Maternal diet, rather than obesity itself, has a main influence on milk triacylglycerol profile in dietary obese rats.

Triacylglycerols (TG) in milk derive from different sources, and their composition may be influenced by both maternal diet and obesity. We used two rat models to ascertain potential changes in TG composition in milk associated to maternal intake of an obesogenic diet during lactation and to distinguish them from the effects attributable to maternal adiposity. Milk samples were obtained from dams fed a cafeteria diet during lactation (CAF) and from dams made obese by cafeteria diet feeding, with dietary normalization before gestation (PCaf). Levels of specific TG species in milk collected at different time points of lactation were determined by shotgun lipidomics. CAF and PCaf dams presented a greater adiposity than their respective controls. The principal component analysis of TG peaks showed a clear separation between milk from CAF dams and milk from control and Pcaf dams, already evident at 5 days of lactation. Milk from CAF dams was enriched with TG species with greater number of carbons and double bonds and reduced in TG with lower number of carbons. TG composition of milk from Pcaf dams was similar to controls, although specific differences were observed at day 5 of lactation. Thus, the intake of a cafeteria diet during lactation, rather than maternal adiposity, alters milk composition. This effect is avoided with dietary normalization before gestation, although the remaining fat reserves may also influence TG composition at initial stages of lactation. Therefore, normalization of maternal diet prior to pregnancy should be considered as a strategy for achieving optimal milk composition.

Transcriptome analysis in blood cells from children reveals potential early biomarkers of metabolic alterations.

OBJECTIVES: The development of effective strategies to prevent childhood obesity and its comorbidities requires new, reliable early biomarkers. Here, we aimed to identify in peripheral blood cells potential transcript-based biomarkers of unhealthy metabolic profile associated to overweight/obesity in children. METHODS: We performed a whole-genome microarray analysis in blood cells to identify genes differentially expressed between overweight and normal weight children to obtain novel transcript-based biomarkers predictive of metabolic complications. RESULTS: The most significant enriched pathway of differentially expressed genes was related to oxidative phosphorylation, for which most of genes were downregulated in overweight versus normal weight children. Other genes were involved in carbohydrate metabolism/glucose homoeostasis or in lipid metabolism (for example, TCF7L2, ADRB3, LIPE, GIPR), revealing plausible mechanisms according to existing biological knowledge. A set of differentially expressed genes was identified to discriminate in overweight children those with high or low triglyceride levels. CONCLUSIONS: Functional microarray analysis has revealed a set of potential blood-cell transcript-based biomarkers that may be a useful approach for early identification of children with higher predisposition to obesity-related metabolic alterations.

Maternal consumption of a cafeteria diet during lactation in rats leads the offspring to a thin-outside-fat-inside phenotype.

BACKGROUND AND OBJECTIVE: The suckling period is a critical phase of development, in which maternal overnutrition may program the susceptibility of developing chronic diseases and disorders, such as obesity and metabolic alterations, in adult life. Here, we questioned whether the consumption of a cafeteria diet throughout lactation in rats affects the macronutrient composition of milk and whether it results in permanent metabolic effects in the offspring. METHODS: Nursing rats were fed a control diet or a cafeteria diet during lactation. Milk was obtained at different time points of lactation. Offspring (males and females) were weaned onto a control diet until the age of 6 months. Circulating parameters were measured under ad libitum feeding and under 12-h fasting conditions at weaning and at 3 and 6 months of age. An oral glucose tolerance test (OGTT) was performed at 3 and 6 months of age. RESULTS: Rats fed a cafeteria diet during lactation consumed an unbalanced diet, with lower protein and higher fat content versus controls, which was reflected in the composition of the milk. The offspring of rats fed a cafeteria diet during lactation showed lower body weight and lower lean mass, but greater fat accumulation, compared with controls. They also displayed hyperleptinaemia, altered lipid profile and impaired response to an OGTT. CONCLUSION: Maternal consumption of a cafeteria diet throughout lactation in rats produces lasting effects in the metabolic health of their offspring, which are not associated with a higher body weight but with a greater fat accumulation, similarly to the thin-outside-fat-inside phenotype.

Oral leptin supplementation throughout lactation in rats prevents later metabolic alterations caused by gestational calorie restriction.

