCP-1, PGC-1α, PRDM16, LC3-II, and p62/SQSTM1. In addition, HDB increased free glycerol content. In HFD-induced obese mice, HDB reduced body weight and total fat weight. In addition, HDB decreased blood LDL-cholesterol, blood total cholesterol, and blood triglyceride. These results indicate that HDB has anti-obesity activity and HDB can be used as a healthy functional food agent for weight reduction.

Anti-obesity effects of Camellia (Camellia oleifera Abel) oil treatment on high-fat diet-induced obesity in C57BL/6J mice.

In the current study, we investigated the effects of camellia oil and camellia oil infused with herbs (Camellia oleifera Abel) on obesity in obese mice fed a high-fat diet (HFD). The antioxidant activity of camellia oil in scavenging free radicals was investigated. Additionally, body and organ weight changes, serum and liver marker parameters, antioxidant enzyme activities, liver and epididymal fat histology, protein and gene expression associated with lipogenesis and hyperglycemia effect on adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, were examined in HFD-induced obese mice. The hepatic steatosis and epididymal fat were significantly reduced by the oral administration of camellia oil and herb-infused camellia oil. Moreover, hepatic and serum marker parameters such as total cholesterol, insulin, triglycerides, tumor necrosis factor-α, adiponectin, thiobarbituric acid reactive substances, aspartate aminotransferase, and alanine transaminase were beneficially impacted. Additionally, the activity of antioxidant enzymes also increased. Camellia oil and herb-infused camellia oil treatments reduced the expression of genes linked to hyperglycemia and lipogenesis via activation of AMPK phosphorylation. For many people, exercise poses an obstacle in the daily routine due to lack of ease, difficulty in maintaining consistency, and hard work. Camellia oil combined with herbs has anti-obesity and antihyperglycemic effects. These findings indicate that treatment with herb-infused camellia oil is most beneficial for elderly individuals who do not prefer frequent exercise.

363-OR: Brown Adipose Tissue m6A mRNA Methylation Regulates Systemic Insulin Sensitivity via a Prostaglandin Interorgan Axis

Brown adipose tissue (BAT) has the capacity to regulate peripheral insulin sensitivity via the secretion of signaling lipids. N6-methyladenosine (m6A) is among the most prevalent and abundant post-transcriptional RNA modifications in eukaryotes. Recently, m6A has been shown to regulate islet and hepatic metabolism as well as BAT adipogenesis and energy expenditure. Here, we demonstrate that deficiency of m6A methyltransferase-like 14 (M14) in BAT positively regulates BAT-secretory function to improve systemic insulin sensitivity through inter-organ communication. Using lipidomic approaches, we identified prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as M14KOBAT-secreted insulin sensitizers. Notably, circulatory PGE2 and PGF2a showed significant inverse correlation with HOMA-IR in humans. Furthermore, in vivo administration of PGE2 and PGF2a in HFD-induced insulin resistant obese mice recapitulated the phenotypes of M14KO mice. Exogenous PGE2 or PGF2a significantly improved insulin stimulated-pAKT by suppressing expression of specific phosphatases in human hepatocyte cell line. Mechanistically, M14-mediated m6A installation destabilizes transcripts encoding PGE2 and PGF2a synthases in brown adipocytes in an YTHDF2/3-dependent manner. Collectively, these results unveil a new mechanism by which m6A-facilitated BAT-secretory function enables the regulation of whole body insulin sensitivity. Disclosure L.Xiao: None. J.Pihlajamaki: None. Y.Tseng: Consultant; Cellarity, LyGenesis. R.Kulkarni: Advisory Panel; Novo Nordisk, Inversago, Biomea Fusion, Inc., REDD Pharma, Research Support; Inversago. D.F.De jesus: None. C.Ju: None. J.Wei: None. J.Hu: None. T.Tsuji: None. C.Cero: None. D.Kaminska: None. A.M.Cypess: None.

Combination of Panax ginseng and Diospyros kaki Leaf Inhibits White Adipocyte Differentiation and Browning Process through AMP-Activated Protein Kinase (AMPK) Activation In Vitro and In Vivo.

