Epigenetic programming for obesity and noncommunicable disease: From womb to tomb.

Several epidemiological, clinical and experimental studies in recent decades have shown the relationship between exposure to stressors during development and health outcomes later in life. The characterization of these susceptible phases, such as preconception, gestation, lactation and adolescence, and the understanding of factors that influence the risk of an adult individual for developing obesity, metabolic and cardiovascular diseases, is the focus of the DOHaD (Developmental Origins of Health and Disease) research line. In this sense, advancements in molecular biology techniques have contributed significantly to the understanding of the mechanisms underlying the observed phenotypes, their morphological and physiological alterations, having as a main driving factor the epigenetic modifications and their consequent modulation of gene expression. The present narrative review aimed to characterize the different susceptible phases of development and associated epigenetic modifications, and their implication in the development of non-communicable diseases. Additionally, we provide useful insights into interventions during development to counteract or prevent long-term programming for disease susceptibility.

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.

Early postnatal overnutrition impairs VO2max gains with moderate exercise and increase post-exercise muscle damage in adult male rats.

Exercise counteracts obesity effects, but information on how early-life obesity may affect long-term adaptation to exercise is lacking. This study investigates the impact of early-life postnatal overfeeding (PO) on animals' adaptation to exercise. Only male Wistar rats were used. On postnatal day (PN) 30, rats from control (NL-9 pups) or PO (SL-3 pups) litters were separated into four groups: NL-sedentary (NL-Se), NL-exercised (NL-Ex), SL-sedentary (SL-Se), and SL-exercised (SL-Ex). Exercised groups performed moderate-intensity exercise, running on a treadmill, from PN30 to PN90. Further experiments were carried out between PN90 and PN92. PO promoted obesity in SL versus NL rats (P < 0.05). Exercise reduced body weight (P < 0.001), body fat (P < 0.01), and improved glucose homeostasis in SL-Ex versus SL-Se. SL-Ex presented lower VO2max (P < 0.01) and higher post-exercise LDH (P < 0.05) compared to NL-Ex rats. Although moderate exercise counteracted obesity in SL rats, early-life overnutrition restricts fitness gains in adulthood, indicating that early obesity may impair animals' adaptation to exercise.

Metformin Improves Autonomic Nervous System Imbalance and Metabolic Dysfunction in Monosodium L-Glutamate-Treated Rats.

Metformin is an antidiabetic drug used for the treatment of diabetes and metabolic diseases. Imbalance in the autonomic nervous system (ANS) is associated with metabolic diseases. This study aimed to test whether metformin could improve ANS function in obese rats. Obesity was induced by neonatal treatment with monosodium L-glutamate (MSG). During 21-100 days of age, MSG-rats were treated with metformin 250 mg/kg body weight/day or saline solution. Rats were euthanized to evaluate biometric and biochemical parameters. ANS electrical activity was recorded and analyzed. Metformin normalized the hypervagal response in MSG-rats. Glucose-stimulated insulin secretion in isolated pancreatic islets increased in MSG-rats, while the cholinergic response decreased. Metformin treatment normalized the cholinergic response, which involved mostly the M3 muscarinic acetylcholine receptor (M3 mAChR) in pancreatic beta-cells. Protein expression of M3 mAChRs increased in MSG-obesity rats, while metformin treatment decreased the protein expression by 25%. In conclusion, chronic metformin treatment was effective in normalizing ANS activity and alleviating obesity in MSG-rats.

Vagotomy and Splenectomy Reduce Insulin Secretion and Interleukin-1ß.

