Adipocyte-Specific Hnrnpa1 Knockout Aggravates Obesity-Induced Metabolic Dysfunction via Upregulation of CCL2.

Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) is involved in lipid and glucose metabolism via mRNA processing. However, whether and how HNRNPA1 alters adipocyte function in obesity remain obscure. Here, we found that the obese state downregulated HNRNPA1 expression in white adipose tissue (WAT). The depletion of adipocyte HNRNPA1 promoted markedly increased macrophage infiltration and expression of proinflammatory and fibrosis genes in WAT of obese mice, eventually leading to exacerbated insulin sensitivity, glucose tolerance, and hepatic steatosis. Mechanistically, HNRNPA1 interacted with Ccl2 and regulated its mRNA stability. Intraperitoneal injection of CCL2-CCR2 signaling antagonist improved adipose tissue inflammation and systemic glucose homeostasis. Furthermore, HNRNPA1 expression in human WAT was negatively correlated with BMI, fat percentage, and subcutaneous fat area. Among individuals with 1-year metabolic surgery follow-up, HNRNPA1 expression was positively related to percentage of total weight loss. These findings identify adipocyte HNRNPA1 as a link between adipose tissue inflammation and systemic metabolic homeostasis, which might be a promising therapeutic target for obesity-related disorders.

Masses and size distributions of mechanically fragmented microplastics from LDPE and EPS under simulated landfill conditions.

Landfills contain significant amounts of plastic waste (PW) and microplastics (MPs). However, the contributions of various PW fragmentation processes to the quality and quantity of MPs in landfills are unclear. In this study, LDPE and EPS pieces were mixed with sand to simulate landfilled solid waste, which experienced one-dimensional abiotic compression under vertical stress of 100-800 kPa for 1-300 days. The generated MPs were stained and quantified with a fluorescent microscope. The numbers and masses of the fragmented MPs increase with the increasing compression stress and duration following linear or exponential trends. EPS has a lower stiffness than LDPE, thus generates more MPs under the same compression conditions. Stress-dependent and time-dependent fragmentation mechanisms are distinguished, the former is driven by sand-plastic porosity reduction and the latter is due to microscopic interfacial creep with minimal porosity reduction. Most of the mechanically fragmented MPs have diameters < 100 µm. The MPs size distributions follow an established power-law model, which are dependent on stress, duration, porosity reduction, and fragmentation mechanism. Our results serve as conservative estimations on long-term MPs generation in real landfills, which provide confirmative and quantitative evidence to support the previous studies reporting the varied MPs abundances and properties within landfills.

Efficacy of epi-1 modified epirubicin and curcumin encapsulated liposomes targeting-EpCAM in the inhibition of epithelial ovarian cancer cells.

Treatment of epithelial ovarian cancer (EOC) is a challenge because it still leads to unsatisfactory clinical prognosis. This is due to the toxicity and poor targeting of chemotherapeutic agents, as well as metastasis of the tumor. In this study, we designed a targeted liposome with nanostructures to overcome these problems. In the liposomes, epirubicin and curcumin were encapsulated to achieve their synergistic antitumor efficacy, while Epi-1 was modified on the liposomal surface to target epithelial cell adhesion molecule (EpCAM). Epi-1, a macrocyclic peptide, exhibits active targeting for enhanced cellular uptake and potent cytotoxicity against tumor cells. The encapsulation of epirubicin and curcumin synergistically inhibited the formation of neovascularization and vasculogenic mimicry (VM) channels, thereby suppressing tumor metastasis on SKOV3 cells. The dual drug loaded Epi-1-liposomes also induced apoptosis and downregulated metastasis-related proteins for effective antitumor in vitro. In vivo studies showed that dual drug loaded Epi-1-liposomes prolonged circulation time in the blood and increased the selective accumulation of drug at the tumor site. H&E staining and immunohistochemistry with Ki-67 also showed that targeted liposomes elevated antitumor activity. Also, targeted liposomes downregulated angiogenesis-related proteins to inhibit angiogenesis and thus tumor metastasis. In conclusion, the production of dual drug loaded Epi-1-liposomes is an effective strategy for the treatment of EOC.

PARP12 is required for mitochondrial function maintenance in thermogenic adipocytes.

PARP12 is a member of poly-ADP-ribosyl polymerase (PARPs), which has been characterized for its antiviral function. Yet its physiological implication in adipocytes remains unknown. Here, we report a central function of PARP12 in thermogenic adipocytes. We show that PARP12 is highly expressed in brown adipose tissue and is mainly localized to the mitochondria. Knockdown of PARP12 in vitro reduced UCP1 expression. In parallel, the deficiency of PARP12 reduced mitochondrial respiration in adipocytes, while overexpression of PARP12 reversed these effects.

CLSTN3 gene variant associates with obesity risk and contributes to dysfunction in white adipose tissue.

