Postnatal Overfeeding in Rodents Induces a Neurodevelopment Delay and Anxious-like Behaviour Accompanied by Sex- and Brain-Region-Specific Synaptic and Metabolic Changes.

Nutritional disturbances during the early postnatal period can have long-lasting effects on neurodevelopment and may be related to behavioural changes at adulthood. While such neuronal connection disruption can contribute to social and behaviour alterations, the dysregulation of the neuroendocrine pathways involved in nutrient-sensing balance may also cause such impairments, although the underlying mechanisms are still unclear. We aimed to evaluate sex-specific neurodevelopmental and behavioural changes upon postnatal overfeeding and determine the potential underpinning mechanisms at the central nervous system level, with a focus on the interconnection between synaptic and neuroendocrine molecular alterations. At postnatal day 3 (PND3) litters were culled to three animals (small litter procedure). Neurodevelopmental tests were conducted at infancy, whereas behavioural tests to assess locomotion, anxiety, and memory were performed at adolescence, together with molecular analysis of the hippocampus, hypothalamus, and prefrontal cortex. At infancy, females presented impaired acquisition of an auditory response, eye opening, olfactory discrimination, and vestibular system development, suggesting that female offspring neurodevelopment/maturation was deeply affected. Male offspring presented a transitory delay in locomotor performance., while both offspring had lower upper limb strength. At adolescence, both sexes presented anxious-like behaviour without alterations in short-term memory retention. Both males and females presented lower NPY1R levels in a region-specific manner. Furthermore, both sexes presented synaptic changes in the hippocampus (lower GABAA in females and higher GABAA levels in males), while, in the prefrontal cortex, similar higher GABAA receptor levels were observed. At the hypothalamus, females presented synaptic changes, namely higher vGLUT1 and PSD95 levels. Thus, we demonstrate that postnatal overfeeding modulates offspring behaviour and dysregulates nutrient-sensing mechanisms such as NPY and GABA in a sex- and brain-region-specific manner.

Exposure to Obesogenic Environments during Perinatal Development Modulates Offspring Energy Balance Pathways in Adipose Tissue and Liver of Rodent Models.

Obesogenic environments such as Westernized diets, overnutrition, and exposure to glycation during gestation and lactation can alter peripheral neuroendocrine factors in offspring, predisposing for metabolic diseases in adulthood. Thus, we hypothesized that exposure to obesogenic environments during the perinatal period reprograms offspring energy balance mechanisms. Four rat obesogenic models were studied: maternal diet-induced obesity (DIO); early-life obesity induced by postnatal overfeeding; maternal glycation; and postnatal overfeeding combined with maternal glycation. Metabolic parameters, energy expenditure, and storage pathways in visceral adipose tissue (VAT) and the liver were analyzed. Maternal DIO increased VAT lipogenic [NPY receptor-1 (NPY1R), NPY receptor-2 (NPY2R), and ghrelin receptor], but also lipolytic/catabolic mechanisms [dopamine-1 receptor (D1R) and p-AMP-activated protein kinase (AMPK)] in male offspring, while reducing NPY1R in females. Postnatally overfed male animals only exhibited higher NPY2R levels in VAT, while females also presented NPY1R and NPY2R downregulation. Maternal glycation reduces VAT expandability by decreasing NPY2R in overfed animals. Regarding the liver, D1R was decreased in all obesogenic models, while overfeeding induced fat accumulation in both sexes and glycation the inflammatory infiltration. The VAT response to maternal DIO and overfeeding showed a sexual dysmorphism, and exposure to glycotoxins led to a thin-outside-fat-inside phenotype in overfeeding conditions and impaired energy balance, increasing the metabolic risk in adulthood.

Sex-specificities in offspring neurodevelopment and behaviour upon maternal glycation: Putative underlying neurometabolic and synaptic changes.

AIM: Lactation is an important programming window for metabolic disease and neuronal alterations later in life. We aimed to study the effect of maternal glycation during lactation on offspring neurodevelopment and behaviour, assessing possible sex differences and underpinning molecular players. METHODS: Female Wistar rats were treated with Glyoxalase-1 inhibitor S-p-Bromobenzylguthione cyclopentyl diester (BBGC 5 mg/kg). A control and vehicle group treated with dimethyl sulfoxide were also considered. Male and female offspring were tested at infancy for neurodevelopment hallmarks. After weaning, triglycerides and total antioxidant capacity were measured in breast milk. At adolescence, offspring were tested for locomotor ability, anxious-like behaviour, and recognition memory. Metabolic parameters were assessed, and the hippocampus and prefrontal cortex were collected for molecular analysis. KEY FINDINGS: Maternal glycation reduced triglycerides and total antioxidant capacity levels in breast milk. At infancy, both male and female offspring presented an anticipation on the achievement of neurodevelopmental milestones. At adolescence, male offspring exposed to maternal glycation presented hyperlocomotion, whereas offspring of both sexes presented a risk-taking phenotype, accompanied by increase GABAA receptor levels in the hippocampus. Females also demonstrated GABAA and PSD-95 changes in prefrontal cortex. Furthermore, lower levels of GLO1 and consequently higher accumulation of AGES were also observed in both male and female offspring hippocampus. SIGNIFICANCE: Early exposure to maternal glycation induces changes in milk composition leading to neurodevelopment changes at infancy, and sex-specific behavioural and neurometabolic changes at adolescence, further evidencing that lactation period is a critical metabolic programming window and in sculpting behaviour.