OBJECTIVES: This study aimed to evaluate the effect of vagotomy, when associated with splenectomy, on adiposity and glucose homeostasis in Wistar rats. METHODS: Rats were divided into 4 groups: vagotomized (VAG), splenectomized (SPL), VAG + SPL, and SHAM. Glucose tolerance tests were performed, and physical and biochemical parameters evaluated. Glucose-induced insulin secretion and protein expression (Glut2/glucokinase) were measured in isolated pancreatic islets. Pancreases were submitted to histological and immunohistochemical analyses, and vagus nerve neural activity was recorded. RESULTS: The vagotomized group presented with reduced body weight, growth, and adiposity; high food intake; reduced plasma glucose and triglyceride levels; and insulin resistance. The association of SPL with the VAG surgery attenuated, or abolished, the effects of VAG and reduced glucose-induced insulin secretion and interleukin-1ß area in ß cells, in addition to lowering vagal activity. CONCLUSIONS: The absence of the spleen attenuated or blocked the effects of VAG on adiposity, triglycerides and glucose homeostasis, suggesting a synergistic effect of both on metabolism. The vagus nerve and spleen modulate the presence of interleukin-1ß in ß cells, possibly because of the reduction of glucose-induced insulin secretion, indicating a bidirectional flow between autonomous neural firing and the spleen, with repercussions for the endocrine pancreas.

Whey protein enriched with Stevia rebaudiana fraction restores the pancreatic function of streptozotocin induced diabetic rats.

The study aims to analyse the treatment of whey protein enriched with Stevia rebaudiana fraction in insulin secretion and its role mitigating streptozotocin-induced hyperglycemia in rats. Thus, diabetic animals were treated with whey protein enriched with S. rebaudiana fraction or with only the protein isolate or only the Stevia fraction. Insulin level in plasma was measured by radioimmunoassay and the viability of ß cells was detected by immunohistochemistry. The results showed that diabetic animals treated with whey protein enriched with S. rebaudiana fraction had a greater recovery from insulinemia, with plasma levels similar to non-diabetic animals (~ 0.13 ng/mL). In addition, the same group showed a higher number of insulin-positive pancreatic B cells (~ 66%) in immunohistochemistry analysis, while the diabetic groups treated with only the fraction of stevia or whey protein showed 38 and 59% of positive cells, respectively. These results show that the treatment may have restored the viability of streptozotocin-injured pancreatic B cells, and consequently increased insulin secretion, suggesting whey protein enriched with S. rebaudiana fraction can be used an adjunct/supplement in diabetic treatment.

Correction to: Impairment of testicular development in rats exposed to acephate during maternal gestation and lactation.

The original publication of this paper contains a mistake.

Multigenerational effects of chronic maternal exposure to a high sugar/fat diet and physical training.

Pregnant individuals who overeat are more likely to predispose their fetus to the development of metabolic disorders in adulthood. Physical training is a prevention and treatment interventional strategy that could treat these disorders, since it improves metabolism and body composition. This study assessed the protective effect of physical exercise against possible metabolic changes in generations F1 and F2, whose mothers were subjected to a high-sugar/high-fat (HS/HF) diet. Wistar rats belonging to generation F0 were distributed into four groups (n = 10): sedentary control (CSed), exercised control (CExe), sedentary HS/HF diet (DHSed) and exercised HS/HF diet (DHExe). From 21 to 120 days of age, maintained during pregnancy and lactation period, CSed/CExe animals received standard feed and DHSed/DHExe animals a HS/HF diet. Animals from the CExe/DHExe underwent physical training from 21 to 120 days of age. Male and female F1 and F2 received a normocaloric feed and did not perform any physical training, categorized into four groups (n = 10) according to the maternal group to which they belonged to. An increase in body weight, adiposity and glucose, and a change in lipid profile in F0 were observed, while exercise reduced the biochemical parameters comparing DHSed with DHExe. Maternal exercise had an effect on future generations, reducing adiposity, glucose and triglyceride concentrations, and preventing deleterious effects on glucose tolerance. Maternal overeating increased health risks both for mother and offspring, demonstrating that an HS/HF diet intake promotes metabolic alterations in the offspring. Importantly, the physical training performed by F0 proved to be protective against such effects.

Whey protein sweetened with Stevia rebaudiana Bertoni (Bert.) increases mitochondrial biogenesis markers in the skeletal muscle of resistance-trained rats.

