These cells undergo cell replication at a significantly faster rate than other hepatocytes. Importantly, these cells are present peri-centrally

in the normal liver lobule, are not dependent on injury and thereby distinct from injury-induced oval cells and Lgr5+ cells. In addition, we have identified the Wnt ligands that act on these progenitor hepatocytes and show that endothelial cells at the central vein of the liver are the Wnt producing niche cells. We hypothesize that this specialized population of peri-central hepatocyte stem cells is responsible for homeostatic renewal in the liver. Disclosures: The following people have nothing to disclose: Bruce M. Wang, Roel Nusse Induced pluripotent stem cell-derived Birinapant human hepatocyte-like cells (iHLCs) have RXDX-106 concentration great potential for applications such as studying the mechanisms underlying human liver development and disease, testing the efficacy and safety of pharmaceuticals across different patients (i.e. personalized medicine), and enabling cell-based therapies such as bioartificial liver devices and implantable cell-laden constructs. However, current in vitro protocols

that utilize growth factors and extracellular matrices (ECM) alone yield iHLCs with fetal levels of liver functions relative to adult primary human hepatocytes (PHHs). Furthermore, these low hepatic functions in iHLCs are difficult to maintain for prolonged times in culture. Here, we have engineered a micropatterned co-culture (iMPCC) platform in a multi-well format (24- and 96-well plates) that significantly enhanced the functional maturation and longevity of fresh and cryopreserved iHLCs in culture for at least 4 weeks in

vitro when compared to standard confluent cultures. In particular, iHLCs were micro-patterned onto ECM-coated domains of empirically optimized dimensions using soft lithographic techniques and subsequently surrounded by supportive 3T3-J2 murine embryonic fibroblasts. Overlaying the iMPCCs with an ECM gel further improved iHLC functions. Mirabegron We assessed iHLC maturity via liver gene expression (i.e. HNF4a), secretion of albumin and urea (5-6 ug/hr/million iHLCs in iMPCCs), basal CYP450 activities (i.e. up to 73% CYP3A4 activity in iMPCCs as compared to stable PHH cultures), phase II conjugation, drug-mediated CYP450 induction, and hepatocyte polarity (LDL uptake, canalicular transport). Moreover, we showed for the first time that the predictive power for classifying drugs as liver-toxic or non-toxic in iMPCCs was remarkably similar to stable cultures of PHHs (∼65-70% sensitivity, 100% specificity), thereby demonstrating iHLC utility in early stages of drug development where a paucity of healthy human liver tissues limits PHH use.

These cells undergo cell replication at a significantly faster rate than other hepatocytes. Importantly, these cells are present peri-centrally

in the normal liver lobule, are not dependent on injury and thereby distinct from injury-induced oval cells and Lgr5+ cells. In addition, we have identified the Wnt ligands that act on these progenitor hepatocytes and show that endothelial cells at the central vein of the liver are the Wnt producing niche cells. We hypothesize that this specialized population of peri-central hepatocyte stem cells is responsible for homeostatic renewal in the liver. Disclosures: The following people have nothing to disclose: Bruce M. Wang, Roel Nusse Induced pluripotent stem cell-derived Alectinib human hepatocyte-like cells (iHLCs) have Rapamycin order great potential for applications such as studying the mechanisms underlying human liver development and disease, testing the efficacy and safety of pharmaceuticals across different patients (i.e. personalized medicine), and enabling cell-based therapies such as bioartificial liver devices and implantable cell-laden constructs. However, current in vitro protocols

that utilize growth factors and extracellular matrices (ECM) alone yield iHLCs with fetal levels of liver functions relative to adult primary human hepatocytes (PHHs). Furthermore, these low hepatic functions in iHLCs are difficult to maintain for prolonged times in culture. Here, we have engineered a micropatterned co-culture (iMPCC) platform in a multi-well format (24- and 96-well plates) that significantly enhanced the functional maturation and longevity of fresh and cryopreserved iHLCs in culture for at least 4 weeks in

vitro when compared to standard confluent cultures. In particular, iHLCs were micro-patterned onto ECM-coated domains of empirically optimized dimensions using soft lithographic techniques and subsequently surrounded by supportive 3T3-J2 murine embryonic fibroblasts. Overlaying the iMPCCs with an ECM gel further improved iHLC functions. Carnitine palmitoyltransferase II We assessed iHLC maturity via liver gene expression (i.e. HNF4a), secretion of albumin and urea (5-6 ug/hr/million iHLCs in iMPCCs), basal CYP450 activities (i.e. up to 73% CYP3A4 activity in iMPCCs as compared to stable PHH cultures), phase II conjugation, drug-mediated CYP450 induction, and hepatocyte polarity (LDL uptake, canalicular transport). Moreover, we showed for the first time that the predictive power for classifying drugs as liver-toxic or non-toxic in iMPCCs was remarkably similar to stable cultures of PHHs (∼65-70% sensitivity, 100% specificity), thereby demonstrating iHLC utility in early stages of drug development where a paucity of healthy human liver tissues limits PHH use.

