•Protein-caloric restriction during lactation programs the offspring at weaning.•Milk composition and dam behavior mediate this programming.•Protein-caloric restriction causes ...hypothalamus–pituitary–adrenal axis hyperactivation in dams and offspring.•Undernourished dams demonstrated altered maternal care.
Maternal protein-caloric restriction during lactation can malprogram offspring into having a lean phenotype associated with metabolic dysfunction in early life and adulthood. The aim of this study was to investigate the relationships between nutritional stress, maternal behavior and metabolism, milk composition, and offspring parameters. Additionally, we focused on the role of hypothalamus–pituitary–adrenal axis hyperactivation during lactation.
Dams were fed a low-protein diet (4% protein) during the first 2 wk of lactation or a normal-protein diet (20% protein) during all lactation. Analyses of dams, milk, and offspring were conducted on postnatal days (PD) 7, 14, and 21.
Body weight and food intake decreased in dams, which was associated with reduced fat pad stores and increased corticosterone levels at PD 14. The stressed low-protein diet dams demonstrated alterations in behavior and offspring care. Despite nutritional deprivation, dams adapted their metabolism to provide adequate energy supply through milk; however, we demonstrated elevated corticosterone and total fat levels in milk at PD 14. Male offspring also showed increased corticosterone at PD 7, associated with a lean phenotype and alterations in white and brown adipose tissue morphology at PD 21.
Exposure to protein-caloric restriction diet of dams during lactation increased the glucocorticoid levels in dams, milk, and offspring, which is associated with alterations in maternal behavior and milk composition. Thus, glucocorticoids and milk composition may play an important role in metabolic programming induced by maternal undernutrition.
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.
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% V̇O2 max . 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 V̇O2 max . 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.
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.
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.
An interaction between obesity, impaired glucose metabolism and sperm function in adults has been observed but it is not known whether exposure to a diet high in fat during the peri-pubertal period ...can have longstanding programmed effects on reproductive function and gonadal structure. This study examined metabolic and reproductive function in obese rats programmed by exposure to a high fat (HF) diet during adolescence. The effect of physical training (Ex) in ameliorating this phenotype was also assessed. Thirty-day-old male Wistar rats were fed a HF diet (35% lard w/w) for 30 days then subsequently fed a normal fat diet (NF) for a 40-day recovery period. Control animals were fed a NF diet throughout life. At 70 days of life, animals started a low frequency moderate exercise training that lasted 30 days. Control animals remained sedentary (Se). At 100 days of life, biometric, metabolic and reproductive parameters were evaluated. Animals exposed to HF diet showed greater body weight, glucose intolerance, increased fat tissue deposition, reduced VO
and reduced energy expenditure. Consumption of the HF diet led to an increase in the number of abnormal seminiferous tubule and a reduction in seminiferous epithelium height and seminiferous tubular diameter, which was reversed by moderate exercise. Compared with the NF-Se group, a high fat diet decreased the number of seminiferous tubules in stages VII-VIII and the NF-Ex group showed an increase in stages XI-XIII. HF-Se and NF-Ex animals showed a decreased number of spermatozoa in the cauda epididymis compared with animals from the NF-Se group. Animals exposed to both treatments (HF and Ex) were similar to all the other groups, thus these alterations induced by HF or Ex alone were partially prevented. Physical training reduced fat pad deposition and restored altered reproductive parameters. HF diet consumption during the peri-pubertal period induces long-term changes on metabolism and the reproductive system, but moderate and low frequency physical training is able to recover adipose tissue deposition and reproductive system alterations induced by high fat diet. This study highlights the importance of a balanced diet and continued physical activity during adolescence, with regard to metabolic and reproductive health.
Purpose
The early-life nutritional environment affects long-term glucose homeostasis, we investigated the effects of maternal low-protein diet combined with postnatal early overfeeding on the male ...offspring’s glucose homeostasis in adulthood.
Methods
Only male rats were used, and their delivery was considered postnatal-day 0 (PN0). Wistar rats’ dams were divided into control (NP) or low-protein diet (LP). LP dams remained on the diet until PN14, after which all animals were supplied with the control diet. At PN2, litters were adjusted to 9 (control-NL) or 3 (postnatal-overfeeding-PO) pups, resulting in four experimental groups: NP-NL, NP-PO, LP-NL, and LP-PO. Litters were weaned on PN21. At PN80, a batch of animals from all experimental groups underwent surgery for cannula implantation, followed by intravenous glucose tolerance test (ivGTT), but the insulinogenic index (ISI) was calculated. At PN81, animals were euthanized and tissues were collected.