BACKGROUND: A combination of resistance training and whey protein supplementation is a common practice among athletes and recreational exercisers to enhance muscle growth and strength. Although their safety as food additives is controversial, artificial sweeteners are present in whey protein supplements. Thus, natural sweeteners extracted from the leaves of Stevia rebaudiana are a potential alternative, due to their safety and health benefits. Here, we investigated the effects of whey protein sweetened with S. rebaudiana on physical performance and mitochondrial biogenesis markers in the skeletal muscle of resistance-trained rats. METHODS: Forty male Wistar rats were distributed into four groups: sedentary rats, trained rats, trained rats receiving whey protein and trained rats receiving whey protein sweetened with S. rebaudiana leaf extracts. Resistance training was performed by climbing a ladder 5 days per week, during 8-weeks. The training sessions consisted of four climbs carrying a load of 50, 75, 90, and 100% of the maximum load-carrying capacity which we determined before by performing a maximum load-carrying test for each animal. After this period, we collected plasma and tissues samples to evaluate biochemical, histological and molecular (western blot) parameters in these rats. RESULTS: Dietary supplementation with whey protein sweetened with S. rebaudiana significantly enhanced the maximum load-carrying capacity of resistance-trained rats, compared with non-sweetened whey protein supplementation. This enhanced physical performance was accompanied by an increase in the weight of the gastrocnemius and soleus muscle pads. Although the muscle pad of the biceps brachii was not altered, we observed a significant increase in PGC-1α expression, which was followed by a similar pattern in TFAM protein expression, two important mitochondrial biogenesis markers. In addition, a higher level of AMPK phosphorylation was observed in these resistance-trained rats. Finally, supplementation with whey protein sweetened with S. rebaudiana also induced a significant decrease in retroperitoneal adipocyte diameter and an increase in the weight of brown adipose tissue pads in resistance-trained rats. CONCLUSION: The addition of Stevia rebaudiana leaf extracts to whey protein appears to be a potential strategy for those who want to increase muscular mass and strength and also improve mitochondrial function. This strategy may be useful for both athletes and patients with metabolic disorders, such as obesity and type 2 diabetes.

Potential attenuation of early-life overfeeding-induced metabolic dysfunction by chronic maternal acetylcholinesterase inhibitor exposure.

Evidence suggests that low concentration perinatal exposure to environmental contaminants, such as organophosphate (OP) is associated with later life insulin resistance and type 2 diabetes. The aim of this work was to investigate whether chronic maternal OP exposure exacerbates metabolic dysfunctions in early-overfed rats. During pregnancy and lactational periods, dams received OP by gavage. To induce neonatal overnutrition at postnatal day 3, pups were standardized to 9 or 3 per nest. At 90-days-old, glucose-insulin homeostasis and insulin release from pancreatic islets were analyzed. While both OP exposure and overfeeding alone did induce diabetogenic phenotypes in adulthood, there was no exacerbation in rats that experienced both. Unexpectedly, the group that experienced both had improved adiposity, metabolic parameters, attenuated insulin release from isolated islets in the presence of glucose and low function of muscarinic acetylcholine receptor M3, as well as an attenuation of beta cell mass hyperplasia. High levels of butyrylcholinesterase and low levels of insulin in milk may contribute to the OP-induced developmental programming. Our study showed that maternal OP exposure may program insulin release as well as endocrine pancreas structure, thus affecting metabolism in adulthood. Our data suggest that while perinatal OP exposure alone increases the risk for later life T2D, it actually reverses many of the programmed metabolic dysfunction that is induced by postnatal overfeeding. These surprising results may suggest that low-dose administration of acetylcholinesterase inhibitors could be of utility in preventing detrimental developmental programming that is caused by early-life overnutrition.

Moderate exercise training since adolescence reduces Walker 256 tumour growth in adult rats.