OBJECTIVES: Calorie-restriction during gestation in rats has been seen to produce lasting detrimental effects in the offspring, affecting energy balance control and other related metabolic functions. Our aim was to assess whether leptin supplementation throughout lactation may prevent the dysmetabolic phenotype in adulthood associated with gestational calorie restriction. METHODS: Three groups of male Wistar rats were followed: the offspring of ad libitum fed dams (controls); the offspring of 20% calorie-restricted dams during gestation (CR); and CR rats supplemented with physiological doses of leptin throughout lactation (CR-Leptin). Pups were weaned with a standard diet (SD) until 4 months of age, and then half of the animals of each group were moved to a Western diet (WD) until 6 months of age. Body weight and food intake were recorded. Energy expenditure, locomotive activity, blood parameters, liver triglycerides (TG), and gene expression and specific proteins in liver and white adipose tissue (WAT) were measured in adulthood. RESULTS: Adult CR rats, but not CR-Leptin rats, displayed greater adiposity index and feed efficiency (both under SD) than controls, along with lower locomotive activity and energy expenditure, higher HOMA-IR index and greater circulating TG and leptin levels. CR animals also exhibited increased values of the respiratory exchange ratio and more severe signs of hepatic steatosis under WD than CR-Leptin animals. Gene expression analysis revealed that CR, but not CR-Leptin, animals displayed indicators of lower capacity for WAT expansion, along with decreased lipogenesis and lipolytic capacity under SD, and impaired lipogenic response of the liver to WD feeding, in accordance with diminished insulin sensitivity and WAT leptin signaling. CONCLUSIONS: Oral leptin supplementation in physiological doses throughout lactation in rats prevents most of the detrimental effects on energy homeostasis and metabolic alterations in adulthood caused by inadequate fetal nutrition.

TAS1R3 and UCN2 Transcript Levels in Blood Cells Are Associated With Sugary and Fatty Food Consumption in Children.

CONTEXT: New types of dietary exposure biomarkers are needed to implement effective strategies for obesity prevention in children. Of special interest are biomarkers of consumption of food rich in simple sugars and fat because their intake has been associated with obesity development. Peripheral blood cells (PBCs) represent a promising new tool for identifying novel, transcript-based biomarkers. OBJECTIVE: This study aimed to study potential associations between the transcripts of taste receptor type 1 member 3 (TAS1R3) and urocortin II (UCN2) genes in PBCs and the frequency of sugary and fatty food consumption in children. DESIGN, SETTING, AND PARTICIPANTS: Four hundred sixty-three children from the IDEFICS cohort were selected to include a similar number of boys and girls, both normal-weight and overweight, belonging to eight European countries. MAIN OUTCOME MEASURES: Anthropometric parameters (measured at baseline and in a subset of 193 children after 2 years), food consumption frequency and transcript levels of TAS1R3 and UCN2 genes in PBCs were measured. RESULTS: Children with low-frequency consumption of sugary foods displayed higher TAS1R3 expression levels with respect to those with intermediate or high frequency. In turn, children with high-frequency consumption of fatty foods showed lower UCN2 expression levels with respect to those with low or intermediate frequency. Moreover, transcripts of TAS1R3 were related with body mass index and fat-mass changes after a 2-year follow-up period, with low expression levels of this gene being related with increased fat accumulation over time. CONCLUSION: The transcripts of TAS1R3 and UCN2 in PBCs may be considered potential biomarkers of consumption of sugary and fatty food, respectively, to complement data of food-intake questionnaires.

Leptin intake in suckling rats restores altered T3 levels and markers of adipose tissue sympathetic drive and function caused by gestational calorie restriction.

BACKGROUND: Maternal calorie restriction during gestation in rats has been associated with altered white adipose tissue (WAT) sympathetic innervation and function in offspring. Here, we aimed to investigate whether supplementation with oral leptin (a breast milk component) throughout the lactation period may revert the aforementioned adverse programming effects. METHODS: Three groups of male and female rats were studied at the postnatal day 25: the offspring of control dams, the offspring of 20% calorie-restricted dams during pregnancy (CR) and CR rats supplemented with physiological doses of leptin throughout lactation (CR-Leptin). Tyrosine hydroxylase (TH) levels and its immunoreactive area, and mRNA expression levels of lipid metabolism-related genes and of deiodinase iodothyronine type II (Dio2) were determined in WAT. Triiodothyronine (T3) levels were determined in the blood. RESULTS: In CR males, leptin treatment restored the decreased TH levels and its immunoreactive area in WAT, and partially normalized expression levels of genes related to lipolysis and fatty acid oxidation (adipose triglyceride lipase, hormone-sensitive lipase, carnitine palmitoyltransferase 1b and peroxisome proliferator-activated receptor gamma coactivator 1-alpha). Leptin treatment also reverted the decreased T3 plasma levels and WAT lipoprotein lipase mRNA levels occurring in CR males and females, and the decreased Dio2 mRNA levels in CR females. CONCLUSIONS: Leptin supplementation throughout the lactation period reverts the malprogrammed effects on WAT structure and function induced by undernutrition during pregnancy. These findings support the relevance of the intake of leptin during lactation, bearing clear characteristics of essential nutrient, and provide a strategy to treat and/or prevent the programmed trend to obesity acquired by inadequate fetal nutrition.

