Fernanda Ornellas

Programming of Obesity and Comorbidities in the Progeny: Lessons from a Model of Diet-Induced Obese Parents

Aim To determine the impact of paternal obesity, maternal obesity or the combination of two obese parents on markers of adult offspring metabolism, with a focus on body mass (BM), lipid and carbohydrate, components of lipogenesis and beta-oxidation in the liver, sex dimorphism in the offspring that received a SC diet during the postnatal period. Materials and Methods Male and female C57BL/6 mice were fed a high-fat diet (HF; 49% lipids) or standard chow (SC; 17% lipids) for 8 weeks before mating until lactation. The offspring were labeled according to sex, maternal diet (first letters), paternal diet (second letters), and received a SCdiet until 12-weeks of age when they were sacrificed. BM, eating behavior, glucose tolerance, plasma analysis, gene and protein expression of the components of lipogenesis and beta-oxidation in the liver of offspring were evaluated. Results HF diet-fed mothers and fathers were overweight, hyperglycemic and glucose intolerant and had a deteriorating lipid profile. The adult male and female offspring of HF-mothers were overweight, with an increased adiposity index, hyperphagic, had an impaired glucose metabolism, increased total cholesterol and triacylglycerol levels, increased lipogenesis concomitant with decreased beta-oxidation resulting in liver steatosis. The male and female offspring of HF-father had impaired glucose metabolism, exacerbated lipogenesis without influencing beta-oxidation and enhanced hepatic steatosis. These findings are independent of BM. Male and female offspring of a mother and father that received a HF diet demonstrated these effects most prominently in adult life. Conclusion Paternal obesity leads to alterations in glucose metabolism, increase in components of lipogenesis and liver steatosis. In contrast, maternal obesity leads to overweight and changes in the metabolic profile and liver resulting from activation of hepatic lipogenesis with impaired beta-oxidation. When both parents are obese, the effects observed in the male and female offspring are exacerbated.

Maternal Obesity during the Preconception and Early Life Periods Alters Pancreatic Development in Early and Adult Life in Male Mouse Offspring

Maternal obesity induced by a high fat (HF) diet may program susceptibility in offspring, altering pancreatic development and causing later development of chronic degenerative diseases, such as obesity and diabetes. Female mice were fed standard chow (SC) or an HF diet for 8 weeks prior to mating and during the gestational and lactational periods. The male offspring were assessed at birth, at 10 days, and at 3 months of age. The body mass (BM) gain was 50% greater before pregnancy and 80% greater during pregnancy in HF dams than SC dams. Dams fed an HF diet showed higher oral glucose tolerance test (OGTT), blood pressure, serum corticosterone, and insulin levels than dams fed SC. At 10 days of age and at 3 mo old the HF offspring showed greater BM and higher blood glucose levels than the SC offspring. The mean diameter of the islets had increased by 37% in the SC offspring and by 155% in the HF offspring at 10 days of age. The islet mass ratio (IM/PM) was 88% greater in the HF offspring at 10 days of age, and 107% greater at 3 mo of age, compared to the values obtained at birth. The HF offspring had a beta cell mass (BCM)/PM ratio 54% lower than SC offspring at birth. However, HF offspring displayed a 146% increase in the BCM/PM ratio at 10 days of age, and 112% increase at 3 months of age than values at birth. A 3 mo of age, the HF offspring showed a greater OGTT and higher levels of than SC offspring. In conclusion, a maternal HF diet consumed during the preconceptional period and throughout the gestational and lactational periods in mice results in dramatic alterations in the pancreata of the offspring.

Sexual dimorphism in fat distribution and metabolic profile in mice offspring from diet-induced obese mothers.