KEY POINTS: Cancer growth, cell proliferation and cachexia index can be attenuated by the beneficial programming effect of moderate exercise training, especially if it begins in adolescence. Walker 256 tumour-bearing rats who started exercise training during adolescence did not revert the basal low glycaemia and insulinaemia observed before tumour cell inoculation. The moderate exercise training improved glucose tolerance and peripheral insulin sensitivity only in rats exercised early in adolescence. The chronic effects of our exercise protocol are be beneficial to prevent cancer cachexia and hold clear potential as a nonpharmacological therapy of insulin sensitization. ABSTRACT: We tested the hypothesis that moderate exercise training, performed early, starting during adolescence or later in life during adulthood, can inhibit tumour cell growth as a result of changes in biometric and metabolic markers. Male rats that were 30 and 70 days old performed a treadmill running protocol over 8 weeks for 3 days week-1 , 44 min day-1 and at 55-65% V̇O2max . After the end of training, a batch of rats was inoculated with Walker 256 carcinoma cells. At 15 days after carcinoma cell inoculation, the tumour was weighed and certain metabolic parameters were evaluated. The data demonstrated that physical performance was better in rats that started exercise training during adolescence according to the final workload and V̇O2max . Early or later moderate exercise training decreased the cachexia index, cell proliferation and tumour growth; however, the effects were more pronounced in rats that exercised during adolescence. Low glycaemia, insulinaemia and tissue insulin sensitivity was not reverted in Walker 256 tumour-bearing rats who trained during adolescence. Cancer growth can be attenuated by the beneficial programming effect of moderate exercise training, especially if it begins during adolescence. In addition, improvement in glucose-insulin homeostasis might be involved in this process.

Environmental monitoring and the developmental origins of health and disease.

Early-life chronic exposure to environmental contaminants, such as bisphenol-A, particulate matter air pollution, organophosphorus pesticides, and pharmaceutical drugs, among others, may affect central tissues, such as the hypothalamus, and peripheral tissues, such as the endocrine pancreas, causing inflammation and apoptosis with severe implications to the metabolism. The Developmental Origins of Health and Disease (DOHaD) concept articulates events in developmental phases of life, such as intrauterine, lactation, and adolescence, to later-life metabolism and health. These developmental phases are more susceptible to environmental changes, such as those caused by environmental contaminants, which may predispose individuals to obesity, metabolic syndrome, and chronic noncommunicable diseases later in life. Alterations in the epigenome are explored as an underlying mechanism to the programming effects on metabolism, as the expression of key genes related with central and peripheral metabolic functions may be altered in response to environmental disturbances. Studies show that environmental contaminants may affect gene expressions in mammals, especially when exposed to during the developmental phases of life, leading to metabolic disorders in adulthood. In this review, we discuss the current obesity epidemics, the DOHaD concept, pollutants' toxicology, environmental control, and the role of environmental contaminants in the central and peripheral programming of obesity and metabolic syndrome. Improving environmental monitoring may directly affect the quality of life of the population and help protect the future generations from metabolic diseases.

Monosodium l-glutamate-obesity onset is associated with disruption of central control of the hypothalamic-pituitary-adrenal axis and autonomic nervous system.

The hypothalamic-pituitary-adrenal axis (HPA) exerts important catabolic peripheral effects and influences autonomic nervous system (ANS)-mediated processes. Impaired negative-feedback control or reduced HPA axis sensitivity and altered ANS activity appear to be associated with the development and maintenance of obesity. In the present study, we examined the hypothesis that the central HPA axis is dysregulated favouring ANS disbalance in monosodium l-glutamate (MSG)-induced rat obesity. Glucose homeostasis, corticosterone, leptin and ANS electrical activity were evaluated. Adult MSG-induced obese rats exhibited fasting hyperinsulinaemia, insulin resistance, glucose intolerance, hypercorticosteronaemia, hyperleptinaemia and altered ANS activity. A decrease in food intake was observed during corticotrophin-releasing hormone (CRH) treatment in both control and MSG-treated rats. By contrast, food intake was significantly elevated in control rats treated with dexamethasone (DEXA), whereas no alterations were observed following DEXA treatment in MSG-induced obese rats. After DEXA injection, an increase in fasting insulin and glucose levels, associated with insulin resistance, was seen in both groups. As expected, there was a decrease of parasympathetic activity and an increase of sympathetic nervous activity in CRH-treated control animals and the opposite effect was seen after DEXA treatment. By contrast, there was no effect on ANS activity in MSG-rats treated with CRH or DEXA. In conclusion, impairment of the HPA axis can lead to disbalance of ANS activity in MSG-treated rats, contributing to the establishment and maintenance of obesity.