After excluding subjects with either or both hepatitis virus infections, the RRs at 1 Gy of HCC for radiation were estimated as shown in Table 3. There were 161 cases including 119 HCV-infected individuals and 452 matched controls including 29 HCV-infected individuals without HBV infection only. There were 66 cases including 24

HBV-infected individuals and 176 matched controls including 5 HBV-infected individuals without HCV infection only. The adjusted analyses indicated that radiation exposure was significantly associated with increased risks for HCC, even after excluding HBV- or HCV-infected individuals. Furthermore, significant association was found between non-B, non-C HCC and radiation dose, resulting in an RR at 1 Gy of 1.90 (95% CI, 1.02-3.92, P = 0.041) for radiation without adjustment for categorical alcohol consumption, BMI, and smoking habit and 2.74 (95% CI, 1.26-7.04, P = 0.007) with such adjustment. Palbociclib manufacturer Effects of alcohol

consumption, BMI, and smoking habit on non-B, non-C HCC risk with or without adjustment for radiation dose were estimated using continuous and categorical covariates as shown in Table 4. RRs for continuous covariates are for a one-unit difference in the factor. Risk of non-B, non-C HCC for alcohol consumption per 20 g of ethanol per day was significant with a log-linear model (adjusted RR 1.64, 95% CI, 1.05-2.81, P = 0.029), but was limited to the category ≥40 g of ethanol per day (adjusted RR 5.49, 95% CI, 0.98-39.2, P = 0.052). Significant log-linear association was not found with continuous BMI, and Selleck Etoposide even the category BMI >25.0 kg/m2 (obese) 10 years before diagnosis did not evidence significant Meloxicam risk despite a rather large estimate of RR (adjusted RR 3.17, 95% CI, 0.92-12.3, P = 0.068). Current smoking evidenced significant risk (adjusted RR 5.95, 95%

CI, 1.34-33.2, P = 0.018), but there were no continuous data on amount smoked. These results indicate that alcohol consumption per 20 g of ethanol per day, current smoking, and perhaps BMI of >25.0 kg/m2 10 years before diagnosis are associated independently with increased risk for non-B, non-C HCC. The present study confirmed that radiation is associated with increased incidence of HCC among atomic bomb survivors. Additionally, the nested case-control study indicates that radiation and HBV and HCV infection are associated with increased risk for HCC, and that radiation remains an independent risk factor for HCC after taking into account hepatitis virus infection, alcohol consumption, BMI 10 years before HCC diagnosis, and smoking habit. Furthermore, significant association was observed between non-B, non-C HCC and radiation dose, alcohol consumption, and smoking, whereas obesity 10 years before diagnosis was marginally significantly associated with increased risk for non-B, non-C HCC.

After excluding subjects with either or both hepatitis virus infections, the RRs at 1 Gy of HCC for radiation were estimated as shown in Table 3. There were 161 cases including 119 HCV-infected individuals and 452 matched controls including 29 HCV-infected individuals without HBV infection only. There were 66 cases including 24

HBV-infected individuals and 176 matched controls including 5 HBV-infected individuals without HCV infection only. The adjusted analyses indicated that radiation exposure was significantly associated with increased risks for HCC, even after excluding HBV- or HCV-infected individuals. Furthermore, significant association was found between non-B, non-C HCC and radiation dose, resulting in an RR at 1 Gy of 1.90 (95% CI, 1.02-3.92, P = 0.041) for radiation without adjustment for categorical alcohol consumption, BMI, and smoking habit and 2.74 (95% CI, 1.26-7.04, P = 0.007) with such adjustment. click here Effects of alcohol