AIMS To investigate whether the effects of diet-induced obesity in mothers are passed on to their offspring fed a control diet in a gender-specific manner. MAIN METHODS Mother mice received either standard chow (SC; 17% energy from fat) or high-fat (HF; 49% energy from fat) diet for eight weeks pre-pregnancy until lactation. After weaning (at 21 days of age), offspring received SC diet and were divided into four groups according to the mothers diet (Mo): male Mo-SC, female Mo-SC, male Mo-HF, and female Mo-HF. Stereology, Elisa and western blotting were performed. KEY FINDINGS HF diet-fed mothers were overweight, and had metabolic abnormalities, all of which were found in their adult offspring. Male Mo-HF offspring had higher cholesterol, triglycerides, leptin and insulin levels and lower circulating adiponectin than female Mo-HF offspring. Mo-HF offspring of both genders had higher expression of tumor necrosis factor-alpha, interleukin-6 and leptin and lower expression of adiponectin than Mo-SC offspring; however, male Mo-HF were more affected than female Mo-HF offspring for these variables, demonstrating sexual dimorphism. SIGNIFICANCE Exposure to HF diet is effective in inducing obesity and metabolic alterations in mothers, and this phenotype can be passed on to their offspring. An adverse pattern in the body fat distribution in males probably has favored the intensification of a pro-inflammatory profile compared with females. In adulthood, the male offspring responds to the maternal obesity more than the female offspring, indicating a relevant sexual dimorphism that is a novel finding in this animal study.

Early hepatic insult in the offspring of obese maternal mice

We hypothesized that the maternal obesity initiates metabolic disorders associated with oxidative stress in the liver of offspring since early life. Mouses mothers were assigned into 2 groups according to the diet offered (n = 10 per group): standard chow (SC) or high-fat diet (HF). The results revealed that HF offspring had an increase in body mass at day 10 (+25%, P < .05) and in glucose levels (+25%, P < .0001). Hepatic triacylglycerol was increased in HF offspring at day 1 and day 10 compared with SC offspring (+30%, P < .01 and +40%, P < .01) as was hepatic steatosis (+110%, P < .001; +145%, P < .0001). Fatty acid synthase was increased in HF offspring at day 1 (+450%, P < .01) and peroxisome proliferator activator receptor-γ was elevated at day 1 and day 10 (+140%, P < .01; +2741%, P < .01). Peroxisome proliferator activator receptor-α was diminished in HF offspring at day 10 compared with SC offspring (-100%, P < .01). Moreover, carnitine palmitoyl-CoA transferase-1 was decreased in HF offspring at day 1 and day 10 (-80%, P < .01; -60%, P < .05). In the HF offspring (compared with the SC offspring), the catalase and the superoxide dismutase were significantly lower in both days 1 and 10 (P < .05). In 10-day-old offspring, glutathione peroxidase 1 and glutathione reductase were lower in HF offspring than in SC offspring (P < .0001). Our findings suggest that the maternal obesity in mice induces an early oxidative dysfunction coupled with hepatic steatosis and might contribute to progressive liver injury later in life.

Combined parental obesity augments single-parent obesity effects on hypothalamus inflammation, leptin signaling (JAK/STAT), hyperphagia, and obesity in the adult mice offspring

We aimed to evaluate the effects of maternal and/or paternal obesity on offspring body mass, leptin signaling, appetite-regulating neurotransmitters and local inflammatory markers. C57BL/6 mice received standard chow (SC, lean groups) or high-fat diet (HF, obese groups) starting from one month of age. At three months, HF mice became obese relative to SC mice. They were then mated as follows: lean mother and lean father, lean mother and obese father, obese mother and lean father, and obese mother and obese father. The offspring received the SC diet from weaning until three months of age, when they were sacrificed. In the offspring, paternal obesity did not lead to changes in the Janus kinase (JAK)/signal transducer and activation of the transcription (STAT) pathway or feeding behavior but did induce hypothalamic inflammation. On the other hand, maternal obesity resulted in increased weight gain, hyperleptinemia, decreased leptin OBRb receptor expression, JAK/STAT pathway impairment, and increased SOCS3 signaling in the offspring. In addition, maternal obesity elevated inflammatory markers and altered NPY and POMC expression in the hypothalamus. Interestingly, combined parental obesity exacerbated the deleterious outcomes compared to single-parent obesity. In conclusion, while maternal obesity is known to program metabolic changes and obesity in offspring, the current study demonstrated that obese fathers induce hypothalamus inflammation in offspring, which may contribute to the development of metabolic syndromes in adulthood.