Strength training reverses ovariectomy-induced bone loss and improve metabolic parameters in female Wistar rats.

Menopause induces osteoporosis, sarcopenia, insulin resistance, and dyslipidemia. Ovariectomized (OVX) rat is an animal model, which mimetics postmenopausal conditions. The present study aimed to test the effects of strength training protocol on bone mineral density and metabolic parameters in OVX rats. Female Wistar rats were randomly separated in four groups: non-ovariectomized rats (Sham); ovariectomized rats (OVX); OVX treated with 17ß-estradiol (HR); and OVX trained group (TR). At 70-days-old OVX groups were submitted to a bilateral ovariectomy. Hormonal replacement and strength training were performed three times per week, for 60 days. 17ß-estradiol was administered by intramuscular injection (50 µg/kg of BW) and strength training protocol was composed by four series of 12 repetitions with 65-75% of 1RM. As expected, OVX impaired glucose homeostasis, promoted weight and adiposity gain, dyslipidemia, sarcopenia and osteoporosis, but hormonal replacement and strength training improved most of these parameters. Both HR and TR normalize glucose homeostasis; however, only TR restores blood insulin. OXV also reduced the maximum force in 42%, but TR improved this parameter in 110%, in addition TR prevents sarcopenia and fat mass gain. Interestingly, strength training was able to improve significantly BMD. Taken together, these data suggest that strength training can be effective in the treatment of damage caused by OVX, which in a translational context, becomes an effective non-pharmacological strategy to improve the health of postmenopausal women, reducing costs with secondary symptoms, mainly caused by weight gain, sarcopenia and osteoporosis.

Maternal diet-induced obesity during suckling period programs offspring obese phenotype and hypothalamic leptin/insulin resistance.

During the early post-natal period, offspring are vulnerable to environmental insults, such as nutritional and hormonal changes, which increase risk to develop metabolic diseases later in life. Our aim was to understand whether maternal obesity during lactation programs offspring to metabolic syndrome and obese phenotype, in addition we aimed to assess the peripheral glucose metabolism and hypothalamic leptin/insulin signaling pathways. At delivery, female Wistar rats were randomly divided in two groups: Control group (CO), mothers fed a standard rodent chow (Nuvilab); and Diet-induced obesity group (DIO), mothers who had free access to a diet performed with 33% ground standard rodent chow, 33% sweetened condensed milk (Nestlé), 7% sucrose and 27% water. Maternal treatment was performed throughout suckling period. All offspring received standard rodent chow from weaning until 91-day-old. DIO dams presented increased total body fat and insulin resistance. Consequently, the breast milk from obese dams had altered composition. At 91-day-old, DIO offspring had overweight, hyperphagia and higher adiposity. Furthermore, DIO animals had hyperinsulinemia and insulin resistance, they also showed pancreatic islet hypertrophy and increased pancreatic ß-cell proliferation. Finally, DIO offspring showed low ObRb, JAK2, STAT-3, IRß, PI3K and Akt levels, suggesting leptin and insulin hypothalamic resistance, associated with increased of hypothalamic NPY level and decreased of POMC. Maternal obesity during lactation malprograms rat offspring to develop obesity that is associated with impairment of melanocortin system. Indeed, rat offspring displayed glucose dyshomeostasis and both peripheral and central insulin resistance.

Particulate Matter Exposure During Perinatal Life Results in Impaired Glucose Metabolism in Adult Male Rat Offspring.

