Low Birth Weight Intensifies Changes in Markers of Hepatocarcinogenesis Induced by Fructose Consumption in Rats.

Intrauterine growth restriction (IUGR) due to fetal exposure to glucocorticoid excess results in metabolic inflexibility and hepatic steatosis upon nutritional stress during adulthood. We previously demonstrated that rats born to dexamethasone (DEX)-treated mothers developed hepatic steatosis when exposed to 10% fructose solution during adult life. Persistent triacylglyceride (TAG) accumulation in the liver, in turn, is a feature of non-alcoholic fatty liver disease (NAFLD), which serves as a risk factor for non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). In the present study, we demonstrate that the combination of IUGR and fructose treatment during adulthood also results in increased hepatic myeloperoxidase (MPO) activity, AKT phosphorylation and serum aspartate transaminase. Growth-restricted rats also presented reduced hepatic TRIB3 and GADD45a after fructose treatment. Other markers of cell proliferation, such as Cyclin D, PCNA, Hgf and Hspa4/Hsp70 expression and the number of Ki-67 positive cells, were all increased in the liver of growth- restricted rats treated with fructose. On the other hand, the combination of IUGR and fructose treatment during adult life reduced the levels of IGF-1. In conclusion, our data indicate that after exposure to fructose, adult rats subjected to dexamethasone-induced IUGR display exacerbated molecular changes in markers of NASH and HCC.

Leptin and its relationship with magnesium biomarkers in women with obesity.

Some studies have demonstrated the participation of leptin in magnesium metabolism. On the other hand, there is evidence of the role of magnesium in the leptin intracellular signaling pathway. Therefore, the aim of this study was to investigate the existence of a relationship between serum leptin concentrations and magnesium biomarkers in women with obesity. Case-control study involving 108 women aged between 20 and 50 years, divided into two groups: obese (n = 52) and control (n = 56). Body weight, height and waist circumference, body mass index, dietary magnesium intake, magnesium biomarkers and serum leptin concentrations were measured. Serum leptin concentrations showed a statistically significant difference between groups (p < 0.001). Mean values of magnesium intake were lower than intake recommended, and with no statistically significant difference between two groups (p > 0.05). Women with obesity had lower plasma and erythrocyte magnesium concentrations than control group did (p < 0.001). Magnesium concentrations found in the urine of women with obesity were higher than the control group was, with a statistically significant difference (p < 0.001). There was a correlation between serum leptin and magnesium biomarkers (p < 0.001). Women with obesity show an inadequate magnesium nutritional status characterized by low plasma and erythrocyte concentrations and high concentrations in urine, and they also have high serum leptin concentrations. Thus, it was possible to observe a correlation between hyperleptinemia and magnesium biomarkers, requiring further studies to determine whether the dysfunction of this hormone can influence the compartmentalization of the mineral in obese organisms.

Tributyrin Attenuates Metabolic and Inflammatory Changes Associated with Obesity through a GPR109A-Dependent Mechanism.

Obesity is linked with altered microbial short-chain fatty acids (SCFAs), which are a signature of gut dysbiosis and inflammation. In the present study, we investigated whether tributyrin, a prodrug of the SCFA butyrate, could improve metabolic and inflammatory profiles in diet-induced obese mice. Mice fed a high-fat diet for eight weeks were treated with tributyrin or placebo for another six weeks. We show that obese mice treated with tributyrin had lower body weight gain and an improved insulin responsiveness and glucose metabolism, partly via reduced hepatic triglycerides content. Additionally, tributyrin induced an anti-inflammatory state in the adipose tissue by reduction of Il-1ß and Tnf-a and increased Il-10, Tregs cells and M2-macrophages. Moreover, improvement in glucose metabolism and reduction of fat inflammatory states associated with tributyrin treatment were dependent on GPR109A activation. Our results indicate that exogenous targeting of SCFA butyrate attenuates metabolic and inflammatory dysfunction, highlighting a potentially novel approach to tackle obesity.

Maternal high-fat diet stimulates proinflammatory pathway and increases the expression of Tryptophan Hydroxylase 2 (TPH2) and brain-derived neurotrophic factor (BDNF) in adolescent mice hippocampus.