consumption, BMI, and smoking habit on non-B, non-C HCC risk with or without adjustment for radiation dose were estimated using continuous and categorical covariates as shown in Table 4. RRs for continuous covariates are for a one-unit difference in the factor. Risk of non-B, non-C HCC for alcohol consumption per 20 g of ethanol per day was significant with a log-linear model (adjusted RR 1.64, 95% CI, 1.05-2.81, P = 0.029), but was limited to the category ≥40 g of ethanol per day (adjusted RR 5.49, 95% CI, 0.98-39.2, P = 0.052). Significant log-linear association was not found with continuous BMI, and Roxadustat ic50 even the category BMI >25.0 kg/m2 (obese) 10 years before diagnosis did not evidence significant Selleckchem CHIR 99021 risk despite a rather large estimate of RR (adjusted RR 3.17, 95% CI, 0.92-12.3, P = 0.068). Current smoking evidenced significant risk (adjusted RR 5.95, 95%

CI, 1.34-33.2, P = 0.018), but there were no continuous data on amount smoked. These results indicate that alcohol consumption per 20 g of ethanol per day, current smoking, and perhaps BMI of >25.0 kg/m2 10 years before diagnosis are associated independently with increased risk for non-B, non-C HCC. The present study confirmed that radiation is associated with increased incidence of HCC among atomic bomb survivors. Additionally, the nested case-control study indicates that radiation and HBV and HCV infection are associated with increased risk for HCC, and that radiation remains an independent risk factor for HCC after taking into account hepatitis virus infection, alcohol consumption, BMI 10 years before HCC diagnosis, and smoking habit. Furthermore, significant association was observed between non-B, non-C HCC and radiation dose, alcohol consumption, and smoking, whereas obesity 10 years before diagnosis was marginally significantly associated with increased risk for non-B, non-C HCC.

The CYP3A4 genotype was *1*1 in 44 of 45 subjects (97.8%) and *1/*1B in only one subject (2.2%). The CYP3A5 genotype was *1*1 in four subjects (8.9%), *1*3 in 20 subjects (44.4%), and *3*3 in 21 subjects (46.7%). Thus, 24 of

Opaganib ic50 45 subjects (53.3%) were Exp with *1, and 21 of 45 (46.7%) were Non-Exp without *1. No obvious differences were seen in the baseline characteristics of patients in the Exp group and the Non-Exp group before starting Tac (Table 1). The genotype of ABCB1 2677G/A/T was G/T in 16 patients (35.6%), G/A in 11 patients (24.4%), G/G in 9 patients (20.0%), T/A in 4 patients (8.9%), and T/T in 5 patients (11.1%). The genotype of ABCB1 3435C/T was C/T in 24 patients (53.3%), C/C in 17 patients (37.8%), and T/T in 4 patients (8.9%). All patients who needed fasting to control their severe symptoms were continued on fasting status until at least day 12 of Tac therapy. Therefore, their fasting status did not affect the analysis of Tac pharmacokinetics on days 2–5 and 7–10. On days 2–5, there was no difference in the Tac dose between the

CYP3A5 Non-Exp group and the Exp group, but the Non-Exp group had a significantly higher trough level (10.16 ± 5.84 vs 4.47 ± 2.50 ng/mL, P < 0.0001) and dose-adjusted trough level (139.36 ± 77.43 vs 61.37 ± 41.55 ng/mL per mg/kg/day, P < 0.0001). On days 2–5, the Non-Exp learn more group had a significantly higher percentage of patients achieving the optimal trough level than the Exp group (40.0% vs 4.3%, P = 0.01). On days 7–10, the Tac dose was significantly higher in the

Exp group because of dose adjustment (0.156 ± 0.036 vs 0.112 ± 0.044 mg/kg, P = 0.001), but the Non-Exp group had significantly higher trough levels (16.81 ± 5.70 vs 9.76 ± 2.90 ng/mL, P < 0.0001) and dose-adjusted trough levels (185.19 ± 109.55 vs 66.52 ± 28.00 ng/mL per mg/kg/day, P < 0.0001) than the Exp group. On days 7–10, the Non-Exp group had a significantly higher percentage of patients achieving the optimal trough level than the Exp group (84.2% vs 45.5%, P = 0.04) (Table 2). For ABCB1, the trough level and dose-adjusted trough level were compared on days 2–5 and 7–10 between the TT type and all other types in find more C3435T and between the TT type and all other types in G2677A/T, but no significant differences were seen (data not shown). 1. Percentage of patients achieving the optimal trough level on days 2–5 and associated factors Nine patients (20.9%) achieved the optimal trough levels on the initial measurement. Univariate analysis was done with a total of 28 items, including CYP3A4, ABCB1, CYP3A5 genotype, patient background, pretreatment, activity index, endoscopic severity, and laboratory data (erythrocyte sedimentation rate, white blood cell count, hemoglobin, platelet count, C-reactive protein, albumin) to determine whether an appropriate trough level was achieved (Table 3).