Cafeteria diet overfeeding in young male rats impairs the adaptive response to fed/fasted conditions and increases adiposity independent of body weight.

OBJECTIVE: We analyzed the effects of a short exposure to a cafeteria diet during early infancy in rats on their metabolic response to fed/fasting conditions in key tissues involved in energy homeostasis. METHODS: Ten-day-old male pups were fed a control or a cafeteria diet for 12 days and then killed under ad libitum feeding conditions or 12 h fasting. The expression of key genes related to energy metabolism in liver, retroperitoneal white adipose tissue (WAT) and hypothalamus were analyzed. RESULTS: Despite no differences in body weight, cafeteria-fed animals had almost double the fat mass of control rats. They also showed higher food intake, higher leptinemia and altered hypothalamic expression of Neuropetide Y, suggesting a dysfunction in the control of food intake. Unlike controls, cafeteria-fed animals did not decrease WAT expression of Pparg, sterol regulatory element binding transcription factor 1 or Cidea under fasting conditions, and displayed lower Pnpla2 expression than controls. In liver, compared with controls, cafeteria animals presented: (i) lower expression of genes related with fatty acid uptake and lipogenesis under ad libitum-fed conditions; (ii) higher expression of fatty acid oxidation-related genes and glucokinase under fasting conditions; (iii) greater expression of leptin and insulin receptors; and higher protein levels of insulin receptor and the pAMPK/AMPK ratio. CONCLUSION: A short period of exposure to a cafeteria diet in early infancy in rat pups is enough to disturb the metabolic response to fed/fasting conditions in key tissues involved in energy homeostasis, particularly in WAT, and hence induces an exacerbated body fat accumulation and increased metabolic risk, with no apparent effects on body weight.

Moderate calorie restriction during gestation programs offspring for lower BAT thermogenic capacity driven by thyroid and sympathetic signaling.

BACKGROUND: Maternal calorie restriction during pregnancy programs offspring for later overweight and metabolic disturbances. Brown adipose tissue (BAT) is responsible for non-shivering thermogenesis and has recently emerged as a very likely target for human obesity therapy. OBJECTIVE: Here we aimed to assess whether the detrimental effects of undernutrition during gestation could be related to impaired thermogenic capacity in BAT and to investigate the potential mechanisms involved. METHODS: Offspring of control and 20% calorie-restricted rats (days 1-12 of pregnancy) (CR) were studied at the age of 25 days. Protein levels of uncoupling protein 1 (UCP1) and tyrosine hydroxylase (TyrOH); mRNA levels of lipoprotein lipase (LPL), carnitine palmitoyltransferase 1 (CPT1) and deiodinase iodothyronine type II (DIO2) in BAT; and blood parameters including thyroid hormones, were determined. The response to 24-h cold exposure was also studied by measuring body temperature changes over time, and final BAT UCP1 levels. RESULTS: Compared with controls, CR animals displayed in BAT lower UCP1 and TyrOH protein levels and lower LPL and CPT1 mRNA levels; they also showed lower triiodothyronine (T3) plasma levels. CR males, but not females, revealed lower DIO2 mRNA levels than controls. When exposed to cold, CR rats experienced a transient decline in body temperature, but the values were reestablished after 24 h, despite having lower UCP1 levels than controls. CONCLUSIONS: These results suggest that BAT thermogenic capacity is diminished in CR animals, involving impaired BAT sympathetic innervation and thyroid hormone signaling. These alterations make animals more sensitive to cold and may contribute to long-term outcomes of gestational calorie restriction in promoting obesity and related metabolic alterations.