BACKGROUND/AIMS: Particulate matter (PM) is an important risk factor for immunological system imbalance due to its small size, which can reach more distal regions of the respiratory tract, independently of its chemical composition. Some studies have suggested that PM exposure is associated with an increased incidence of diabetes, especially in industrialized urban regions. However, studies regarding the effects of PM exposure during perinatal life on glucose metabolism are limited. We tested whether exposure to PM from an urban area with poor air quality during pregnancy and lactation could cause short- and long-term dysfunction in rat offspring. METHODS: Samples of < 10 µm PM were collected in an urban area of Cotonou, Benin (West Africa), and reconstituted in corn oil. Pregnant Wistar rats received 50 µg PM/day by gavage until the end of lactation. After birth, we analyzed the dams' biochemical parameters as well as those of their male offspring at 21 and 90 days of age. RESULTS: The results showed that PM exposure did not lead to several consequences in dams; however, the male offspring of both ages presented an increase of approximately 15% in body weight. Although the blood glucose levels remained unchanged, the insulin levels were increased 2.5- and 2-fold in PM exposure groups of both ages, respectively. HOMA-IR and HOMA-ß were also increased at both ages. We also demonstrated that the number, islet area and insulin immunodensity of pancreatic islets were significantly increased at both ages from PM exposure. CONCLUSION: Our data show that chronic PM exposure by the oral route during perinatal life in rats leads to glucose dyshomeostasis in male offspring both in early and later life. Thus, we suggest that an ambience with poor air quality, mainly where traffic is dense, can contribute to an increase in metabolic disease incidence.

Aerobic Exercise Training Attenuates Tumor Growth and Reduces Insulin Secretion in Walker 256 Tumor-Bearing Rats.

Aerobic exercise training can improve insulin sensitivity in many tissues; however, the relationship among exercise, insulin, and cancer cell growth is unclear. We tested the hypothesis that aerobic exercise training begun during adolescence can attenuate Walker 256 tumor growth in adult rats and alter insulin secretion. Thirty-day-old male Wistar rats engaged in treadmill running for 8 weeks, 3 days/week, 44 min/day, at 55-65% VO2max until they were 90 days old (TC, Trained Control). An equivalently aged group was kept inactive during the same period (SC, Sedentary Control). Then, half the animals of the SC and TC groups were reserved as the control condition and the other half were inoculated with Walker 256 cancer cells, yielding two additional groups (Sedentary Walker and Trained Walker). Zero mortalities were observed in tumor-bearing rats. Body weight (BW), food intake, plasma glucose, insulin levels, and peripheral insulin sensitivity were analyzed before and after tumor cell inoculation. We also evaluated tumor growth, metastasis and cachexia. Isolated pancreatic islets secretory activity was analyzed. In addition, we evaluated mechanic sensibility. Our results showed improved physical performance according to the final workload and VO2max and reduced BW in trained rats at the end of the running protocol. Chronic adaptation to the aerobic exercise training decreased tumor weight, cachexia and metastasis and were associated with low glucose and insulin levels and high insulin sensitivity before and after tumor cell inoculation. Aerobic exercise started at young age also reduced pancreatic islet insulin content and insulin secretion in response to a glucose stimulus, without impairing islet morphology in trained rats. Walker 256 tumor-bearing sedentary rats also presented reduced pancreatic islet insulin content, without changing insulin secretion through isolated pancreatic islets. The mechanical sensitivity test indicated that aerobic exercise training did not cause injury or trigger inflammatory processes prior to tumor cell inoculation. Taken together, the current study suggests that aerobic exercise training applied during adolescence may mitigate tumor growth and related disorders in Walker 256 tumor-bearing adult rats. Improved insulin sensibility, lower glucose and insulin levels and/or reduced insulin secretion stimulated by glucose may be implicated in this tumor attenuation.

Stevia Nonsweetener Fraction Displays an Insulinotropic Effect Involving Neurotransmission in Pancreatic Islets.