[1] No specific treatment for SOS is currently available. Defibrotide is an antithrombotic agent reported to improve symptoms and signs of SOS in 42% of patients.[3] The diagnosis of SOS is established by liver biopsy, with histologic findings including endothelial cell damage, dilatation of

the sinusoids, hepatocyte necrosis, and collagen deposition in the sinusoids, Mitomycin C mw with subsequent liver fibrosis.[4] In hepatocytes, FDG is taken up by surface glucose transporter-2 expressed by the sinusoidal endothelium. The prevailing hypothesis of SOS pathophysiology focuses on damage to the hepatic venular and sinusoidal endothelium as an initial event that activates the coagulation cascade. The venular and sinusoidal lumen is reduced due to concentric subendothelial zone edema.[1, 5] We suggest that PET findings in the

liver could be explained by trapping of FDG in dilated sinusoids; FDG cannot enter hepatocytes due to destruction of the sinusoidal endothelium. An inflammatory reaction is a less likely hypothesis, as no inflammatory cells Ku-0059436 concentration were observed on liver biopsy. Interestingly, patient 2 presented more severe clinical features and histologic findings, but obtained complete recovery in response to treatment, while patient 1 had no significant clinical findings, only moderate damage on liver biopsy, and derived no benefit from treatment. Differences in sinusoidal injuries may be predictive of response to defibrotide, but this aspect requires further investigation. In conclusion, FDG-PET/CT imaging may be a useful tool to assess the prognosis of SOS

and the therapeutic efficacy of SPTLC1 defibrotide, but further data need to be generated and validated by larger studies. “
“Due to improvement in the immunosuppression regimens and monitoring, chronic rejection (CR) represents only a minor cause for the allograft failure after liver transplantation. Excluding other causes of abnormal liver chemistry tests after liver transplantation is critical in differential diagnosis of CR. Proper recognition and staging of CR is essential for the long-term management of this condition. An active interaction with liver expert pathologist to identify features of late and early CR is critical. There are histological predictors of graft failure but none are pathognomonic. There are only limited options regarding treatment of CR and none have been compared in a randomized controlled trial. “
“A 19-year-old woman presented to her family physician with sharp right flank pain during deep inspiration or twisting of the upper body. An abdominal ultrasound showed a large mass in the right lobe of the liver. On contrast-enhanced computed tomography (Fig. 1A-C), a slight arterial enhancement was found in the center of the lesion (Fig. 1B), which was more pronounced during the portal venous phase (Fig. 1C).

[1] No specific treatment for SOS is currently available. Defibrotide is an antithrombotic agent reported to improve symptoms and signs of SOS in 42% of patients.[3] The diagnosis of SOS is established by liver biopsy, with histologic findings including endothelial cell damage, dilatation of

the sinusoids, hepatocyte necrosis, and collagen deposition in the sinusoids, Crizotinib with subsequent liver fibrosis.[4] In hepatocytes, FDG is taken up by surface glucose transporter-2 expressed by the sinusoidal endothelium. The prevailing hypothesis of SOS pathophysiology focuses on damage to the hepatic venular and sinusoidal endothelium as an initial event that activates the coagulation cascade. The venular and sinusoidal lumen is reduced due to concentric subendothelial zone edema.[1, 5] We suggest that PET findings in the

liver could be explained by trapping of FDG in dilated sinusoids; FDG cannot enter hepatocytes due to destruction of the sinusoidal endothelium. An inflammatory reaction is a less likely hypothesis, as no inflammatory cells http://www.selleckchem.com/products/Rapamycin.html were observed on liver biopsy. Interestingly, patient 2 presented more severe clinical features and histologic findings, but obtained complete recovery in response to treatment, while patient 1 had no significant clinical findings, only moderate damage on liver biopsy, and derived no benefit from treatment. Differences in sinusoidal injuries may be predictive of response to defibrotide, but this aspect requires further investigation. In conclusion, FDG-PET/CT imaging may be a useful tool to assess the prognosis of SOS

