Increasing evidence indicates that brown adipose tissue (BAT) transplantation enhances whole-body energy metabolism in a mouse model of diet-induced obesity. However, it remains unclear whether BAT also has such beneficial effects on genetically obese mice. To address this issue, we transplanted BAT from C57/BL6 mice into the dorsal subcutaneous region of age- and sex-matched leptin deficient Ob/Ob mice. Interestingly, BAT transplantation led to a significant reduction of body weight gain with increased oxygen consumption and decreased total body fat mass, resulting in improvement of insulin resistance and liver steatosis. In addition, BAT transplantation increased the level of circulating adiponectin, whereas it reduced the levels of circulating free T3 and T4, which regulate thyroid hormone sensitivity in peripheral tissues. BAT transplantation also increased β3-adrenergic receptor and fatty acid oxidation related gene expression in subcutaneous and epididymal (EP) white adipose tissue. Accordingly, BAT transplantation increased whole-body thermogenesis. Taken together our results demonstrate that BAT transplantation may reduce obesity and its related diseases by activating endogenous BAT.

Active thermogenesis in the brown adipose tissue (BAT) facilitating the utilization of lipids and glucose is critical for maintaining body temperature and reducing metabolic diseases, whereas inactive BAT accumulates lipids in brown adipocytes (BAs), leading to BAT whitening. Although cellular crosstalk between endothelial cells (ECs) and adipocytes is essential for the transport and utilization of fatty acid in BAs, the angiocrine roles of ECs mediating this crosstalk remain poorly understood. Using single-nucleus RNA sequencing and knock-out male mice, we demonstrate that stem cell factor (SCF) derived from ECs upregulates gene expressions and protein levels of the enzymes for de novo lipogenesis, and promotes lipid accumulation by activating c-Kit in BAs. In the early phase of lipid accumulation induced by denervation or thermoneutrality, transiently expressed c-Kit on BAs increases the protein levels of the lipogenic enzymes via PI3K and AKT signaling. EC-specific SCF deletion and BA-specific c-Kit deletion attenuate the induction of the lipogenic enzymes and suppress the enlargement of lipid droplets in BAs after denervation or thermoneutrality in male mice. These data provide insight into SCF/c-Kit signaling as a regulator that promotes lipid accumulation through the increase of lipogenic enzymes in BAT when thermogenesis is inhibited.

Vanillin, a simple phenolic compound, exists marginally in some plants and can be produced by microbes. This study uses high-fat-diet (HFD) induced obese mice to study the effect of vanillin on obesity and obtain positive results. First, both body and adipose tissue weight are reduced. Second, the blood properties signaling certain disorders such as ALT, LDH, glucose, cholesterol, LDL-C, TG and HDL-C are ameliorated and both insulin sensitivity, and glucose tolerance are improved. Third, vanillin reduced elevated levels of inflammatory factors including LPS, IL-6, and TNF-α in plasma and liver tissue resulting from obesity. Finally, the production of short chain fatty acids (SCFAs) is enhanced. Additionally, study results demonstrate that vanillin significantly alleviates obesity-related gut microbiota (GM) disorders including the decrease of alpha- and beta-diversity. Furthermore, vanillin reduces the abundance of Firmicutes phylum, increases the richness of Bacteroidetes and Verrucomicrobiota phyla, and inhibits the expansion of the lipopolysaccharide (LPS)-producing bacteria Bilophila genus and the H2S-producing bacteria Desulfovibrio genus.

Proper storage of excessive dietary fat into subcutaneous adipose tissue (SAT) prevents ectopic lipid deposition-induced insulin resistance, yet the underlying mechanism remains unclear. Here, we identify angiopoietin-2 (Angpt2)-integrin α5β1 signaling as an inducer of fat uptake specifically in SAT. Adipocyte-specific deletion of Angpt2 markedly reduced fatty acid uptake and storage in SAT, leading to ectopic lipid accumulation in glucose-consuming organs including skeletal muscle and liver and to systemic insulin resistance. Mechanistically, Angpt2 activated integrin α5β1 signaling in the endothelium and triggered fatty acid transport via CD36 and FATP3 into SAT. Genetic or pharmacological inhibition of the endothelial integrin α5β1 recapitulated adipocyte-specific Angpt2 knockout phenotypes. Our findings demonstrate the critical roles of Angpt2-integrin α5β1 signaling in SAT endothelium in regulating whole-body fat distribution for metabolic health and highlight adipocyte-endothelial crosstalk as a potential target for prevention of ectopic lipid deposition-induced lipotoxicity and insulin resistance.