Results
LP-diet and early postnatal-overfeeding were effective in promoting the expected biometric outcomes at PN21 and PN81, but the LP-PO animals present a biometric profile similar to the control (NP-NL) group. Postnatal-overfeeding increased fasting glycemia in LP-PO animals (
p
< 0.01). In the ivGTT, postnatal-overfeeding elevated the glycemia (
p
< 0.0001), exacerbated in LP-PO animals (
p
< 0.0001). Insulinemia was reduced by both, maternal LP-diet and postnatal-overfeeding, with a higher degree of reduction in LP-PO animals (
p
< 0.0001). Maternal LP-diet and postnatal-overfeeding reduced the ISI (
p
< 0.0001). Factors interaction lead the LP-PO to a lower ISI compared to all other groups (
p
< 0.0001).
Conclusions
The combination of low-protein diet in breastfeeding dams with postnatal overfeeding disturbed the offspring’s glucose metabolism in adulthood.
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.
Purpose
Environmental and nutritional disorders during perinatal period cause metabolic dysfunction in the progeny and impair human health. Advanced glycation end products (AGEs) are primarily ...produced during metabolism of excess blood glucose, which is observed in diabetes. Methylglyoxal (MG) is a precursor for the generation of endogenous AGEs, which disturbs the metabolism. This work aimed to investigate whether the maternal MG treatment during lactation programs the progeny to metabolic dysfunction later in life.
Methods
Female Wistar rats were divided into two groups: control group (C) treated with saline and MG group treated with MG (60 mg/kg/day) by gavage throughout the lactation period. Both mothers and offspring were fed a standard chow. At weaning, breast milk composition was analyzed and mothers euthanized for blood and tissue sample collections. At 90 days of age, offspring were submitted to glucose tolerance test (ivGTT) and euthanized for blood and tissue samples collection.
Results
MG mothers showed increase in glucose and fructosamine levels; however, they showed low insulin levels and failure in β-cell function (
p
< 0.05). MG mothers also showed dyslipidemia (
p
< 0.05). Moreover, breast milk had elevated levels of glucose, triglycerides, cholesterol and fructosamine and low insulin (
p
< 0.05). Interestingly, MG offspring had increased body weight and adipose tissue at adulthood, and they also showed glucose intolerance and failure in β-cell function (
p
< 0.05). Besides, MG offspring showed dyslipidemia (
p
< 0.05) increasing cardiovascular diseases risk.
Conclusions
Maternal MG treatment negatively affects the male rat offspring, leading to type 2 diabetes and dyslipidemia in later life, possibly by changes in breast milk composition.
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.
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% VO
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 VO
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.
Perturbations to nutrition during critical periods are associated with changes in embryonic, fetal or postnatal developmental patterns that may render the offspring more likely to develop ...cardiovascular disease in later life. The aim of this study was to evaluate whether autonomic nervous system imbalance underpins in the long-term hypertension induced by dietary protein restriction during peri-pubertal period. Male Wistar rats were assigned to groups fed with a low protein (4% protein, LP) or control diet (20.5% protein; NP) during peri-puberty, from post-natal day (PN) 30 until PN60, and then all were returned to a normal protein diet until evaluation of cardiovascular and autonomic function at PN120. LP rats showed long-term increased mean arterial pressure (
= 0.002) and sympathetic arousal; increased power of the low frequency (LF) band of the arterial pressure spectral (
= 0.080) compared with NP animals. The depressor response to the ganglion blocker hexamethonium was increased in LP compared with control animals (
= 0.006). Pulse interval variability showed an increase in the LF band and LF/HF ratio (
= 0.062 and
= 0.048) in LP animals. The cardiac response to atenolol and/or methylatropine and the baroreflex sensitivity were similar between groups. LP animals showed ventricular hypertrophy (
= 0.044) and increased interstitial fibrosis (
= 0.028) compared with controls. Reduced protein carbonyls (PC) (
= 0.030) and catalase activity (
= 0.001) were observed in hearts from LP animals compared with control. In the brainstem, the levels of PC (
= 0.002) and the activity of superoxide dismutase and catalase (
= 0.044 and
= 0.012) were reduced in LP animals, while the levels of GSH and total glutathione were higher (
= 0.039 and
= 0.038) compared with NP animals. Protein restriction during peri-pubertal period leads to hypertension later in life accompanied by sustained sympathetic arousal, which may be associated with a disorganization of brain and cardiac redox state and structural cardiac alteration.
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