Maternal high-fat diet (HFD) consumption can promote a systemic inflammatory condition that may impair the offspring brain development, damaging memory and learning, when it reaches the hippocampus. This study aims to evaluate maternal HFD effects, during pregnancy and lactation, upon dams/mice offspring nutritional status, protein and gene expression of inflammatory pathway (JNK, pJNK and TNF-α), serotonin system molecules (Tryptophan Hydroxylase 2 (TPH2), key-enzyme of serotonin synthesis, serotonin transporter (SERT); 5-HT1A serotonergic receptor (5-HT1A)) and brain derived neurotrophic factor (BDNF) on recently weaned mice offspring hippocampus. Female Swiss mice were fed a control diet (CD, 11,5% fat) or a HFD (45.0% fat) from pre-mating to lactation. After weaning, the offspring received CD up to 28 post-natal days (PND28). Body weight and visceral adiposity (retroperitoneal and gonadal adipose tissue) of dams and offspring were measured. After euthanasia, the offspring hippocampus was dissected for evaluations of BDNF, inflammatory pathway and serotonergic system molecules protein and gene expression, through the techniques of Western Blotting, RTqPCR and ELISA. Our findings show that, during pregnancy, HFD-dams and HFD-offspring exhibited an increase in body weight gain and visceral adipose tissue compared to control animals. The hippocampus of HFD-offspring showed increased protein expression of TPH2, BDNF, pJNK and increased mRNA levels of TNF-α. However, the TPH2 increase in HFD-offspring did not alter hippocampal serotonin levels quantified through ELISA. Maternal HFD promoted an obesity phenotype in its offspring with increased body weight and visceral adiposity, increased protein and gene expression of the pro-inflammatory proteins pJNK and TNF-α. These changes were accompanied by increased TPH2 and BDNF protein expression. Thus, our findings show that maternal HFD during gestation and lactation increased pJNK and TNF-α expression in their offspring hippocampus indicating a pro-inflammatory state, with increased BDNF expression and alterations in its serotonergic system reflected by increased TPH2 expression.

Tributyrin attenuates metabolic and inflammatory changes associated with obesity through a GPR109A-dependent mechanism

Obesity is linked with altered microbial short-chain fatty acids (SCFAs), which are a signature of gut dysbiosis and inflammation. In the present study, we investigated whether tributyrin, a prodrug of the SCFA butyrate, could improve metabolic and inflammatory profiles in diet-induced obese mice. Mice fed a high-fat diet for eight weeks were treated with tributyrin or placebo for another six weeks. We show that obese mice treated with tributyrin had lower body weight gain and an improved insulin responsiveness and glucose metabolism, partly via reduced hepatic triglycerides content. Additionally, tributyrin induced an anti-inflammatory state in the adipose tissue by reduction of Il-1β and Tnf-a and increased Il-10, Tregs cells and M2-macrophages. Moreover, improvement in glucose metabolism and reduction of fat inflammatory states associated with tributyrin treatment were dependent on GPR109A activation. Our results indicate that exogenous targeting of SCFA butyrate attenuates metabolic and inflammatory dysfunction, highlighting a potentially novel approach to tackle obesity

Maternal Consumption of High-fat Diet in Mice Alters Hypothalamic Notch Pathway, NPY Cell Population and Food Intake in Offspring.

Studies show that maternal consumption of a high-fat diet (HFD) can impair the formation of hypothalamic neuronal circuits in mouse offspring. This damage can be mediated by Notch1/Hes5 signaling activation, leading to repression of proneural factors such as Mash1 and Ngn2/3, which are essential for neuronal differentiation and neurogenesis. Thus, we aimed to investigate the effects of maternal HFD consumption during gestation and lactation on the Notch1/Mash1 pathway in the hypothalamus and arcuate nucleus (ARC) of mouse offspring (neonates and 28 days old). Our results showed that maternal HFD consumption increases body weight and adiposity of mouse offspring, accompanied by increased levels of Il-1ß mRNA compared to those in control offspring. We noticed high mRNA levels of Hes5 accompanied by diminished mRNA levels of Ascl1 (Mash1). The number of Mash1-labeled cells in the ARC was diminished in HFD-O. Additionally, the population of NPY neurons was increased in these animals. Mash1 is important for the development of POMC and NPY neurons in the ARC. Therefore, the reduction in Mash1-labeled cells could be related to modification of the NPY neuron population in the ARC. This scenario favors hyperphagia and weight gain, and could be responsible for the development of obesity in adulthood.

Prolonged fasting elicits increased hepatic triglyceride accumulation in rats born to dexamethasone-treated mothers.

