Oxytetracycline (OTC) and Cu are prevalent in aquatic ecosystems and their pollution are issues of serious concern. The present working hypothesis is that the toxicity of Cu and OTC mixture on physiological activity of fish was different from single OTC and Cu alone. The present study indicated that, compared to single OTC or Cu alone, Cu+OTC mixture reduced growth performance and feed utilization of grass carp, escalated the contents of Cu, OTC and TG, increased lipogenesis, induced oxidative stress, damaged the mitochondrial structure and functions and inhibited the lipolysis in the liver tissues and hepatocytes of grass carp. Cu+OTC co-treatment significantly increased the mRNA abundances and protein expression of Nrf2. Moreover, we found that Cu+OTC mixture-induced oxidative stress promoted Nrf2 recruitment to the SREBP-1 promoter and increased SREBP-1-mediated lipogenesis; Nrf2 sited at the crossroads of oxidative stress and lipid metabolism, and mediated the regulation of oxidative stress and lipid metabolism. Our findings clearly indicated that OTC and Cu mixture differed in environmental risks from single antibiotic or metal element itself, and thus posed different toxicological responses to aquatic animals. Moreover, our findings suggested that Nrf2 functioned as an important antioxidant regulator linking oxidative stress to lipogenic metabolism, and thus elucidated a novel regulatory mechanism for lipid metabolism.

Lipid metabolism could be used as a biomarker for environmental monitoring of metal pollution, including Cu. Given the potential role of the Wnt/β-catenin signaling pathway and acetylation in lipid metabolism, the aim of this study was to investigate the mechanism of Wnt signaling and acetylation mediating Cu-induced lipogenesis. Grass carp Ctenopharyngodon idella, widely distributed freshwater teleost, were used as the model. We found that waterborne Cu exposure increased the accumulation of Cu and lipid, up-regulated lipogenesis, suppressed Wnt signaling, reduced β-catenin protein level and its nuclear location, reduced the sirt1 mRNA levels and up-regulated the β-catenin acetylation level. Further investigation found that Cu up-regulated lipogenesis through Wnt/β-catenin pathway; Cu regulated the β-catenin acetylation, and K311 was the key acetylated residue after Cu incubation. SIRT1 mediated Cu-induced changes of acetylated β-catenin and played an essential role in nuclear accumulation of β-catenin and Cu-induced lipogenesis. Cu facilitated lipid accumulation via the regulation of Wnt pathway by SIRT1. For the first time, our study uncovered the novel mechanism for Wnt/β-catenin pathway and β-catenin acetylation levels mediating Cu-induced lipid deposition, which provided insights into the association between Cu exposure and lipid metabolism in fish and had important environmental implications for monitoring metal pollution in the water by using new biomarkers involved in lipid metabolism.

Previous in vitro studies have implied that triphenyl phosphate (TPHP) may act as an obesogen. However, its specific contributions to the progression of obesity and related metabolic diseases are still unclear in vivo in mice. In this study, we evaluated the effects of in utero and lactational exposure to three doses of TPHP (10, 100, and 1000 μg/kg BW) on obesity and metabolic dysfunctions in adult male mice fed a low-fat diet (LFD) or high-fat diet (HFD), by examining body weight, liver weight, histopathology, blood biochemistry, gene expression, and gut microbiota compositions and metabolic functions. Results showed that TPHP exposure led to increased body weight, liver weight, fat mass, hepatic steatosis, impaired glucose homeostasis, and insulin resistance, and mRNA levels of genes involved in lipid metabolism, especially lipogenesis and lipid accumulation, were significantly altered by TPHP treatment. Gas chromatography-mass spectrometry (GC-MS) analysis further supported the changes in fatty acid composition. Intestinal flora measurements by 16S rRNA gene sequencing and ¹H NMR based fecal metabolomics indicated that TPHP treatment modulated gut microbiome composition and influenced host-gut co-metabolism, especially for bile acids and short chain fatty acids (SCFAs). These results suggest that fetal exposure to TPHP can promote the development of obesity and metabolic dysfunctions in adult mice.

Glyphosate is the active ingredient in Roundup, one of the most popular herbicides in the world, and its toxicity has caused increasing concerns. The present study aims to investigate the toxic effects of prenatal exposure to pure glyphosate or Roundup on lipid metabolism in offspring. During gestational days (GDs), ICR mice (from Institute of Cancer Research) were given distilled water, 0.5% glyphosate solution (w/v, 0.5 g/100 ml) or 0.5%-glyphosate Roundup solution orally. The livers and serum samples of the offspring were collected on gestational day 19 (GD19), postnatal day 7 (PND7) and PND21. The results showed a significant decrease in the body weight and obvious hepatic steatosis with excessive lipid droplet formation in offspring. Moreover, the concentrations of lipids such as triglycerides (TGs), total cholesterol (T-CHO), and low-density lipoprotein cholesterols (LDL-C) increased to a significant extent in both the serum and livers. Furthermore, there were significant differences in the expression levels of the genes SREBP1C, SREBP2, Fasn, Hmgcr, Hmgcs and PPARα, which are related to lipid biosynthesis or catabolism in the liver. These results demonstrate that chronic prenatal exposure to glyphosate can result in lipid metabolism disruption in the offspring of mice, as glyphosate exerts a negative influence on the expression of lipogenesis genes.

