Anti-obesity effects of Lactiplantibacillus plantarum SKO-001 in high-fat diet-induced obese mice.

PURPOSE: Previous reports showed that some probiotics provide beneficial effects on various diseases including metabolic disorders. This study aimed to investigate the anti-obesity effects of Lactiplantibacillus (L.) plantarum SKO-001 (SKO-001), a probiotic strain newly isolated from Angelica gigas. METHODS: C57BL/6J mice were fed with high-fat diet (HFD, 60% fat) for four weeks, and then different doses of SKO-001 (n = 10 each group) were orally given for 12 weeks. Following treatment, body weight, fat weight, serum parameters and adipose and liver tissues were analyzed. RESULTS: SKO-001 (2 × 1010 CFU/day, per os) reduced body weight gain after 10th week of administration, accompanied by a reduction in body fat mass of mice. In the SKO-001-fed group, increased serum adiponectin, decreased leptin, insulin, total cholesterol, low-density lipoprotein cholesterol, free fatty acids, and triglyceride levels were observed. Hematoxylin and eosin staining of various fat depots showed that increased adipocyte size caused by HFD intake was markedly reduced and correlated with reduced mRNA levels of lipogenesis genes, including sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor gamma, and CCAAT/enhancer binding protein alpha, and increased uncoupling protein 1 levels. Similarly, SKO-001 reduced lipid accumulation, decreased the mRNA levels of lipogenic genes, and reduced α-smooth muscle actin and collagen type 1 alpha 1 levels in the liver. CONCLUSIONS: SKO-001 ameliorates obesity and related metabolic abnormalities in adipose and liver tissues, possibly via the regulation of lipid metabolism. Based on the results of the present study, SKO-001 may be applicable as an anti-obesity therapeutic or functional food.

Melatonin ameliorates hepatic fibrosis via the melatonin receptor 2-mediated upregulation of BMAL1 and anti-oxidative enzymes.

Hepatic fibrosis, when left untreated, causes serious health problems that progress to cirrhosis and, in some cases, liver cancer. Activation of hepatic stellate cells may be a key characteristic in the development of hepatic fibrosis. Melatonin, a pineal hormone, exerts anti-fibrotic effects; however, the exact mechanisms remain unclear. In this study, the beneficial effects of melatonin against hepatic fibrosis and the underlying mechanisms were investigated using the human hepatic stellate cell line, LX-2, and in vivo murine animal models. The results showed that melatonin suppressed the expression of transforming growth factor (TGF)-ß1-induced fibrosis markers and production of reactive oxygen species in LX-2 cells. Either 4-phenyl-2-propionamidotetralin, a melatonin receptor 2 selective antagonist, or melatonin receptor 2 small interfering RNA abolished the suppressive effects of melatonin, suggesting the involvement of melatonin receptor 2 in melatonin-induced anti-fibrotic and anti-oxidative actions. Melatonin increased the expression of the brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1), a positive circadian clock gene. BMAL1 knockdown reduced the anti-fibrotic and anti-oxidative effects of melatonin, demonstrating the protective effects of melatonin against TGF-ß1-induced hepatic stellate cell activation by exhibiting melatonin receptor 2-BMAL1-anti-oxidative effects. In high-fat diet-induced and carbon tetrachloride-induced hepatic fibrosis models, oral melatonin administration decreased the expression of hepatic fibrosis markers and increased the expression of messenger RNA and levels of proteins of BMAL1 and melatonin receptor 2. Thus, melatonin exerted protective effects against hepatic fibrosis through melatonin receptor 2 activation, followed by an upregulation of the BMAL1-anti-oxidative enzyme pathways.

Tranilast protects pancreatic ß-cells from palmitic acid-induced lipotoxicity via FoxO-1 inhibition.

Tranilast, an anti-allergic drug used in the treatment of bronchial asthma, was identified as an inhibitor of the transcription factor Forkhead box O-1 (FoxO-1) by high throughput chemical library screening in the present study. Based on FoxO-1's role in apoptotic cell death and differentiation, we examined the effect of tranilast on palmitic acid (PA)-induced cell damage in INS-1 cells. Tranilast substantially inhibited lipoapoptosis and restored glucose-stimulated insulin secretion under high PA exposure. Moreover, PA-mediated downregulation of PDX-1, MafA, and insulin expression was attenuated by tranilast. PA-induced oxidative and ER stress were also reduced in the presence of tranilast. These protective effects were accompanied by increased phosphorylation and decreased nuclear translocation of FoxO-1. Conversely, the effects of tranilast were diminished when treated in transfected cells with FoxO-1 phosphorylation mutant (S256A), suggesting that the tranilast-mediated effects are associated with inactivation of FoxO-1. Examination of the in vivo effects of tranilast using wild type and diabetic db/db mice showed improved glucose tolerance along with FoxO-1 inactivation in the pancreas of the tranilast-treated groups. Thus, we report here that tranilast has protective effects against PA-induced lipotoxic stress in INS-1 cells, at least partly, via FoxO-1 inactivation, which results in improved glucose tolerance in vivo.