We investigated the effect of dexamethasone during the last week of pregnancy on glucose and lipid metabolism in male offspring. Twelve-week old offspring were evaluated after fasting for 12-hours (physiological) and 60-hours (prolonged). Physiological fasting resulted in glucose intolerance, decreased glucose clearance after pyruvate load and increased PEPCK expression in rats born to dexamethasone-treated mothers (DEX). Prolonged fasting resulted in increased glucose tolerance and increased glucose clearance after pyruvate load in DEX. These modulations were accompanied by accumulation of hepatic triglycerides (TG). Sixty-hour fasted DEX also showed increased citrate synthase (CS) activity, ATP citrate lyase (ACLY) content, and pyruvate kinase 2 (pkm2), glucose transporter 1 (slc2a1) and lactate dehydrogenase-a (ldha) expressions. Hepatic AKT2 was increased in 60-hour fasted DEX, in parallel with reduced miRNAs targeting the AKT2 gene. Altogether, we show that metabolic programming by prenatal dexamethasone is characterized by an unexpected hepatic TG accumulation during prolonged fasting. The underlying mechanism may depend on increased hepatic glycolytic flux due to increased pkm2 expression and consequent conversion of pyruvate to non-esterified fatty acid synthesis due to increased CS activity and ACLY levels. Upregulation of AKT2 due to reduced miRNAs may serve as a permanent mechanism leading to increased pkm2 expression.

Diet-Induced Maternal Obesity Alters Insulin Signalling in Male Mice Offspring Rechallenged with a High-Fat Diet in Adulthood.

Modern lifestyle has resulted in an increase in the prevalence of obesity and its comorbidities in pregnant women and the young population. It has been well established that the consumption of a high-fat diet (HFD) has many direct effects on glucose metabolism. However, it is important to assess whether maternal consumption of a HFD during critical periods of development can lead to metabolic changes in the offspring metabolism. This study evaluated the potential effects of metabolic programming on the impairment of insulin signalling in recently weaned offspring from obese dams. Additionally, we investigated if early exposure to an obesogenic environment could exacerbate the impairment of glucose metabolism in adult life in response to a HFD. Swiss female mice were fed with Standard Chow (SC) or a HFD during gestation and lactation and tissues from male offspring were analysed at d28 and d82. Offspring from obese dams had greater weight gain and higher adiposity and food intake than offspring from control dams. Furthermore, they showed impairment in insulin signalling in central and peripheral tissues, which was associated with the activation of inflammatory pathways. Adipose tissue was ultimately the most affected in adult offspring after HFD rechallenge; this may have contributed to the metabolic deregulation observed. Overall, our results suggest that diet-induced maternal obesity leads to increased susceptibility to obesity and impairment of insulin signalling in offspring in early and late life that cannot be reversed by SC consumption, but can be aggravated by HFD re-exposure.

Autophagy proteins are modulated in the liver and hypothalamus of the offspring of mice with diet-induced obesity.

Nutritional excess during pregnancy and lactation has a negative impact on offspring phenotype. In adulthood, obesity and lipid overload represent factors that compromise autophagy, a process of lysosomal degradation. Despite knowledge of the impact of obesity on autophagy, changes in offspring of obese dams have yet to be investigated. In this study, we tested the hypothesis that maternal obesity induced by a high fat diet (HFD) modulates autophagy proteins in the hypothalamus and liver of the offspring of mice. At birth (d0), offspring of obese dams (HFD-O) showed an increase in p62 protein and a decrease in LC3-II, but only in the liver. After weaning (d18), the offspring of HFD-O animals showed impairment of autophagy markers in both tissues compared to control offspring (SC-O). Between day 18 and day 42, both groups received a control diet and we observed that the protein content of p62 remained increased in the livers of the HFD-O offspring. However, after 82days, we did not find any modulation in offspring autophagy proteins. On the other hand, when the offspring of obese dams that received an HFD from day 42 until day 82 (OH-H) were compared with the offspring from the controls that only received an HFD in adulthood (OC-H), we saw impairment in autophagy proteins in both tissues. In conclusion, this study describes that HFD-O offspring showed early impairment of autophagy proteins. Although the molecular mechanisms have not been explored, it is possible that changes in autophagy markers could be associated with metabolic disturbances of offspring.

High-fat diet during pregnancy and lactation impairs the cholinergic anti-inflammatory pathway in the liver and white adipose tissue of mouse offspring.

Cholinergic anti-inflammatory pathway (CAP) prevents inflammatory cytokines production. The main was to evaluate the effect of maternal obesity on cholinergic pathway in the offspring. Female mice were subjected to either standard chow (SC) or high-fat diet (HFD) during pregnancy and the lactation period. After weaning, only male offspring from HFD dams (HFD-O) and from SC dams (SC-O) were fed the SC diet. Key proteins of the CAP were downregulated and serum TNF-α was elevated in the HFD-O mice. STAT3 and NF-κB activation in HFD-O mice ICV injected with nicotine (agonist) were lower than SC-O mice. Basal cholinesterase activity was upregulated in HFD-O mice in both investigated tissues. Lipopolysaccharide increased TNF-α and IL-1ß expression in the liver and WAT of SC-O mice, but this effect was greater in HFD-O mice. In conclusion these changes exacerbated cytokine production in response to LPS and contributed to the reduced sensitivity of the CAP.