Activating brown adipose tissue (BAT) and stimulating white adipose tissue (WAT) browning is a prospective obesity treatment method. Dietary components derived from plants are the most effective approach to activate BAT and promote WAT browning in rodents. This study investigated the synergistic effects of Panax ginseng (PG) and Diospyros kaki leaf (DKL) extract on adipocyte differentiation and browning, as well as the molecular mechanism underlying their beneficial effects. The administration of PG and DKL to HFD-induced obese mice significantly decreased body weight and epididymal and abdominal adipose tissue mass. In in vitro, PG inhibited the adipogenesis of 3T3-L1 adipocytes by regulating the expression of key adipogenic regulators, such as peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/enhancer-binding protein (C/EBP)-α. In contrast, DKL negligibly influenced the adipogenesis of 3T3-L1 adipocytes but greatly increased the protein expression of UCP-1, PGC-1α, and PPARα in BAT and/or WAT. Moreover, PG and DKL inhibited adipogenesis synergistically and activated white adipocyte browning via AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) pathways. These results suggest that a combination of PG and DKL regulates adipogenesis in white adipocytes and browning in brown adipocytes by activating AMPK/SIRT1 axis. The potential use of PG and DKL may represent an important strategy in obesity management that will be safer and more effective.

Salidroside protects mice from high-fat diet-induced obesity by modulating the gut microbiota

Obesity is a systemic disease with multisystem inflammation associated with gut dysbiosis. Salidroside (SAL) which is a major glycoside extracted from Rhodiola rosea L. has a wide range of pharmacological effects, but the role of gut microbiota in the protective effects of SAL on obesity has not been studied. Herein, we aim to explore whether SAL could ameliorate high-fat diet (HFD)-induced obesity in mice by modulating microbiota. Results showed that oral treatment with SAL alleviated HFD-induced obesity in mice as evidenced by body weight and fat weight. SAL supplementation effectively attenuated fat accumulation, lipid synthesis genes expression, liver inflammation, and metabolic endotoxemia. In addition, SAL treatment alleviated intestinal damage and increased the expression of mucin protein (Mucin-2) and tight junction (TJ) proteins (Occludin and Zonula Occludens-1). 16S rRNA sequencing analysis revealed that the gut microbiota of obese mice was also partly improved by SAL via restoring the microbial community structure and diversity. A fecal microbiota transplantation (FMT) study was designed to verify the causality. Compared with fecal transplantation (FM) from the HFD-treated mice, FM from the SAL-treated mice significantly mitigate the symptoms of obese mice, including decreasing body weight, fat accumulation, and attenuating pathological damage in the gut. Thus, SAL could be a remarkable candidate to prevent obesity.

Amelioration of Obesity-Related Disorders in High-Fat Diet-Fed Mice following Fecal Microbiota Transplantation from Inulin-Dosed Mice.

The role of inulin in alleviating obesity-related disorders has been documented; yet, its underlying mechanisms still need to be further investigated. This study attempted to elucidate the causative link between the gut microbiota and the beneficial effect of inulin on obesity-related disorders via transferring the fecal microbiota from inulin-dosed mice to high-fat diet (HFD)-induced obese recipient mice. The results show that inulin supplementation can decrease body weight, fat accumulation, and systemic inflammation and can also enhance glucose metabolism in HFD-induced obese mice. Treatment with inulin reshaped the structure and composition of the gut microbiota in HFD-induced obese mice, as characterized by increases in the relative abundances of Bifidobacterium and Muribaculum and decreases in unidentified_Lachnospiraceae and Lachnoclostridium. In addition, we found that these favorable effects of inulin could be partially transferable by fecal microbiota transplantation, and Bifidobacterium and Muribaculum might be the key bacterial genera. Therefore, our results suggest that inulin ameliorates obesity-related disorders by targeting the gut microbiota.

Transient Receptor Potential (TRP) based polypharmacological combination stimulates energy expending phenotype to reverse HFD-induced obesity in mice

Background & aimObesity is a worldwide epidemic leading to decreased quality of life, higher medical expenses and significant morbidity. Enhancing energy expenditure and substrate utilization in adipose tissues through dietary constituents and polypharmacological approaches is gaining importance for the prevention and therapeutics of obesity. An important factor in this regard is Transient Receptor Potential (TRP) channel modulation and resultant activation of “brite” phenotype. Various dietary TRP channel agonists like capsaicin (TRPV1), cinnamaldehyde (TRPA1), and menthol (TRPM8) have shown anti-obesity effects, individually and in combination. We aimed to determine the therapeutic potential of such combination of sub-effective doses of these agents against diet-induced obesity, and explore the involved cellular processes. Key findingsThe combination of sub-effective doses of capsaicin, cinnamaldehyde and menthol induced “brite” phenotype in differentiating 3T3-L1 cells and subcutaneous white adipose tissue of HFD-fed obese mice. The intervention prevented adipose tissue hypertrophy and weight gain, enhanced the thermogenic potential, mitochondrial biogenesis and overall activation of brown adipose tissue. These changes observed in vitro as well as in vivo, were linked to increased phosphorylation of kinases, AMPK and ERK. In the liver, the combination treatment enhanced insulin sensitivity, improved gluconeogenic potential and lipolysis, prevented fatty acid accumulation and enhanced glucose utilization. SignificanceWe report on the discovery of therapeutic potential of TRP-based dietary triagonist combination against HFD-induced abnormalities in metabolic tissues. Our findings indicate that a common central mechanism may affect multiple peripheral tissues. This study opens up avenues of development of therapeutic functional foods for obesity.