Influence of breastfeeding on blood-cell transcript-based biomarkers of health in children.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The expression of specific genes in peripheral blood cells (PBCs) may be used as biomarkers of the metabolic status. High levels of expression of CPT1A, SLC27A2, INSR, LEPR, FASN and PPARα in PBCs are indicative of a lower risk for the insulin resistant or dyslipidaemic state associated with obesity in children. Breastfeeding seems to confer protective effects against obesity and its related metabolic problems. WHAT THIS STUDY ADDS: Children who had been breastfed showed higher expression levels of SLC27A2, FASN, PPARα and INSR in PBCs compared with formula-fed subjects. The relationship of the PBC transcript levels of SLC27A2, INSR, FASN and PPARα with insulin resistance and dyslipidaemia may be dependent on the type of infant feeding (breast vs. formula). The transcript levels of the mentioned biomarkers could be useful to distinguish the formula-fed children who are at higher risk of metabolic alterations. BACKGROUND: Blood-cell transcripts have showed to be good biomarkers of metabolic alterations and their use in early detection and prevention of future disorders is promising. OBJECTIVE: This study aimed to examine the relation between previously proposed transcriptional biomarkers of metabolic health (SLC27A2, CPT1A, FASN, PPARα, INSR, LEPR) in peripheral blood cells and the type of infant feeding in a subset of children from the IDEFICS (Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants) cohort. SUBJECTS: A total of 237 children aged 2-9 years from eight European countries were studied. RESULTS: Breastfed children showed higher expression levels of SLC27A2, FASN, PPARα and INSR, and lower risk of being overweight and of having high plasma triglyceride levels vs. formula-fed children. Besides, overweight formula-fed children presented higher HOMA-index than overweight breastfed children (1.90 vs. 1.62); however, this negative effect was absent in formula-fed children with high expression of SLC27A2. Moreover, formula-fed children with low expression of SLC27A2, FASN, PPARα and INSR presented higher triglyceride levels than subjects with high expression of these genes (77.7 mg dL(-1) vs. 44.8 mg dL(-1) ). This difference was absent in breastfed children. CONCLUSIONS: Protective effects of breastfeeding are reflected in higher expression levels of SLC27A2, FASN, PPARα and INSR in blood cells. These biomarkers may also serve to discriminate the formula-fed children that are at higher risk of metabolic alterations.

Identification of early transcriptome-based biomarkers related to lipid metabolism in peripheral blood mononuclear cells of rats nutritionally programmed for improved metabolic health.

Moderate maternal calorie restriction during lactation protects rat offspring against obesity development in adulthood, due to an improved ability to handle and store excess dietary fuel. We used this model to identify early transcriptome-based biomarkers of metabolic health using peripheral blood mononuclear cells (PBMCs), an easily accessible surrogate tissue, by focusing on molecular markers of lipid handling. Male and female offspring of control and 20 % calorie-restricted lactating dams (CR) were studied. At weaning, a set of pups was killed, and PBMCs were isolated for whole-genome microarray analysis. The remaining pups were killed at 6 months of age. CR gave lower body weight, food intake and fat accumulation, and improved levels of insulin and leptin throughout life, particularly in females. Microarray analysis of weaned rat PBMCs identified 278 genes significantly differentially expressed between control and CR. Among lipid metabolism-related genes, expression of Cpt1a, Lipe and Star was increased and Fasn, Lrp1 and Rxrb decreased in CR versus control, with changes fully confirmed by qPCR. Among them, Cpt1a, Fasn and Star emerged as particularly interesting. Transcript levels of Cpt1a in PBMCs correlated with their levels in WAT and liver at both ages examined; Fasn expression levels in PBMCs at an early age correlated with their expression levels in WAT; and early changes in Star expression levels in PBMCs correlated with their expression levels in liver and were sustained in adulthood. These findings reveal the possibility of using transcript levels of lipid metabolism-related genes in PBMCs as early biomarkers of metabolic health status.

Histopathologic resolution of adult liver transplantation adenovirus hepatitis with cidofovir and intravenous immunoglobulin: a case report.