and the therapeutic efficacy of BCKDHB defibrotide, but further data need to be generated and validated by larger studies. “
“Due to improvement in the immunosuppression regimens and monitoring, chronic rejection (CR) represents only a minor cause for the allograft failure after liver transplantation. Excluding other causes of abnormal liver chemistry tests after liver transplantation is critical in differential diagnosis of CR. Proper recognition and staging of CR is essential for the long-term management of this condition. An active interaction with liver expert pathologist to identify features of late and early CR is critical. There are histological predictors of graft failure but none are pathognomonic. There are only limited options regarding treatment of CR and none have been compared in a randomized controlled trial. “
“A 19-year-old woman presented to her family physician with sharp right flank pain during deep inspiration or twisting of the upper body. An abdominal ultrasound showed a large mass in the right lobe of the liver. On contrast-enhanced computed tomography (Fig. 1A-C), a slight arterial enhancement was found in the center of the lesion (Fig. 1B), which was more pronounced during the portal venous phase (Fig. 1C).

5 hours prior to treatment with ConA or D-galactosamine/LPS. Hydrodynamic perfusion was performed essentially as described.21, 22 Details are reported in the Supporting Methods. For the detection of aminotransferases, blood was drawn by way of

cardiac puncture 15 hours after ConA injection. Livers were removed in toto. The left lower lobe was split into two equal parts. One half was encapsulated together with the left upper lobe for histology. The remaining half was divided into three parts—one part in RNAlater (Qiagen, Hilden, Germany), and two parts were snap-frozen together with the right upper lobe in liquid nitrogen. The right middle lobe was embedded in Tissue-TEK OCT compound (Sakura, Alphen aan den Rijn, the Netherlands) and stored at −80°C until further analysis. Liver damage was quantified by measurement DNA Damage inhibitor of plasma enzyme activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) using an automated procedure. One half of the left lower lobe and the left upper lobe were encapsulated and fixed in 10% buffered formalin overnight at room temperature. Tissue

was then embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Sections were photographed using a 5× objective lens, and necrosis fields were marked and quantified using ImageJ processing and analysis software (National Institutes of Health, Bethesda, MD). All experiments were performed using FL83B murine hepatocytes (American Type Culture NVP-LDE225 supplier Collection No. CRL-2390). For PBEF gene silencing, FL83B cells were either stably transfected using Vasopressin Receptor short hairpin RNA (shRNA) -producing lentiviral particles or transfected with PBEF1-specific small interfering RNAs. Primary Kupffer cells were prepared as

described.23 Details including apoptosis experiments are described in the Supporting Methods. Total RNA was extracted from cells and tissues using TRIZOL reagent according to the manufacturer’s instructions (Invitrogen). Further polymerase chain reaction details are outlined in the Supporting Methods. Protein from cells and tissue was extracted using M-PER mammalian protein extraction reagent supplemented with Halt protease inhibitor cocktail according to the manufacturer’s instructions (Pierce, Rockford, IL). Protein concentrations were determined using Bradford reagent (Bio-Rad Laboratories, Hercules, CA). Western Blot analyses are detailed in the Supporting Methods. Concentrations of CXCL1/KC in cell culture supernatants were determined using commercially available antibody pairs and protein standards from R&D Systems (McKinley Place, Minneapolis, MN). Circulating human PBEF was assayed using a human visfatin (C-terminal) enzyme immunometric assay (Phoenix Pharmaceuticals, Burlingame, CA). Mouse serum PBEF was determined using a mouse visfatin/PBEF enzyme-linked immunosorbent assay (ELISA) kit (MBL, Woburn, MA).

48 In addition, lupeol was able to sensitize HCC cells to chemotherapeutic agents (doxorubicin and cisplatin) through the phosphatase and tensin homolog (PTEN)-AKT-ABCG2, pathway. The combination of lupeol, doxorubicin and cisplatin was found to exert a synergistic effect on tumor suppression, allowing the use of a lower dosage of conventional chemotherapeutic

drugs, which may have cytotoxic effects when used at high concentrations.48 As our understanding of CSC grows, new drug discoveries are also underway with the anticipation of attaining the complete eradication of cancer. Recent studies have highlighted the importance and necessity Romidepsin of exploring the susceptibility of CSCs to existing therapies in combination Opaganib chemical structure with the disruption of key “stemness” pathways controlling self-renewal, chemoresistance and angiogenesis through molecular-targeted therapy, as conceptualized in Figure 2. Other novel and important directions for effective therapies may include the disruption of the tumor niche essential for CSC homeostasis