DEHP is commonly found in the environment, biota, food, and humans, raising significant health concerns. Whether developmental stage and exposure duration modify the obesogenic effects of DEHP is unclear, especially the underlying mechanisms by which chronic exposure to DEHP as well as its metabolites remain largely unknown. This study investigated the obesogenic effects of chronic DEHP exposure, with levels below environmentally-relevant amounts and provide the mechanism in Caenorhabditis elegans. We show that early-life DEHP exposure resulted in an increased lipid and triglyceride (TG) accumulation mainly attributed to DEHP itself, not its metabolite mono-2-ethylhexyl phthalate (MEHP). In addition, developmental stage and exposure timing influence DEHP-induced TG accumulation and chronic DEHP exposure resulted in the most significant effect. Analysis of fatty acid composition shows that chronic DEHP exposure altered fatty acid composition and TG, resulting in an increased ω-6/ω-3 ratio. The increased TG content by chronic DEHP exposure required lipogenic genes fat-6, fat-7, pod-2, fasn-1, and sbp-1. Moreover, chronic DEHP exposure induced XBP-1-mediated endoplasmic reticulum (ER) stress which might lead to up-regulation of sbp-1. This study suggests the possible involvement of ER stress and SBP-1/SREBP-mediated lipogenesis in chronic DEHP-induced obesogenic effects. Results from this study implies that chronic exposure to DEHP disrupts lipid metabolism, which is likely conserved across species due to evolutionary conservation of molecular mechanisms, raising concerns in ecological and human health.

Exposure of Bisphenol A (BPA) is closely associated with an increased prevalence of obesity-related metabolic syndrome. However, the potential mechanism of BPA-induced adipogenesis remains to be fully elucidated. Herein, potential mechanisms of BPA-induced adipogenesis in 3T3-L1 preadipocytes were evaluated using RNA-Seq. Then, using an early-life BPA exposure model, we further evaluated the effects of BPA exposure on lipid and glucose homeostasis. The results showed that lipid content in 3T3-L1 adipocytes was significantly increased after BPA exposure (p < 0.01) and male C57BL/6 mice with the dose of 500 μg/kg/day BPA by once-a-day oral administration for 8 weeks displayed a NAFLD-like phenotype. RNA-Seq analysis of preadipocytes showed that BPA exposure affected multiple biological processes including glycosphingolipid biosynthesis, regulation of lipolysis in adipocytes, PPAR signaling pathway and fatty acid metabolism. The dysregulation in a series of genes of mice was associated to de novo lipogenesis and lipid transport, which was linked to obesity. Importantly, we also found a significant expression increase of stearoyl-CoA desaturase 1 (SCD1) and a significant decrease of apolipoprotein D (APOD) in both fat (p < 0.01) and livers (p < 0.01) of male mice. Besides, the dysregulation of pro-inflammatory genes (TNF-α,IL-6 and SAA3) showed that BPA exposure promoted progression of hepatic inflammation. In conclusion, this study elucidated a novel mechanism in which obesity associated with BPA exposure by targeting SCD1. Exposure to BPA should be carefully examined in the chronic liver metabolic diseases.

Tributyltin (TBT), a bioaccumulative and persistent environmental pollutant, has been proposed as a metabolism disruptor and obesogen through targeting peroxisome proliferator-activated receptor gamma (PPARγ) receptor pathway. However, it remains unknown whether this biological effect occurs in macrophage, a cell type which cooperates closely with hepatocytes and adipocytes to regulate lipid metabolism. This study for the first time investigated the effect of TBT on PPARγ pathway in macrophages. Our results indicated that nanomolar levels of TBT was able to strongly activate PPARγ in human macrophages. TBT treatment also markedly increased the intracellular lipid accumulation, and enhanced the expression of lipid metabolism-related genes in macrophages, while these effects were all significantly down-regulated in PPARγ-deficient macrophages, confirming the involvement of PPARγ in TBT-induced lipogenesis. Next, a mouse model that C57BL/6 mice were orally exposed to TBT with the doses (250 and 500 μg/kg body weight) lower than NOAEL (no observed adverse effect level) was used to further investigate the in vivo mechanisms. And the in vivo results were consistent with cellular assays, confirming the induction of PPARγ and the increased expression of lipogenesis-regulating and lipid metabolism-related genes by TBT in vivo. In conclusion, this study not only provided the first evidence that TBT stimulated lipogenesis, activated PPARγ and related genes in human macrophages, but also provided insight into the mechanism of TBT-induced metabolism disturbance and obesity through targeting PPARγ via both in vitro cellular assays and in vivo animal models.