Distinct Impact of Natural Sugars from Fruit Juices and Added Sugars on Caloric Intake, Body Weight, Glycaemia, Oxidative Stress and Glycation in Diabetic Rats.

Although fruit juices are a natural source of sugars, there is a controversy whether their sugar content has similar harmful effects as beverages' added-sugars. We aimed to study the role of fruit juice sugars in inducing overweight, hyperglycaemia, glycation and oxidative stress in normal and diabetic animal models. In diabetic Goto-Kakizaki (GK) rats, we compared the effects of four different fruit juices (4-weeks) with sugary solutions having a similar sugar profile and concentration. In vitro, the sugary solutions were more susceptible to AGE formation than fruit juices, also causing higher postprandial glycaemia and lower erythrocytes' antioxidant capacity in vivo (single intake). In GK rats, ad libitum fruit juice consumption (4-weeks) did not change body weight, glycaemia, oxidative stress nor glycation. Consumption of a matched volume of sugary solutions aggravated fasting glycaemia but had a moderate impact on caloric intake and oxidative stress/glycation markers in tissues of diabetic rats. Ad libitum availability of the same sugary solutions impaired energy balance regulation, leading to higher caloric intake than ad libitum fruit juices and controls, as well as weight gain, fasting hyperglycaemia, insulin intolerance and impaired oxidative stress/glycation markers in several tissues. We demonstrated the distinct role of sugars naturally present in fruit juices and added sugars in energy balance regulation, impairing oxidative stress, glycation and glucose metabolism in an animal model of type 2 diabetes.

Early AGEing and metabolic diseases: is perinatal exposure to glycotoxins programming for adult-life metabolic syndrome?

Perinatal early nutritional disorders are critical for the developmental origins of health and disease. Glycotoxins, or advanced glycation end-products, and their precursors such as the methylglyoxal, which are formed endogenously and commonly found in processed foods and infant formulas, may be associated with acute and long-term metabolic disorders. Besides general aspects of glycotoxins, such as their endogenous production, exogenous sources, and their role in the development of metabolic syndrome, we discuss in this review the sources of perinatal exposure to glycotoxins and their involvement in metabolic programming mechanisms. The role of perinatal glycotoxin exposure in the onset of insulin resistance, central nervous system development, cardiovascular diseases, and early aging also are discussed, as are possible interventions that may prevent or reduce such effects.

IL-8 and MCP-1 Impact on Tau Phosphorylation and Phosphatase Activity.

BACKGROUND: Chronic inflammation is a feature of Alzheimer´s disease (AD), resulting in excessive production of inflammatory mediators that can lead to neuroinflammation, contributing to alterations in Aß production and deposition as Senile Plaques (SPs), and to neurofibrillary tangles (NFTs) formation, due to hyperphosphorylated Tau protein. OBJECTIVE: This work addressed the impact of the interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), two chemokines, on Tau phosphorylation; and also evaluated the chemokines' levels in plasma using samples from a regional cohort. METHODS: Human neuronal SH-SY5Y cells exposed to IL-8 and MCP-1 chemokines were monitored for their protein and phosphorylated protein levels by western blotting analysis. A serine/threonine protein phosphatase (PPs) activity assay was employed to monitor PPs activity. Subsequently, flow cytometry was used to monitor chemokines levels in plasma samples from individuals with cognitive deficits. RESULTS: Chemokines' exposure resulted only in minor cytotoxicity effects on SH-SY5Y, and in increased Tau phosphorylation, particularly at the S396 residue. Tau phosphorylation correlated with PPs inhibition and was consistent with GSK3ß phosphorylation-mediated inhibition. Subsequent analysis of plasma from individuals with cognitive deficits showed that IL-8 levels were decreased. CONCLUSION: Data shows that both chemokines tested can exert an effect on GSK3ß phosphorylation and modulate PPs activity, potentially resulting in increased Tau phosphorylation and subsequent NFTs formation. One can deduce that increased chemokines stimulation during chronic inflammation can exacerbate this event. The work contributes to a better understanding of the mode of action of these chemokines on AD pathogenesis and opens novel research avenues.