Chronic voluntary wheel running exercise ameliorates metabolic dysfunction via PGC-1α expression independently of FNDC5/irisin pathway in high fat diet-induced obese mice

Exercise is an effective intervention to ameliorate metabolic diseases including obesity and insulin resistance, but the mechanisms involved in the metabolic amelioration have not yet been fully elucidated. This study aimed to determine whether AMPK–SIRT1–PGC-1α–FNDC5/Irisin-UCP1 expression is activated and whether metabolic dysfunction is ameliorated by chronic voluntary wheel running (VWR) in high-fat diet (HFD) induced obese mice. C57BL6J mice were randomly assigned into three groups at the age of 7 weeks for 10 weeks: normal chow diet (CON) group, HFD group, and HFD + VWR group. Chronic VWR ameliorates metabolic parameters and leads to increases in the expression of PGC-1α in the gastrocnemius muscle in HFD-induced obese mice. In contrast, the expression of AMPKα, SIRT1, and FNDC5, or circulating irisin levels did not lead to alteration. Improvement of metabolic health was partly mediated via PGC-1α expression by chronic VWR, but not FNDC5/Irisin pathway in HFD-induced obese mice.

Hepatic G Protein-Coupled Receptor 180 Deficiency Ameliorates High Fat Diet-Induced Lipid Accumulation via the Gi-PKA-SREBP Pathway.

Single-nucleotide polymorphisms in G protein-coupled receptor 180 (GPR180) are associated with hypertriglyceridemia. The aim of this study was to determine whether hepatic GPR180 impacts lipid metabolism. Hepatic GPR180 was knocked down using two approaches: Gpr180-specific short hairpin (sh)RNA carried by adeno-associated virus 9 (AAV9) and alb-Gpr180-/- transgene established by crossbreeding albumin-Cre mice with Gpr180flox/flox animals, in which Gpr180 was specifically knocked down in hepatocytes. Adiposity, hepatic lipid contents, and proteins related to lipid metabolism were analyzed. The effects of GPR180 on triglyceride and cholesterol synthesis were further verified by knocking down or overexpressing Gpr180 in Hepa1-6 cells. Gpr180 mRNA was upregulated in the liver of HFD-induced obese mice. Deficiency of Gpr180 decreased triglyceride and cholesterol contents in the liver and plasma, ameliorated hepatic lipid deposition in HFD-induced obese mice, increased energy metabolism, and reduced adiposity. These alterations were associated with downregulation of transcription factors SREBP1 and SREBP2, and their target acetyl-CoA carboxylase. In Hepa1-6 cells, Gpr180 knockdown decreased intracellular triglyceride and cholesterol contents, whereas its overexpression increased their levels. Overexpression of Gpr180 significantly reduced the PKA-mediated phosphorylation of substrates and consequent CREB activity. Hence, GPR180 might represent a novel drug target for intervention of adiposity and liver steatosis.

Effect and mechanism of Magnolia officinalis pharmacopuncture for treating localized fat via network pharmacology and experimental study

BackgroundRecently, for various reasons, the need for non-invasive treatment for localized fat has emerged. This study confirmed whether Magnolia officinalis (MO) pharmacopuncture reduces localized fat by promoting lipolysis and inhibiting adipogenesis. MethodsThe network was built using genes related to the active compound of MO and the mode of action of MO was predicted by the functional enrichment analysis. Based on the result from network analysis, 100 µL of 2 mg/mL MO pharmacopuncture was injected into the inguinal fat pad for 6 weeks in obese C57BL/6J mice. Normal saline was injected into the right-side inguinal fat pad as a self-control. ResultsIt was expected that the AMP-activated protein kinase (AMPK) signaling pathway would be affected by the MO Network. MO pharmacopuncture reduced the weight and size of inguinal fat in HFD-induced obese mice. The phosphorylation of AMPK along with the increases of lipases was significantly increased by MO injection. Also, the expression levels of fatty acid synthesize-related mediators were suppressed by MO injection. ConclusionOur results demonstrated that MO pharmacopuncture promoted the expression of AMPK, which has beneficial effects on activation of lipolysis and inhibition of lipogenesis. Pharmacopuncture of MO can be a non-surgical alternative therapy in the treatment of local fat tissue.