Adapalene induces adipose browning through the RARß-p38 MAPK-ATF2 pathway.

Adipose browning has recently been reported to be a novel therapeutic strategy for obesity. Because the retinoic acid receptor (RAR) is a potential target involved in browning, adapalene (AD), an anti-acne agent with RAR agonism, was examined in detail for its effects on adipose browning and the underlying mechanisms in vitro and in vivo. AD upregulated the expression of adipose browning-related markers in a concentration-dependent manner, promoted mitochondrial biogenesis, increased oxygen consumption rates, and lowered lipid droplet sizes in differentiated 3T3/L1 white adipocytes. Among the three retinoic acid receptors (RARα, RARß, and RARγ), knockdown of the gene encoding RARß mitigated AD-induced adipose browning. Similarly, LE135 (a selective RARß antagonist) attenuated AD action, suggesting that AD promotes adipose browning through RARß. Sequential phosphorylation of p38 mitogen-activated protein kinase (MAPK) and activating transcription factor 2 (ATF2) was critical for AD-induced adipose browning, based on the observations that either SB203580 (a p38 MAPK inhibitor) or ATF2 siRNA reduced the effects of AD. In vivo browning effects of AD were confirmed in C57BL/6J mice and high-fat diet-induced obese (DIO) mice after oral administration of AD either acutely or chronically. This study identifies new actions of AD as an adipose browning agent and demonstrates that RARß activation followed by increased phosphorylation of p38 MAPK and ATF2 appears to be a key mechanism of AD action.

Sodium salicylate induces browning of white adipocytes via M2 macrophage polarization by HO-1 upregulation.

Browning, a white to brown-like (beige) adipocyte conversion, offers a promising therapeutic strategy for the treatment of human obesity. In the present study, the effects of sodium salicylate, a nonsteroidal anti-inflammatory drug, on adipocyte browning were investigated. We found sodium salicylate altered the macrophage phenotype to M2 in RAW264.7 cells, mediated by up-regulation of heme oxygenase-1 (HO-1), and sodium salicylate-treated conditioned medium from macrophages (Sal-M2 CM) induced browning of fully differentiated 3T3-L1 adipocytes. Conversely, the conditioned medium obtained from macrophages when treated with sodium salicylate in the presence of either ZnPP (a HO-1 inhibitor) or HO-1 siRNA did not induce browning. In association with macrophage HO-1 induction by sodium salicylate, iron production also increased, and deferoxamine (an iron chelator) blunted the browning effects of Sal-M2 CM, suggesting that iron may play a role in the Sal-M2 CM-induced browning. The in vivo browning effects of sodium salicylate were confirmed in ob/ob mice, whereas in vivo macrophage depletion by clodronate as well as HO-1 blockade by either ZnPP or adeno-associated virus carrying HO-1 shRNA (AAV-HO-1 shRNA) attenuated the browning effects of sodium salicylate. These results reveal sodium salicylate induces browning in vitro and in vivo by up-regulating HO-1 thus promoting M2 polarization.

Role of non-thermal electrons in ultrafast spin dynamics of ferromagnetic multilayer.

Understanding of ultrafast spin dynamics is crucial for future spintronic applications. In particular, the role of non-thermal electrons needs further investigation in order to gain a fundamental understanding of photoinduced demagnetization and remagnetization on a femtosecond time scale. We experimentally demonstrate that non-thermal electrons existing in the very early phase of the photoinduced demagnetization process play a key role in governing the overall ultrafast spin dynamics behavior. We simultaneously measured the time-resolved reflectivity (TR-R) and the magneto-optical Kerr effect (TR-MOKE) for a Co/Pt multilayer film. By using an extended three-temperature model (E3TM), the quantitative analysis, including non-thermal electron energy transfer into the subsystem (thermal electron, lattice, and spin), reveals that energy flow from non-thermal electrons plays a decisive role in determining the type I and II photoinduced spin dynamics behavior. Our finding proposes a new mechanism for understanding ultrafast remagnetization dynamics.