Adenovirus (ADV) infections in adult solid organ transplant recipients, although rare, are associated with high mortality. There are no randomized controlled trials establishing the efficacy of specific treatment modalities. To our knowledge apparent response to treatment with combination therapy with intravenous cidofovir (CDV) and immunoglobulin (IVIG) has only been demonstrated in 2 adult renal transplant recipients in whom ADV was documented in body fluids only. We describe an adult liver transplant recipient diagnosed with ADV hepatitis based on positive immunohistochemical staining of a liver biopsy specimen, positive blood ADV DNA polymerase chain reaction (PCR), and treated with the combination of CDV and IVIG. We demonstrated both clearance of viremia and histopathologic resolution of the hepatitis despite the patient's fatal outcome. To our knowledge this is the only case documenting eradication of tissue-invasive ADV disease in any solid organ transplant recipient using CDV and IVIG. This case provides evidence to support the use of this drug combination, which has many potential toxicities that might discourage its use otherwise.

The anti-viral effect of sorafenib in hepatitis C-related hepatocellular carcinoma.

BACKGROUND: Sorafenib is currently the only approved systemic therapy shown to have efficacy in the treatment of advanced hepatocellular carcinoma (HCC). Recent studies suggest that hepatitis C (HCV)-related HCC patients derive more clinical benefit from sorafenib than other subgroups, but the mechanism for this effect is unknown. In vitro data suggest that sorafenib may exert anti-viral properties, and thus our aim in this study was to evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC. AIM: To evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC. METHODS: We prospectively enrolled patients with HCV-related HCC treated with sorafenib for up to 6 months. Baseline clinical, viral and oncologic data were collected. Patients' HCV viral loads were obtained at various time points, and compared with their baseline viral levels. No patients received any known anti-viral therapy during this time. RESULTS: Thirty-three patients were identified with baseline and subsequent HCV levels available for analysis. Six patients completed 6 months of full dose sorafenib, and comparisons of their HCV viral loads showed no significant change at week 24 (difference of means = 0.3500, CI: -0.1799-0.8799, P = 0.150), or the interim time points. Similarly, the HCV viral loads of all patients who received sorafenib and the viral loads of those patients who had tumour response to sorafenib showed no significant changes at any time point. CONCLUSION: Despite preclinical data and previous subgroup analyses suggesting that sorafenib has an anti-viral effect against HCV, this study suggests that sorafenib lacks significant anti-viral activity in HCV patients with HCC.

The combination of sorafenib with transarterial chemoembolisation for hepatocellular carcinoma.

BACKGROUND: Standard of practice involves using transarterial therapy for multifocal hepatocellular carcinoma (HCC) alone and sorafenib only for more advanced HCC, but the sorafenib and transarterial therapy combination may provide greater efficacy. AIM: To evaluate the safety and efficacy of concurrent sorafenib and transarterial therapy in HCC. METHODS: Consecutive cases of HCC were treated with sorafenib and transarterial therapy, receiving sorafenib 2 to 4weeks before transarterial therapy. Baseline clinical parameters, adverse events (AEs) and survival were collected. RESULTS: A total of 47 patients received sorafenib and transarterial therapy. The majority of the patients were male (70%) with HCV (60%), median age of 60years, good performance status (0-1), stable cirrhosis (Child: A 72%; B 28%), unresectable tumour (stage: B 81%; C 19%) and median AFP of 24ng/mL. Median follow-up was 12months and median time on sorafenib was 6months. LC Bead TACE was used with a median frequency of 3. The majority of the patients (89%) experienced AEs. The most common AEs were fatigue (51%), hand-foot skin reaction (51%) and diarrhoea (43%). Grade 3 and 4 AEs included fatigue (13%) and hand-foot skin reaction (26%). Most patients required a dose reduction (66%). The main AE related to transarterial therapy was post-TACE syndrome (23%). The disease control rate was 68% at 6months. Overall median survival rate was 18.5months (95% CI 16.1-20.9months). CONCLUSION: Concurrent sorafenib and transarterial therapy is overall safe with no unexpected side effects and encouraging efficacy that warrants further study.

Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid.