Stevia rebaudiana (Bert.) Bertoni besides being a source of noncaloric sweeteners is also an important source of bioactive molecules. Many plant extracts, mostly obtained with ethyl acetate solvent, are rich in polyphenol compounds that present insulinotropic effects. To investigate whether the nonsweetener fraction, which is rich in phenolic compounds isolated from Stevia rebaudiana with the solvent ethyl acetate (EAF), has an insulinotropic effect, including interference at the terminals of the autonomic nervous system of the pancreatic islets of rats. Pancreatic islets were isolated from Wistar rats and incubated with EAF and inhibitory or stimulatory substances of insulin secretion, including cholinergic and adrenergic agonists and antagonists. EAF potentiates glucose-stimulated insulin secretion (GSIS) only in the presence of high glucose and calcium-dependent concentrations. EAF increased muscarinic insulinotropic effects in pancreatic islets, interfering with the muscarinic receptor subfamily M3. Adrenergic inhibitory effects on GSIS were attenuated in the presence of EAF, which interfered with the adrenergic α2 receptor. Results suggest that EAF isolated from stevia leaves is a potential therapy for treating type 2 diabetes mellitus by stimulating insulin secretion only in high glucose concentrations, enhancing parasympathetic signal transduction and inhibiting sympathetic signal transduction in beta cells.

Protein-restriction diet during the suckling phase programs rat metabolism against obesity and insulin resistance exacerbation induced by a high-fat diet in adulthood.

Protein restriction during the suckling phase can malprogram rat offspring to a lean phenotype associated with metabolic dysfunctions later in life. We tested whether protein-caloric restriction during lactation can exacerbate the effect of a high-fat (HF) diet at adulthood. To test this hypothesis, we fed lactating Wistar dams with a low-protein (LP; 4% protein) diet during the first 2 weeks of lactation or a normal-protein (NP; 23% protein) diet throughout lactation. Rat offspring from NP and LP mothers received a normal-protein diet until 60 days old. At this time, a batch of animals from both groups was fed an HF (35% fat) diet, while another received an NF (7% fat) diet. Maternal protein-caloric restriction provoked lower body weight and fat pad stores, hypoinsulinemia, glucose intolerance, higher insulin sensitivity, reduced insulin secretion and altered autonomic nervous system (ANS) function in adult rat offspring. At 90 days old, NP rats fed an HF diet in adulthood displayed obesity, impaired glucose homeostasis and altered insulin secretion and ANS activity. Interestingly, the LP/HF group also presented fat pad and body weight gain, altered glucose homeostasis, hyperleptinemia and impaired insulin secretion but at a smaller magnitude than the NP-HF group. In addition, LP/HF rats displayed elevated insulin sensitivity. We concluded that protein-caloric restriction during the first 14 days of life programs the rat metabolism against obesity and insulin resistance exacerbation induced by an obesogenic HF diet.

Maternal low intensity physical exercise prevents obesity in offspring rats exposed to early overnutrition.

Low intensity exercise during pregnancy and lactation may create a protective effect against the development of obesity in offspring exposed to overnutrition in early life. To test these hypotheses, pregnant rats were randomly assigned into 2 groups: Sedentary and Exercised, low intensity, on a rodent treadmill at 30% VO2Max /30-minute/session/3x/week throughout pregnancy and the lactation. Male offspring were raised in small litters (SL, 3 pups/dam) and normal litters (NL, 9 pups/dam) as models of early overnutrition and normal feed, respectively. Exercised mothers showed low mesenteric fat pad stores and fasting glucose and improved glucose-insulin tolerance, VO2max during lactation and sympathetic activity. Moreover, the breast milk contained elevated levels of insulin. In addition, SL of sedentary mothers presented metabolic dysfunction and glucose and insulin intolerance and were hyperglycemic and hyperinsulinemic in adulthood. SL of exercised mothers showed lower fat tissue accretion and improvements in glucose tolerance, insulin sensitivity, insulinemia and glycemia. The results suggest that maternal exercise during the perinatal period can have a possible reprogramming effect to prevent metabolic dysfunction in adult rat offspring exposed to early overnutrition, which may be associated with the improvement in maternal health caused by exercise.