White adipose tissue (WAT) expansion is associated with angiogenesis. Although, activation of lipolysis by exercise induces adipocyte hypotrophy and reduction of fat mass, it is poorly understood whether exercise regulates angiogenesis by altering angiogenic gene expression in WAT. Therefore, the purpose of this study was to evaluate the effect of 6 weeks voluntary wheel running exercise on angiogenic gene expression in adipose tissues. Male C57BL/6J mice performed voluntary wheel running for 6 weeks. At 24 hr after the last exercise training, tibialis anterior (TA), soleus (Sol), epididymal WAT (eWAT), inguinal WAT (iWAT), and brown adipose tissue (BAT) were isolated and then the expressions of vascular endothelial growth factor A (VEGFA), angiopoietin1 (Ang1), Ang2, platelet-derived growth factor B (PDGF-B) and their corresponding receptors were analyzed by reverse transcription-polymerase chain reaction. In skeletal muscles, VEGFA expression was upregulated in TA and Sol and PDDGF-B expression was increased in Sol after exercise training. In eWAT, the expressions of VEGFA and Flk-1 were dramatically downregulated, whereas Ang2 and PDGFRβ was upregulated after exercise training. In iWAT, VEGF expression was increased with the downregulation of Ang1. However, there was no alteration of any of these genes in BAT. These results suggest that angiogenic gene expression is altered by exercise training and voluntary wheel running regulates VEGFA, Ang1, and Ang2 expressions in a fat depot specific manner.

Flavonoids have been reported to play an essential role in modulating processes of cellular redox homeostasis such as scavenging ROS. Meanwhile, they also induce oxidative stress that exerts potent antitumor bioactivity. However, the contradiction between these two aspects still remains unclear. In this study, four typical flavonoids were selected and studied. The results showed that low-dose flavonoids slightly promoted the proliferation of breast cancer cells under normal growth via gradually reducing accumulated oxidative products and demonstrated a synergistic effect with reductants NAC or VC. Besides, low-dose flavonoids significantly reduced the content of ROS and MDA induced by LPS or Rosup but restored the activity of SOD. However, high-dose flavonoids markedly triggered the cell death via oxidative stress as evidenced by upregulated ROS, MDA and downregulated SOD activity that could be partly rescued by NAC pretreatment, which was also confirmed by antioxidative gene expression levels. The underlying mechanism of such induced cell death was pinpointed as apoptosis, cell cycle arrest, accumulated mitochondrial superoxide, impaired mitochondrial function and decreased ATP synthesis. Transcriptomic analysis of apigenin and quercetin uncovered that high-dose flavonoids activated TNF-α signaling, as verified through detecting inflammatory gene levels in breast cancer cells and RAW 264.7 macrophages. Moreover, we identified that BRCA1 overexpression effectively attenuated such oxidative stress, inflammation and inhibited ATP synthesis induced by LPS or high dose of flavonoids possibly through repairing DNA damage, revealing an indispensable biological function of BRCA1 in resisting oxidative damage and inflammatory stimulation caused by exogenous factors.