BACKGROUND: Newer therapies are needed for patients with primary biliary cirrhosis and incomplete response to ursodeoxycholic acid (UDCA). Fenofibrate is a fibric acid postulated to regulate immune response and cell proliferation. AIM: To evaluate the efficacy and safety of fenofibrate in patients with primary biliary cirrhosis and incomplete response to UDCA. METHODS: We undertook a pilot study involving 20 patients with primary biliary cirrhosis and serum alkaline phosphatase (ALP) ≥ 2× ULN. Nonparametric statistical tests and Spearman correlation test were used as appropriate. RESULTS: Twenty patients received fenofibrate (160 mg/day) in addition to UDCA for 48 weeks. Median serum ALP decreased significantly at 48 weeks compared with baseline values [351 (214-779) U/L at baseline vs. 177 (60-384) U/L at 48 weeks, P < 0.05]. A rebound in ALP occurred upon drug discontinuation. Serum aspartate aminotransferase and Immunoglobulin M also decreased significantly, while bilirubin and albumin remained unchanged. Median IL-1 decreased from 28.9 (2.7-10 000) to 11.3 (2.5-277.7) pg/mL (P = 0.049), and median IL-6 from 4.6 (3.2-5205) to 3.5 (3.2-73.4) pg/mL (P = 0.027). Heartburn was the most frequent adverse event, leading to discontinuation of two study subjects. CONCLUSIONS: Combination therapy of fenofibrate and UDCA induced significant biochemical improvement in patients with primary biliary cirrhosis and incomplete response to UDCA. Further studies are warranted.

[Physiological mechanisms in the development of adiposity]. / Physiologische Mechanismen in der Entwicklung von Adipositas.

The phenomenon of the so-called "obesity pandemic" having arisen over the last decades has to be, in large part, attributed to changes of lifestyle and the associated changes in dietary habits and physical activity observed world-wide. The resulting interference in energy homeostasis plays a central role in the development of obesity in a large proportion of the population worldwide. In this article, current knowledge about central biological mechanisms of energy intake, energy storage, and energy expenditure is summarized. This includes, for example, the feeling of hunger/satiety, lipid turnover with the two components of lipolysis and lipogenesis, adipogenesis, as well as energy-consuming processes like (adaptive) thermogenesis, resting metabolic rate, and physical activity energy expenditure. Based on examples, the possible influence of genetic polymorphisms contributing to the development of adiposity are illustrated.

Moderate caloric restriction during gestation results in lower arcuate nucleus NPY- and alphaMSH-neurons and impairs hypothalamic response to fed/fasting conditions in weaned rats.

AIM: We aimed to characterize the developmental programming effects of moderate caloric restriction during early pregnancy on factors involved in hypothalamic control of energy balance. METHODS: Twenty-five-days-old offspring Wistar rats from 20% caloric restricted dams (from 1 to 12 days of pregnancy) (CR) and from control dams were studied under fed and 12 h fasting conditions. Morphometric studies on arcuate nucleus (ARC) and determinations of circulating parameters and hypothalamic levels of neuropeptide Y (NPY), proopiomelanocortin (POMC), long-form leptin receptor (ObRb), insulin receptor (InsR) and suppressor of cytokine signalling-3 (SOCS-3) mRNA were performed. RESULTS: CR animals did not show different body weight with respect to their controls, but presented higher food intake. They exhibited lower neuropeptide Y- and alpha-melanocyte-stimulating hormone-neurons (decreases of 18 and 13% in males, and 10 and 18% in females respectively) and lower total cells (decrease of 3% in males and 18% in females) in ARC. Under fed conditions, CR animals presented lower circulating leptin and ghrelin levels (decreases of 37 and 43% in males, and 15 and 34% in females respectively); furthermore, hypothalamic POMC, NPY (only in females), ObRb and InsR mRNA levels were reduced (39, 16 and 26% in males, and 112, 33, 61 and 56% in females), and those of SOCS-3 were increased (86% in males and 74% in females). Unlike control animals, under fasting conditions, ObRb, InsR and POMC mRNA levels did not decrease in CR females, and NPY mRNA decreased instead of increase in CR males. CONCLUSIONS: Moderate caloric restriction during gestation affects offspring hypothalamic structure and function, impairing its response to fed/fasting conditions, which suggests a predisposition to insulin and leptin resistance.

Dietary l-leucine supplementation of lactating rats results in a tendency to increase lean/fat ratio associated to lower orexigenic neuropeptide expression in hypothalamus.