and the depletion of CSCs by forced differentiation. However, more work is still required to advance our knowledge on the role of CSCs in tumor hierarchy and to design more effective and specific anti-CSC therapy. Overall, the current state of knowledge strongly indicates the advantage of targeting CSCs to improve the limited efficiency of existing therapies, and it has provided an important framework for the development of novel therapeutic regimens with the ultimate hope of bringing long-term clinical benefits to the patient. We thank members of our laboratory for helpful discussion. Racecadotril Work in our laboratory is partially

supported by grants from the Sir Michael and Lady Kadoorie Funded Research into Cancer Genetics, Research Grant Council Collaborative Research Fund (HKU1/06C, HKU7/CRG/09 and HKU5/CRF/08), National Key Sci-Tech Special Project of Infectious Diseases (2008ZX1002-022) and The University of Hong Kong Strategic Research Theme in Cancer. “
“The etiology of primary biliary cirrhosis (PBC) is far from clear. Both genetic and environmental factors are likely to be involved. We have previously reported evidence of space-time clustering, suggesting that a transient environmental agent may be involved in etiology. To further examine whether a seasonally varying environmental agent may contribute to the etiology of PBC, we have analyzed seasonal variation with respect to month of diagnosis using population-based data from northeast England over a defined period (1987-2003). Date of diagnosis was defined as the earliest date at which the patient was found to have fulfilled any two of three diagnostic criteria (i.e., antimitochondrial antibody–positive titer ≥1 in 40, cholestatic liver blood tests, diagnostic or compatible liver histology).

Serum ALT, as a marker of liver injury, was markedly and significantly raised in OffCon-OD and further increased in OffOb-OD (Fig. 3A). These Ruxolitinib ic50 increases were paralleled by raised expression of IL-6 and TNF-α messenger RNA (mRNA) (Fig. 3B,C). α-SMA, TGF-β, and collagen were all profoundly up-regulated in OffOb-OD (Fig. 3D-F). Histological assessment of hepatosteatosis revealed greater fat infiltration in OffCon-OD, compared to control, at both 3 (Fig. 4A) and 12 months (Fig. 4B). Previous exposure to maternal obesity (OffOb-OD) exacerbated hepatosteatosis at 3 and 12 months (Fig. 4A,B) which was more advanced at 12 months (Fig.

4B). In parallel, there was, at 12 months, clear evidence of histological liver injury in OffCon-OD, as confirmed by the increased Brunt-Kleiner NAS (Fig. 4D), with more-profound injury in OffOb-OD. There was an independent

effect of maternal and postnatal diet on the NAS. Biochemical evidence of fibrogenic pathway activation was corroborated by clear findings of pericellular fibrosis, BYL719 in vitro on Masson’s trichrome staining, in OffOb-OD (Fig. 4C,E). We then investigated hepatic nonparenchymal cell fraction. The KC population examined by FACS analyses and corroborated by IHC staining was increased in OffOb-OD, but not in OffCon-OD, compared to OffCon-SC (Fig. 5A,B). Despite the increased numbers, KC phagocytic function was impaired (Fig. 5C) in OffOb-OD, compared to OffCon-SC. In contrast, KC ROS production was significantly increased upon LPS stimulation in OffOb-OD, compared to both OffCon-SC Interleukin-3 receptor and OffCon-OD, with a significant interaction between maternal obesity and postweaning diet (Fig. 5D). Furthermore, hepatic expression of the proinflammatory cytokines, IL-12 and IL-18, were similarly up-regulated

in OffOb-OD, compared to controls. There was an independent main effect of maternal diet on IL-12 expression as well as a significant interaction between maternal obesity and postnatal diet for IL-18 expression (Fig. 6A,B). Interestingly, NKT cell numbers were significantly reduced in OffOb-OD (Fig. 6C,D), and there was a significant interaction between maternal and postweaning diets. A substantial body of literature currently suggests that maternal obesity or a hypercalorific diet may, through perturbation of the intrauterine environment, lead to life-long risk of obesity and related metabolic disorders.7 Animal models in particular have proven invaluable in understanding the mechanisms underlying the persistent effects of maternal obesity on the developing offspring and strongly support the hypothesis of the developmental origins of disease.20, 21 Employing a mouse model of maternal obesity, we have previously demonstrated evidence of offspring hyperphagia, increased adiposity, hypertension, IR, and NAFLD in tandem with reduced hepatic insulin signalling and raised sympathetic tone.