Liver and Metformin: Lessons of a fructose diet in mice

Studies show that the continuous consumption of fructose can lead to nonalcoholic fatty liver disease (NAFLD) and steatohepatitis. We aimed to investigate the role of Metformin in an animal model of liver injury caused by fructose intake, focusing on the molecular markers of lipogenesis, beta-oxidation, and antioxidant defenses. Male three months old C57BL/6 mice were divided into control group (C) and fructose group (F, 47% fructose), maintained for ten weeks. After, the groups received Metformin or vehicle for a further eight weeks: control (C), control + Metformin (CM), fructose (F), and fructose + Metformin (FM). Fructose resulted in hepatic steatosis, insulin resistance and lower insulin sensitivity in association with higher mRNA levels of proteins linked with de novo lipogenesis and increased lipid peroxidation. Fructose diminished mRNA expression of antioxidant enzymes, and of proteins responsible for mitochondrial biogenesis. Metformin reduced de novo lipogenesis and increased the expression of proteins related to mitochondrial biogenesis, thereby increasing beta-oxidation and decreasing lipid peroxidation. Also, Metformin upregulated the expression and activity of antioxidant enzymes, providing a defense against increased reactive oxygen species generation. Therefore, a significant reduction in triglyceride accumulation in the liver, steatosis and lipid peroxidation was observed in the FM group. In conclusion, fructose increases de novo lipogenesis, reduces the antioxidant defenses, and diminishes mitochondrial biogenesis. After an extended period of fructose intake, Metformin treatment, even in continuing the fructose intake, can reverse, at least partially, the liver injury and prevents NAFLD progression to more severe states.

Obese fathers lead to an altered metabolism and obesity in their children in adulthood: review of experimental and human studies

OBJECTIVE To discuss the recent literature on paternal obesity, focusing on the possible mechanisms of transmission of the phenotypes from the father to the children. SOURCES A non-systematic review in the PubMed database found few publications in which paternal obesity was implicated in the adverse transmission of characteristics to offspring. Specific articles on epigenetics were also evaluated. As the subject is recent and still controversial, all articles were considered regardless of year of publication. SUMMARY OF FINDINGS Studies in humans and animals have established that paternal obesity impairs their hormones, metabolism, and sperm function, which can be transmitted to their offspring. In humans, paternal obesity results in insulin resistance/type 2 diabetes and increased levels of cortisol in umbilical cord blood, which increases the risk factors for cardiovascular disease. Notably, there is an association between body fat in parents and the prevalence of obesity in their daughters. In animals, paternal obesity led to offspring alterations on glucose-insulin homeostasis, hepatic lipogenesis, hypothalamus/feeding behavior, kidney of the offspring; it also impairs the reproductive potential of male offspring with sperm oxidative stress and mitochondrial dysfunction. An explanation for these observations (human and animal) is epigenetics, considered the primary tool for the transmission of phenotypes from the father to offspring, such as DNA methylation, histone modifications, and non-coding RNA. CONCLUSIONS Paternal obesity can induce programmed phenotypes in offspring through epigenetics. Therefore, it can be considered a public health problem, affecting the childrens future life.

Telmisartan, when compared to losartan, shows additional beneficial effects to pancreatic islet structure and function in diet-induced obese mice.

Materials and methods C57BL/6 mice were fed a standard chow (SC; 10% lipids) or a high-fat diet (HF; 50% lipids) for 10 weeks. Then, animals were randomly allocated into six groups to start the treatment with Telmisartan (T) or Losartan (L): SC, SC-L, SC-T, HF, HF-L and HF-T. The treatment phase lasted 5 weeks. Pair feeding (PF) groups were carried out to telmisartan treated groups (SCT-PF and HFT-PF) so as to isolate the effects of the treatment from the effects of reduced diet intake upon the evaluated parameters. Differences among the groups were tested with One-way ANOVA and Holm-Sidak post hoc test (P<0.05).