The microbial community structure associated with wine in a wine-growing region is shaped by diverse ecological factors within that region, profoundly impacting the wine flavor. In wine fermentation, fungi contribute more sensory-active biochemical compounds than bacteria. In this study, we employed amplicon sequencing to measure samples from the spontaneous fermentation process of cabernet sauvignon wines from two wine-growing regions in China to study the diversity and structural evolution of fungi during spontaneous fermentation and analyze the correlation between fungi and volatile compounds. The results showed significant differences in fungal community structure and diversity in cabernet sauvignon musts from different geographical origins, and these differences affected the flavor quality of the wines. As alcoholic fermentation progressed, Saccharomyces became the dominant fungal genus and reshaped the fungal community structure, and the diversity of the fungal community decreased. However, the fungal communities of each wine-growing region remained distinct throughout the fermentation process. Furthermore, the correlation between the fungal community and volatile compounds indicated that wine is a product of fermentation involving multiple fungal genera, and the flavor is influenced by a variety of fungi. Our study enhances the comprehension of fungal communities in Chinese wine-growing regions, explaining the regulatory role of wine-related fungal microorganisms in wine flavor.

Many types of apoptotic cells are phagocytosed and digested by macrophages. Adipocytes can be hundreds of times larger than macrophages, so they are too large to be digested by conventional phagocytic processes. The nature of the interaction between macrophages and apoptotic adipocytes has not been studied in detail. We describe a cellular process, termed exophagy, that is important for macrophage clearance of dead adipocytes and adipose tissue homeostasis. Using mouse models of obesity, human tissue, and a cell culture model, we show that macrophages form hydrolytic extracellular compartments at points of contact with dead adipocytes using local actin polymerization. These compartments are acidic and contain lysosomal enzymes delivered by exocytosis. Uptake and complete degradation of adipocyte fragments, which are released by extracellular hydrolysis, leads to macrophage foam cell formation. Exophagy-mediated foam cell formation is a highly efficient means by which macrophages internalize large amounts of lipid, which may ultimately overwhelm the metabolic capacity of the macrophage. This process provides a mechanism for degradation of objects, such as dead adipocytes, that are too large to be phagocytosed by macrophages.

Recent studies have demonstrated the immunomodulatory effects of heat-killed lactic acid bacteria. The aim of this study was to evaluate the protective effect of heat-killed Enterococcus faecalis EF-2001 (EF-2001) on a model of inflammatory bowel disease (IBD). A total of 28 female NC/Nga mice were divided into 4 treatment groups. Controls were fed a normal commercial diet. In the experimental groups, colitis was induced by rectal administration of dinitrobenzene sulfonic acid. Two groups were orally administered 2 and 17 mg/kg EF-2001, respectively. EF-2001 treatment decreased the expression of several cytokines, including cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), interferon (IFN)-γ, interleukin (IL)-1β, and IL-6 in inflamed colon compared to the DNBS alone group. In addition, EF-2001 suppressed DNBS-induced colonic tissue destruction. Therefore, this study strongly suggests that EF-2001 could alleviate the inflammation associated with mouse IBD.

Upon severe head injury (HI), blood vessels of the meninges and brain parenchyma are inevitably damaged. While limited vascular regeneration of the injured brain has been studied extensively, our understanding of meningeal vascular regeneration following head injury is quite limited. Here, we identify key pathways governing meningeal vascular regeneration following HI. Rapid and complete vascular regeneration in the meninges is predominantly driven by VEGFR2 signaling. Substantial increase of VEGFR2 is observed in both human patients and mouse models of HI, and endothelial cell-specific deletion of Vegfr2 in the latter inhibits meningeal vascular regeneration. We further identify the facilitating, stabilizing and arresting roles of Tie2, PDGFRβ and Dll4 signaling, respectively, in meningeal vascular regeneration. Prolonged inhibition of this angiogenic process following HI compromises immunological and stromal integrity of the injured meninges. These findings establish a molecular framework for meningeal vascular regeneration after HI, and may guide development of wound healing therapeutics.

Ginsenoside Rg3 (Rg3), a main active component of Panax ginseng, has various therapeutic properties in literatures, and it has been studied for its potential use in obesity control due to its antiadipogenic effects in white adipocytes. However, little is known about its effects on brown adipocytes.