OBJECTIVE: White adipose tissue (WAT) possesses the remarkable remodeling capacity, and maladaptation of this ability contributes to the development of obesity and associated comorbidities. Calsyntenin-3 (CLSTN3) is a transmembrane protein that promotes synapse development in brain. Even though this gene has been reported to be associated with adipose tissue, its role in the regulation of WAT function is unknown yet. We aim to further assess the expression pattern of CLSTN3 gene in human adipose tissue, and investigate its regulatory impact on WAT function. METHODS: In our study, we observed the expression pattern of Clstn3/CLSTN3 gene in mouse and human WAT. Genetic association study and expression quantitative trait loci analysis were combined to identify the phenotypic effect of CLSTN3 gene variant in humans. This was followed by mouse experiments using adeno-associated virus-mediated human CLSTN3 overexpression in inguinal WAT. We investigated the effect of CLSTN3 on WAT function and overall metabolic homeostasis, as well as the possible underlying molecular mechanism. RESULTS: We observed that CLSTN3 gene was routinely expressed in human WAT and predominantly enriched in adipocyte fraction. Furthermore, we identified that the variant rs7296261 in the CLSTN3 locus was associated with a high risk of obesity, and its risk allele was linked to an increase in CLSTN3 expression in human WAT. Overexpression of CLSTN3 in inguinal WAT of mice resulted in diet-induced local dysfunctional expansion, liver steatosis, and systemic metabolic deficiency. In vivo and ex vivo lipolysis assays demonstrated that CLSTN3 overexpression attenuated catecholamine-stimulated lipolysis. Mechanistically, CLSTN3 could interact with amyloid precursor protein (APP) in WAT and increase APP accumulation in mitochondria, which in turn impaired adipose mitochondrial function and promoted obesity. CONCLUSION: Taken together, we provide the evidence for a novel role of CLSTN3 in modulating WAT function, thereby reinforcing the fact that targeting CLSTN3 may be a potential approach for the treatment of obesity and associated metabolic diseases.

Bifidobacterium animalis subsp. lactis A6 Alleviates Obesity Associated with Promoting Mitochondrial Biogenesis and Function of Adipose Tissue in Mice.

Probiotics are widely known for their health benefits. Mitochondrial dysfunction is related to obesity. The aim of this study was to illuminate whether Bifidobacterium animalis subsp. lactis A6 (BAA6) could improve obesity due to increased mitochondrial biogenesis and function of adipose tissues. Four-week-old male C57BL/6 mice were fed with a high-fat diet (HFD) for 17 weeks. For the final eight weeks, the HFD group was divided into three groups including HFD, HFD with BAA6 (HFD + BAA6 group), and HFD with Akkermansia muciniphila (AKK) (HFD + AKK group as positive control). The composition of the microbiota, serum lipopolysaccharides (LPS), and mitochondrial biosynthesis and function of epididymal adipose tissues were measured. Compared with the HFD group, body weight, relative fat weight, the relative abundance of Oscillibacter and Bilophila, and serum LPS were significantly decreased in the HFD + BAA6 and HFD + AKK groups (p < 0.05). Furthermore, the addition of BAA6 and AKK increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) (by 21.53- and 18.51-fold), estrogen-related receptor α (ERRα) (by 2.83- and 1.24-fold), and uncoupling protein-1 (UCP-1) (by 1.51- and 0.60-fold) in epididymal adipose tissues. Our results suggest that BAA6 could improve obesity associated with promoting mitochondrial biogenesis and function of adipose tissues in mice.

Growth Performance and Post-Weaning Diarrhea in Piglets Fed a Diet Supplemented with Probiotic Complexes.

Weaning stress can affect the growth performance and intestinal health of piglets. Dietary alternatives to antibiotics, such as dietary probiotics, especially those containing multiple microbial species, are a preventive strategy for effectively controlling post-weaning diarrhea. In this study, we investigated forty-eight crossbred piglets in three treatment groups for 21 days: the control and experimental groups were supplemented with Enterococcus faecium DSM 7134, Bacillus subtilis AS1.836 plus Saccharomyces cerevisiae ATCC 28338 (EBS) or Lactobacillus paracasei L9 CGMCC No. 9800 (EBL). On day 21, weaned piglets supplemented with two kinds of probiotic complexes showed increased growth performance and significantly reduced post-weaning diarrhea (p ＜ 0.05). The EBS treatment increased acetic acid and propionic acid in the feces (p ＜ 0.05), and the EBL treatment increased fecal acetic acid, propionic acid, butyrate and valerate (p ＜ 0.05). Moreover, the fecal microbiota of the piglets changed markedly in EBL treatment. The addition of EBS and EBL may have similar effects on the prevention of diarrhea by improving the intestinal morphology and regulating the microbiota during the weaning period.

Ameliorative effects of aspirin against lipopolysaccharide-induced preeclampsia-like symptoms in rats by inhibiting the pro-inflammatory pathway.

Preeclampsia is an inflammatory disease and has connection with increased pro-inflammatory cytokines. Aspirin reduces the incidence of preeclampsia complications. However, the effects of aspirin on lipopolysaccharide-induced preeclampsia-like symptoms in rats have not been reported and the underlying molecular mechanism has not been illuminated. Hence, we investigated the anti-inflammatory effects of aspirin on lipopolysaccharide-induced preeclampsia-like phenotypes in pregnant rats and elucidated the potential molecular mechanism. Preeclampsia-like phenotypes were induced by tail vein injection of lipopolysaccharide (1 µg/kg) on gestational day 14. Aspirin (2 mg/kg per day) were administered from gestational day 14 to 19. Clinical phenotypes were recorded. Placenta tissues and serum were obtained to measure inflammatory cytokines levels using ELISA kit on gestational day 20. The mRNA expressions of IL-6, IL-1ß, and MCP-1 were measured by real-time PCR. Protein expressions including TLR4, MyD88, NF-κBp65, and TLR2 were determined by Western blot analysis in the rat placentas of each group. Aspirin obviously assuaged lipopolysaccharide-induced preeclampsia-like phenotypes in pregnant rats. Aspirin treatment significantly decreased the levels of pro-inflammatory cytokines in serum and placenta tissues of preeclampsia rats. Aspirin also obviously downregulated the mRNA expressions of IL-6, IL-1ß, and MCP-1 and assuaged the activation of TLR4, MyD88, NF-κBp65, and TLR2 in the placental tissue. Our results indicated that aspirin could assuage preeclampsia-like phenotypes, and this improvement effect is possibly the result of the suppression of pro-inflammatory cytokines via the TLR4, MyD88, NF-κBp65, and TLR2 signaling pathway.