Maternal exercise attenuates the lower skeletal muscle glucose uptake and insulin secretion caused by paternal obesity in female adult rat offspring.

KEY POINTS: Paternal obesity negatively influences metabolic outcomes in adult rat offspring. Maternal voluntary physical activity has previously been reported to improve glucose metabolism in adult rat offspring sired by healthy fathers. Here, we investigated whether a structured programme of maternal exercise training before and during gestation can attenuate the negative impacts that paternal obesity has on insulin sensitivity and secretion in female adult offspring. Exercise before and during pregnancy normalised the lower insulin sensitivity in skeletal muscle and the lower insulin secretion observed in female offspring sired by obese fathers. This paper presents a feasible, low-cost and translatable intervention strategy that can be applied perinatally to support multifactor interventions to break the cycle of metabolic dysfunction caused by paternal obesity. ABSTRACT: We investigated whether maternal exercise before and during gestation could attenuate the negative metabolic effects of paternal high-fat diet-induced obesity in female adult rat offspring. Fathers consumed a normal chow or high-fat diet before mating. Mothers exercised on a treadmill before and during gestation or remained sedentary. In adulthood, female offspring were assessed using intraperitoneal insulin and glucose tolerance tests (IPITT and IPGTT, respectively), pancreatic morphology, ex vivo skeletal muscle insulin-stimulated glucose uptake and mitochondrial respiratory function. Paternal obesity impaired whole-body and skeletal muscle insulin sensitivity and insulin secretion in adult offspring. Maternal exercise attenuated the lower insulin-stimulated glucose uptake in offspring sired by obese fathers but distal insulin signalling components (p-AKT Thr308 and Ser473, p-TBC1D4 Thr642 and GLUT4) remained unchanged (P > 0.05). Maternal exercise increased citrate synthase activity only in offspring sired by obese fathers. Maternal exercise also reversed the lower insulin secretion in vivo observed in offspring of obese fathers, probably due to an attenuation of the decrease in pancreatic beta cell mass. In summary, maternal exercise before and during pregnancy in rats attenuated skeletal muscle insulin resistance and attenuated the decrease in pancreatic beta cell mass and insulin secretion observed in the female offspring of obese fathers.

Four weeks of exercise early in life reprograms adult skeletal muscle insulin resistance caused by a paternal high-fat diet.

KEY POINTS: A paternal high-fat diet/obesity before mating can negatively influence the metabolism of offspring. Exercise only early in life has a remarkable effect with respect to reprogramming adult rat offspring exposed to detrimental insults before conception. Exercise only early in life normalized adult whole body and muscle insulin resistance as a result of having a high-fat fed/obese father. Unlike the effects on the muscle, early exercise did not normalize the reduced adult pancreatic beta cell mass as a result of having a high-fat fed/obese father. Early-life exercise training may be able to reprogram an individual whose father was obese, inducing long-lasting beneficial effects on health. ABSTRACT: A paternal high-fat diet (HFD) impairs female rat offspring glucose tolerance, pancreatic morphology and insulin secretion. We examined whether only 4 weeks of exercise early in life could reprogram these negative effects. Male Sprague-Dawley rats consumed a HFD for 10 weeks before mating with chow-fed dams. Female offspring remained sedentary or performed moderate intensity treadmill exercise (5 days week-1 , 60 min day-1 , 20 m min-1 ) from 5 to 9 weeks of age. Paternal HFD impaired (P < 0.05) adult offspring whole body insulin sensitivity (i.p. insulin sensitivity test), as well as skeletal muscle ex vivo insulin sensitivity and TBC1D4 phosphorylation. It also lowered ß-cell mass and reduced in vivo insulin secretion in response to an i.p. glucose tolerance test. Early-life exercise in offspring reprogrammed the negative effects of a paternal HFD on whole body insulin sensitivity, skeletal muscle ex vivo insulin-stimulated glucose uptake and TBC1D4 phosphorylation and also increased glucose transporter 4 protein. However, early exercise did not normalize the reduced pancreatic ß-cell mass or insulin secretion. In conclusion, only 4 weeks of exercise early in life in female rat offspring reprograms reductions in insulin sensitivity in adulthood caused by a paternal HFD without affecting pancreatic ß-cell mass or insulin secretion.

Acute exercise increases insulin sensitivity in adult sheep: a new preclinical model.