(1) Background: Brown adipose tissue (BAT) burns energy to produce heat. Cyanidin-3-O-glucoside (C3G) can then enhance the thermogenic ability of BAT in vivo. However, the mechanism by which C3G regulates Ucp1 protein expression remains unclear. (2) Methods: In this study, C3H10T12 brown adipose cells and db/db mice and mice with high-fat, high-fructose, diet-induced obesity were used as the model to explore the effect of C3G on the expression of the Ucp1 gene. Furthermore, the 293T cell line was used for an in vitro cell transgene, a double luciferase reporting system, and yeast single hybridization to explore the mechanism of C3G in regulating Ucp1 protein. (3) Results: we identified that, under the influence of C3G, Prdm16 directly binds to the -500 to -150 bp promoter region of Ucp1 to activate its transcription and, thus, facilitate BAT programming. (4) Conclusions: This study clarified the mechanism by which C3G regulates the expression of the Ucp1 gene of brown fat to a certain extent.

Coconut oil (CO) and its main ingredients, medium-chain fatty acids (MCFA), present many benefits. Whether MCFA and CO play an equally valuable role in anti-obesity remains unclear. This study compared the anti-obesity effects of CO and MCFA [octanoic acid (C8:0) and decanoic acid (C10:0)] to gain insight into the underlying mechanism. Male C57BL/6J mice were fed either a low-fat diet (LFD) or high-fat diet (100% HFD) replaced with 2.5% MCFA (97.5% HFD + 2.5% MCFA) or 5% CO (95% HFD + 5% CO) for 17 weeks. CO and MCFA ameliorated the HFD-induced abnormal body and adipose depot weights, insulin sensitivity, and energy expenditure (EE), which was associated with brown adipose tissue (BAT) thermogenesis. Furthermore, CO enhanced the expression of thermogenesis markers in BAT, which was consistent with increased BAT activity. CO showed a better effect than MCFA in activating BAT to increase thermogenesis and energy metabolism to combat obesity, which may be attributed to the cooperation of MCFA and other substances in CO. This work provides evidence for the anti-obesity effects of CO, which could be a better alternative to lard in daily diet, rather than pure MCFA.

Sweet potato is widely consumed as a healthy and nutritive vegetable containing bioactive constituents for health promotion. This study investigated the beneficial impact of white-fleshed sweet potato extract (SPE) on high fat diet (HFD)-induced obese mice.

Breast cancer, the most common cancer in women, usually exhibits intrinsic insensitivity to drugs, even without drug resistance. MUC1 is a highly glycosylated transmembrane protein, overexpressed in breast cancer, contributing to tumorigenesis and worse prognosis. However, the molecular mechanism between MUC1 and drug sensitivity still remains unclear. Here, natural flavonoid apigenin was used as objective due to the antitumor activity and wide availability. MUC1 knockout (KO) markedly sensitized breast cancer cells to apigenin cytotoxicity in vitro and in vivo. Both genetical and pharmacological inhibition significantly enhanced the chemosensitivity to apigenin and clinical drugs whereas MUC1 overexpression conversely aggravated such drug resistance. Constitutively re-expressing wild type MUC1 in KO cells restored the drug resistance; however, the transmembrane domain deletant could not rescue the phenotype. Notably, further investigation discovered that membrane-dependent drug resistance relied on the extracellular glycosylated modification since removing O-glycosylation via inhibitor, enzyme digestion, or GCNT3 (MUC1 related O-glycosyltransferase) knockout markedly reinvigorated the chemosensitivity in WT cells, but had no effect on KO cells. Conversely, inserting O-glycosylated sites to MUC1-N increased the drug tolerance whereas the O-glycosylated deletant (Ser/Thr to Ala) maintained high susceptibility to drugs. Importantly, the intracellular concentration of apigenin measured by UPLC and fluorescence distribution firmly revealed the increased drug permeation in MUC1 KO and BAG-pretreated cells. Multiple clinical chemotherapeutics with small molecular were tested and obtained the similar conclusion. Our findings uncover a critical role of the extracellular O-glycosylation of MUC1-N in weakening drug sensitivity through acting as a barrier, highlighting a new perspective that targeting MUC1 O-glycosylation has great potential to promote drug sensitivity and efficacy.