The aim of this study was to assess the effects of dietary leucine supplementation in lactating dams, particularly on energy homeostasis through signaling mechanisms in the central nervous system. Dams were fed ad libitum with standard diet during pregnancy (control dams) or supplemented with 2% leucine (leucine-supplemented dams) from delivery onwards. Food intake, body weight and composition were periodically recorded. Hypothalamus was collected at the end of lactation, and the expression of neuropeptide Y (NPY), agouti-related protein (AgRP) pro-opiomelanocortin (POMC), cocaine and amphetamine regulated transcript (CART), insulin receptor (InsR), ghrelin receptor (GSHR), melanocortin receptor (MCR4), leptin receptor (Ob-Rb) and suppressor of cytokine signaling 3 (SOCS3) were analyzed. Dietary leucine supplementation to lactating rats increased plasma leucine by 56%, modulated body composition and contributed to a tendency of higher ratio of lean/fat mass content of dams during lactation, without affecting food intake, thermogenesis capacity or body or tissue/organs weights. No differences in body weight of offspring from control and leucine-supplemented dams were found. The expression of orexigenic peptides (NPY and AgRP) decreased in leucine-dams, whereas the expression of anorexigenic peptides (POMC and CART), the hypothalamic receptors of insulin, ghrelin, melanocortin and leptin and SOCS3 did not change by leucine supplementation. In conclusion, increased leucine intake during lactation may contribute to a healthier profile of body composition in dams, without compromising the growth and development of the progeny by a mechanism associated with lower expression of orexigenic neuropeptides in hypothalamus.

Impact of virologic breakthrough and HBIG regimen on hepatitis B recurrence after liver transplantation.

The availability of hepatitis B immune globulin (HBIG) and several oral antiviral therapies has reduced but not eliminated hepatitis B virus (HBV) recurrence. We aimed to determine the rate of HBV recurrence after orthotopic liver transplantation (OLT) in relation to virologic breakthrough pre-OLT and HBIG regimens post-OLT. Data from the NIH HBV-OLT database were analyzed. A total of 183 patients transplanted between 2001 and 2007 followed for a median of 42 months (range 1-81) post-OLT were studied. At transplant, 29% were hepatitis B e antigen (HBeAg) (+), 38.5% had HBV DNA > 5 log(10) copies/mL, 74% were receiving antiviral therapy. Twenty-five patients experienced virologic breakthrough before OLT. Post-OLT, 26%, 22%, 40% and 12% of patients received intravenous (IV) high-dose, IV low-dose, intramuscular low-dose and a finite duration of HBIG, respectively as maintenance prophylaxis. All but two patients also received antiviral therapy. Cumulative rates of HBV recurrence at 1 and 5 years were 3% and 9%, respectively. Multivariate analysis showed that listing HBeAg status and HBV DNA level at OLT were the only factors associated with HBV recurrence. In conclusion, low rates of HBV recurrence can be accomplished with all the HBIG regimens used when combined with antiviral therapy including patients with breakthrough pre-OLT as long as rescue therapy is administered pre- and post-OLT.

Leptin intake during the suckling period improves the metabolic response of adipose tissue to a high-fat diet.

BACKGROUND: The intake of leptin during the suckling period protects against obesity and improves insulin and central leptin sensitivity in adult rats. OBJECTIVE: We analyzed whether leptin treatment to neonates may also improve later peripheral leptin sensitivity in adipose tissue under high-fat (HF) diet conditions. DESIGN: Male rats were supplemented with a daily oral dose of leptin or the vehicle (controls) during the suckling period. After weaning, animals were fed a normal-fat or an HF diet until the age of 6 months. At this age, mRNA and protein levels of the long-form leptin receptor (OB-Rb) and the expression of other genes related with energy metabolism were measured in various adipose depots (inguinal, mesenteric and retroperitoneal). RESULTS: HF-diet feeding resulted in lower OB-Rb mRNA and protein levels in internal depots in controls but not in leptin-treated animals; these animals maintained OB-Rb mRNA and protein levels under HF-diet conditions in these depots, particularly in the mesenteric one, and this was accompanied by increased expression of genes related with energy uptake (GLUT4, CD36), fatty acid oxidation (peroxisome proliferator activated receptor-alpha (PPARalpha), CPT1, UCP3) and lipogenesis (PPARgamma, GPAT). Leptin-treatment also ameliorated HF-diet-induced hepatic fat accumulation occurring in control animals. CONCLUSION: Leptin treatment during the suckling period may improve the lasting effects of HF-diet feeding on leptin receptor abundance in the adipose tissue and increase its oxidative capacity, resulting in a better handling and partitioning of excess fuel. This, together with the described improvement of central leptin sensitivity, may explain why these animals are more protected against diet-induced obesity and its metabolic-related disorders.