In healthy humans and rodents, chronic and acute exercise improves subsequent insulin sensitivity of skeletal muscle. A large animal species with similar metabolic responses to exercise would permit longitudinal studies, including repeated biopsies of muscle and other tissues not possible in rodents, and enable study of interactions with insulin-resistant physiological states not feasible in humans. Therefore, we examined whether acute exercise increases insulin sensitivity in adult sheep. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp (HEC) in mature female sheep (n = 7). Sheep were familiarized to treadmill walking and then performed an acute exercise bout (30 min, 8% slope, up to 4.4 km/h). A second HEC was conducted ∼18 h after the acute exercise. Musculus semimembranosus biopsies were obtained before and after each HEC. Glucose infusion rate during the HEC increased 40% (P = 0.003) and insulin sensitivity (glucose infusion rate/plasma insulin concentration) increased 32% (P = 0.028) after acute exercise. Activation of proximal insulin signaling in skeletal muscle after the HEC, measured as Ser(473) phosphorylation of Akt, increased approximately five-fold in response to insulin (P < 0.001) and was unaltered by acute exercise performed 18 h earlier. PGC1α and GLUT4 protein, glycogen content and citrate synthase activity in skeletal muscle did not change in response to insulin or exercise. In conclusion, improved insulin sensitivity and unchanged proximal insulin signaling on the day after acute exercise in sheep are consistent with responses in humans and rodents, suggesting that the sheep is an appropriate large-animal model in which to study responses to exercise.

Exercise as an intervention to improve metabolic outcomes after intrauterine growth restriction.

Individuals born after intrauterine growth restriction (IUGR) are at an increased risk of developing diabetes in their adult life. IUGR impairs ß-cell function and reduces ß-cell mass, thereby diminishing insulin secretion. IUGR also induces insulin resistance, with impaired insulin signaling in muscle in adult humans who were small for gestational age (SGA) and in rodent models of IUGR. There is epidemiological evidence in humans that exercise in adults can reduce the risk of metabolic disease following IUGR. However, it is not clear whether adult IUGR individuals benefit to the same extent from exercise as do normal-birth-weight individuals, as our rat studies suggest less of a benefit in those born IUGR. Importantly, however, there is some evidence from studies in rats that exercise in early life might be able to reverse or reprogram the long-term metabolic effects of IUGR. Studies are needed to address gaps in current knowledge, including determining the mechanisms involved in the reprogramming effects of early exercise in rats, whether exercise early in life or in adulthood has similar beneficial metabolic effects in larger animal models in which insulin resistance develops after IUGR. Human studies are also needed to determine whether exercise training improves insulin secretion and insulin sensitivity to the same extent in IUGR adults as in control populations. Such investigations will have implications for customizing the recommended level and timing of exercise to improve metabolic health after IUGR.

Programmed changes in the adult rat offspring caused by maternal protein restriction during gestation and lactation are attenuated by maternal moderate-low physical training.

The effects of maternal moderate-low physical training on postnatal development, glucose homeostasis and leptin concentration in adult offspring subjected to a low-protein diet during the perinatal period were investigated. Male Wistar rats (aged 150 d old) were divided into four groups according to maternal group: untrained (NTp, n 8); trained (Tp, n 8); untrained with a low-protein diet (NT+LPp, n 8); trained with a low-protein diet (T+LPp, n 8). The trained mothers were subjected to a protocol of moderate physical training over a period of 4 weeks (treadmill, 5 d/week, 60 min/d, at 65 % VO(2max)) before mating. At pregnancy, the intensity and duration of exercise was progressively reduced (50-20 min/d, at 65-30 % VO(2max)). The low-protein diet groups received an 8 % casein diet, and their peers received a 17 % casein diet during gestation and lactation. The pups' birth weight and somatic growth were recorded weekly up to the 150th day. Fasting blood glucose, cholesterol, serum leptin concentration, glucose and insulin tolerance tests were evaluated. The Tp animals showed no changes in somatic and biochemical parameters, while the NT+LPp group showed a greater abdominal circumference, hyperglycaemia, hypercholesterolaemia, glucose intolerance and lower plasma leptin. In the T+LPp animals, all of those alterations were reversed except for plasma leptin concentration. In conclusion, the effects of a perinatal low-protein diet on growth and development, glucose homeostasis and serum leptin concentration in the offspring were attenuated in pups from trained mothers.

Maternal moderate physical training during pregnancy attenuates the effects of a low-protein diet on the impaired secretion of insulin in rats: potential role for compensation of insulin resistance and preventing gestational diabetes mellitus.