Finding the potential environmental obesogens is crucial to explain the prevalence of obesity and the related pathologies. Increasing evidence has showed that many chemicals with endocrine disrupting effects can disturb lipid metabolism. Whether 4-hexylphenol (4-HP), a widely-used surfactant and a potential endocrine disrupting chemical (EDC), is associated to influence adipogenesis and hepatic lipid accumulation remained to be elucidated. In this study, both the 3T3-L1 differentiation model and oleic acid (OA)-treated HepG2 cells were used to investigate the effects of 4-HP on lipid metabolism, and the underlying estrogen receptor (ER)-involved mechanism was explored using MVLN assay, molecular docking simulation and the antagonist test. The results based on lipid droplet staining and triglyceride accumulation assay showed that 4-HP treatment promoted the adipogenic differentiation of 3T3-L1 cells and increased hepatic cellular OA accumulation in exposure concentration-dependent manners. The study on the elaborated transcription networks indicated that 4-HP activated peroxisome proliferator-activated receptor γ (PPARγ) as well as the subsequent adipogenic gene program in 3T3-L1 cells. This chemical also induced the increase of OA uptake and decreases of de novo lipogenesis and fatty acid oxidation in HepG2 cells. The agonistic activity of 4-HP in triggering ER-mediated pathway was shown to correlate with its perturbation in lipid metabolism, as evidenced by the enhanced development of mature lipid-laden adipocytes and suppression of excessive hepatic lipid accumulation upon its co-treatment with ER antagonist. Altogether, these findings provide new insights into the potential health impacts of 4-HP exposure as it may relate to obesity and nonalcoholic fatty liver disease.

Previous in vitro studies have indicated that 2,3,3′,4,4′,5-hexachlorobiphenyl (PCB 156) may be a new contributor to metabolic disruption and may further cause the occurrence of nonalcoholic fatty liver disease (NAFLD). However, no study has clarified the specific contributions of PCB 156 to NAFLD progression by constructing an in vivo model. Herein, we evaluated the effects of PCB 156 treatment (55 mg/kg, i.p.) on the livers of C57BL/6 mice fed a control diet (CD) or a high-fat diet (HFD). The results showed that PCB 156 administration increased intra-abdominal fat mass, hepatic lipid levels and dyslipidemia in the CD-fed group and aggravated NAFLD in HFD-fed group. By using transcriptomics studies and biological methods, we found that the genes expression involved in lipid metabolism pathways, such as lipogenesis, lipid accumulation and lipid β-oxidation, was greatly altered in liver tissues exposed to PCB 156. In addition, the cytochrome P450 pathway, peroxisome proliferator-activated receptors (PPARs) and the glutathione metabolism pathway were significantly activated following exposure to PCB 156. Furthermore, PCB 156 exposure increased serum transaminase levels and lipid peroxidation, and the redox-related genes were significantly dysregulated in liver tissue. In conclusion, our data suggested that PCB 156 could promote NAFLD development by altering the expression of genes related to lipid metabolism and inducing oxidative stress.

Light at night (LAN) negatively impacts the behaviour and physiology; however, very little is known about molecular correlates of LAN-induced effects in diurnal animals. Here, we assessed LAN-induced effects on behaviour and physiology, and examined molecular changes in the liver of diurnal zebra finches (Taeniopygia guttata). Birds were exposed to dim LAN (dLAN: 12L = 150 lux: 12D = 5 lux), with controls on 12L (150 lux): 12D (0 lux). dLAN altered daily activity-rest and eating patterns, induced nocturnal eating and caused body fattening and weight gain, and reduced nocturnal melatonin levels. Concomitant increased nighttime glucose levels, decreased daytime thyroxine and triglycerides levels, and hepatic lipid accumulation suggested the impairment of metabolism under dLAN. Transcriptional assays evidenced dLAN-induced negative effects on metabolism in the liver, the site of metabolic homeostasis. Particularly, increased g6pc and foxo1 mRNA expressions suggested an enhanced gluconeogenesis, while increased egr1 and star expressions suggested enhanced cholesterol biosynthesis and lipid metabolism, respectively. Similarly, overexpressed sirt1 indicated protection from the metabolic damage due to elevated gluconeogenesis and cholesterol biosynthesis under dLAN. However, no effect on genes involved in lipogenesis (fasn) and insulin signalling pathway (socs3 and insig1) might indicate for the post transcriptional/post translational modification effects or the involvement of other genetic pathways in LAN-induced effects. We also found daily rhythm in the hepatic expression of selected clock and clock-controlled genes (per2, bmal1 and reverb-beta), with an elevated mesor and amplitude of per2 oscillation, suggesting a role of per2 in the liver metabolism. These results demonstrate dLAN-induced negative effects on the behaviour and physiology, and provide molecular insights into metabolic risks of the exposure to illuminated nights to diurnal animals including humans in an urban setting.