The effects of pregestational and gestational low-to-moderate physical training on insulin secretion in undernourished mothers were evaluated. Virgin female Wistar rats were divided into four groups as follows: control (C, n = 5); trained (T, n = 5); low-protein diet (LP, n = 5); trained with a low-protein diet (T + LP, n = 5). Trained rats ran on a treadmill over a period of 4 weeks before mate (5 days week⁻¹ and 60 min day⁻¹, at 65% of VO(2max)). At pregnancy, the intensity and duration of the exercise were reduced. Low-protein groups were provided with an 8% casein diet, and controls were provided with a 17% casein diet. At third day after delivery, mothers and pups were killed and islets were isolated by collagenase digestion of pancreas and incubated for a further 1 h with medium containing 5.6 or 16.7 mM glucose. T mothers showed increased insulin secretion by isolated islets incubated with 16.7 mM glucose, whereas LP group showed reduced secretion of insulin by isolated islets when compared with both C and LP + T groups. Physical training before and during pregnancy attenuated the effects of a low-protein diet on the secretion of insulin, suggesting a potential role for compensation of insulin resistance and preventing gestational diabetes mellitus.

Maternal low-protein diet-induced delayed reflex ontogeny is attenuated by moderate physical training during gestation in rats.

We evaluated the effects of moderate- to low-intensity physical training during gestation on reflex ontogeny in neonate rats whose mothers were undernourished. Virgin female Wistar rats were divided into four groups as follows: untrained (NT, n 7); trained (T, n 7); untrained with a low-protein diet (NT+LP, n 7); trained with a low-protein diet (T+LP, n 4). Trained rats were subjected to a protocol of moderate physical training on a treadmill over a period of 4 weeks (5 d/week and 60 min/d, at 65 % of VO2max). After confirming the pregnancy, the intensity and duration of the exercise were reduced. Low-protein groups were provided with an 8 % casein diet, and controls were provided with a 17 % casein diet. Their respective offspring were evaluated (during the 10th-17th days of postnatal life) in terms of physical feature maturation, somatic growth and reflex ontogeny. Pups born to mothers provided with the low-protein diet during gestation and lactation showed delayed physical feature and reflex maturation and a deficit in somatic growth when compared with controls. However, most of these deficiencies were attenuated in pups of undernourished mothers undergoing training. In conclusion, physical training during gestation attenuates the effects of perinatal undernutrition on some patterns of maturation in the central nervous system during development.

Moderate physical training attenuates muscle-specific effects on fibre type composition in adult rats submitted to a perinatal maternal low-protein diet.

AIM: To verify whether moderate physical training affects the muscle fibre composition of adult rats subjected to a low protein diet during the perinatal period. METHODS: Male Wistar rats were divided into two groups according to their mother's diet during gestation and lactation: control (17% casein, C) and low-protein (8% casein, LP). On postnatal day 60, half of each group was submitted to moderate physical training (8 weeks, 5 days/week(-1), 60 min/day(-1), at 70% of VO(2max), T) or not. After the physical training period, soleus and extensor digitorum longus (EDL) muscles were removed. Myofibrillar ATPase staining was used to classify muscle fibres as type I, IIa, IIb, and intermediate. RESULTS: In the EDL muscle, LP rats showed no changes in the fibre type proportion. Both the C + T and LP + T groups showed a higher percentage of fibres of type IIa, and a lower proportion of fibres of type IIb. In the soleus muscle, LP animals showed a reduction in the proportion of fibre types I and intermediate. C + T rats showed an increase in the fibre type I and IIa. In the LP + T rats, the proportions of the fibre types remained similar to control rats. CONCLUSIONS: Moderate physical training acts as a positive environmental stimulus that reverts the effects of a perinatal low-protein diet on the proportion of fibre types in skeletal muscle.

Maternal low-protein diet reduces skeletal muscle protein synthesis and mass via Akt-mTOR pathway in adult rats.

Several studies have demonstrated that a maternal low-protein diet induces long-term metabolic disorders, but the involved mechanisms are unclear. This study investigated the molecular effects of a low-protein diet during pregnancy and lactation on glucose and protein metabolism in soleus muscle isolated from adult male rats. Female rats were fed either a normal protein diet or low-protein diet during gestation and lactation. After weaning, all pups were fed a normal protein diet until the 210th day postpartum. In the 7th month of life, mass, contractile function, protein and glucose metabolism, and the Akt-mTOR pathway were measured in the soleus muscles of male pups. Dry weight and contractile function of soleus muscle in the low-protein diet group rats were found to be lower compared to the control group. Lipid synthesis was evaluated by measuring palmitate incorporation in white adipose tissue. Palmitate incorporation was higher in the white adipose tissue of the low-protein diet group. When incubated soleus muscles were stimulated with insulin, protein synthesis, total amino acid incorporation and free amino acid content, glucose incorporation and uptake, and glycogen synthesis were found to be reduced in low-protein diet group rats. Fasting glycemia was higher in the low-protein diet group. These metabolic changes were associated with a decrease in Akt and GSK-3ß signaling responses to insulin and a reduction in RPS6 in the absence of the hormone. There was also notably lower expression of Akt in the isolated soleus muscle of low-protein diet group rats. This study is the first to demonstrate how maternal diet restriction can reduce skeletal muscle protein and mass by downregulating the Akt-mTOR pathway in adulthood.

Efeitos do treinamento físico durante a gestação sobre a evolução ponderal, glicemia e colesterolemia de ratos adultos submetidos à desnutrição perinatal / Effects of physical training during pregnancy on body weight gain, blood glucose and cholesterol in adult rats submitted to perinatal undernutrition

A incompatibilidade entre a desnutrição perinatal e uma nutrição adequada durante o desenvolvimento aumenta o risco de aparecimento precoce de doenças não transmissíveis na vida adulta. Todavia, acredita-se que a atividade física materna possa atenuar estas consequências. O presente estudo teve como objetivo avaliar os efeitos do treinamento físico durante a gestação na evolução ponderal, circunferência abdominal, glicemia e colesterolemia de filhotes adultos submetidos à desnutrição perinatal. Ratas Wistar (n = 12) foram divididas em quatro grupos: controle (C, n = 3), treinada (T, n = 3), desnutrida (D, n = 3) e treinada desnutrida (T+D, n = 3). Durante a gestação e lactação, os grupos D e T+D receberam dieta baixa em proteína (8% caseína) e os grupos C e T receberam dieta normoproteica (caseína a 17%). O protocolo de treinamento físico moderado foi realizado em esteira ergométrica (cinco dias/semana, 60 min/dia, a 65% do VO2max) e iniciou quatro semanas antes da gestação. Na gestação, a duração e a intensidade do treinamento foram reduzidas (cinco dias/semana, 20 min/dia, a 30% do VO2max) até o 19º dia pré-natal. Após o desmame, os filhotes (C F = 9, T F = 9, D F = 7, T+D F = 9) receberam dieta padrão de biotério e foram avaliados aos 270 dias de idade. A circunferência abdominal (CA) foi avaliada relativa ao peso corporal. Para avaliação da glicemia e colesterolemia foi utilizado o método enzimático colorimétrico da glicose-oxidase/peroxidase e da colesterol-oxidase, respectivamente. Ratos do grupo D F apresentaram um maior ganho de peso corporal ao longo do crescimento, maiores valores de CA, glicemia e colesterolemia quando comparados ao grupo C F. Para o grupo T+D F, o ganho de peso foi atenuado, e a CA, a glicemia e a colesterolemia foram normalizadas (p < 0,05). Esses resultados demonstram que o treinamento físico durante a gestação atenua os efeitos da desnutrição perinatal sobre alguns indicadores murinométricos e bioquímicos nos filhotes adultos.

The incompatibility of perinatal undernutrition and adequate nutrition during development increases the risk of early onset of non-communicable diseases in adulthood. However, it has been considered that maternal physical activity may attenuate these effects. This study aimed to evaluate the effects of physical training during pregnancy on body weight gain, waist circumference, glycaemia and cholesterolemia in adult offspring submitted to perinatal undernutrition. Female Wistar rats (n = 12) were divided into four groups: control (C, n = 3), trained (T, n = 3), undernourished (D, n = 3) undernourished and trained (T+D, n = 3). During gestation and lactation, D and T+D groups were fed a low protein diet (8% casein) and C and T groups fed a normal protein diet (17% casein). The protocol of moderate physical training was performed on a treadmill (5 days/week, 60 min/day, at 65% of VO2max) and began 4 weeks before pregnancy. At pregnancy, the duration and intensity of training were reduced (5 days/week, 20 min/day, at 30% VO2max) until the 19th prenatal day. At weaning, male pups (CP = 9, TP = 9, DP = 7, T+DP = 9) received standard diet and evaluations took place at 270 days old. Abdominal circumference (AC) was evaluated in relation to body weight. Enzymatic colorimetric method glucose-oxidase/peroxidase and cholesterol-oxidase was used to evaluate fasting glycaemia and cholesterolemia, respectively. Rats from DP group showed high body weight gain during growth, values of CA, glycaemia and cholesterolemia when compared to CP. Concerning the T+DP group,body weight gain was attenuated, and the CA, glycaemia and cholesterolemia were normalized (p<0.05). These results demonstrate that physical training during pregnancy reduces the effects of perinatal undernutrition on some murinometric and biochemical indicators of adult offspring.