Maternal training during lactation modifies breast milk fatty acid composition and male offspring glucose homeostasis in rat.

The perinatal exposome can modify offspring metabolism and health later in life. Within this concept, maternal exercise during gestation has been reported modifying offspring glucose sensing and homeostasis, while the impact of such exercise during lactation is little-known. We thus aimed at evaluating short- and long-term effects of it on offspring pancreatic function, assuming a link with changes in breast milk composition. Fifteen-week-old primiparous female Wistar rats exercised during lactation at a constant submaximal intensity (TR) or remained sedentary (CT). Male offspring were studied at weaning and at 7 months of age for growth, pancreas weight, glycemia and insulin responses. Milk protein content was determined by the bicinchoninic acid assay (BCA colorimetric method), and lipid content and fatty acid composition by gas chromatography. Mature milk from TR rats contained significantly less saturated (-7 %) and more monounsaturated (+18 %) and polyunsaturated (PUFA +12 %) fatty acids compared to CT rats, with no difference in total lipid and protein concentrations. In offspring from TR vs CT mothers, fasting glycemia was lower, pancreas weight was higher with a lower insulin content (-37 %) at weaning. Such outcomes were correlated with milk PUFA levels and indices of desaturase or elongase activities. These effects were no longer present at 7 months, whereas a more efficient muscle insulin sensitivity was observed. Maternal training during lactation led to a specific milk phenotype that was associated with a short-term impact on glucose homeostasis and pancreatic function of the male offspring.

Overexpression of Gjb4 impairs cell proliferation and insulin secretion in primary islet cells.

OBJECTIVE: Altered gene expression contributes to the development of type 2 diabetes (T2D); thus, the analysis of differentially expressed genes between diabetes-susceptible and diabetes-resistant mouse models is an important tool for the determination of candidate genes that participate in the pathology. Based on RNA-seq and array data comparing pancreatic gene expression of diabetes-prone New Zealand Obese (NZO) mice and diabetes-resistant B6.V-ob/ob (B6-ob/ob) mice, the gap junction protein beta 4 (Gjb4) was identified as a putative novel T2D candidate gene. METHODS: Gjb4 was overexpressed in primary islet cells derived from C57BL/6 (B6) mice and INS-1 cells via adenoviral-mediated infection. The proliferation rate of cells was assessed by BrdU incorporation, and insulin secretion was measured under low (2.8 mM) and high (20 mM) glucose concentration. INS-1 cell apoptosis rate was determined by Western blotting assessing cleaved caspase 3 levels. RESULTS: Overexpression of Gjb4 in primary islet cells significantly inhibited the proliferation by 47%, reduced insulin secretion of primary islets (46%) and INS-1 cells (51%), and enhanced the rate of apoptosis by 63% in INS-1 cells. Moreover, an altered expression of the miR-341-3p contributes to the Gjb4 expression difference between diabetes-prone and diabetes-resistant mice. CONCLUSIONS: The gap junction protein Gjb4 is highly expressed in islets of diabetes-prone NZO mice and may play a role in the development of T2D by altering islet cell function, inducing apoptosis and inhibiting proliferation.

Pancreatic adipocytes mediate hypersecretion of insulin in diabetes-susceptible mice.

OBJECTIVE: Ectopic fat accumulation in the pancreas in response to obesity and its implication on the onset of type 2 diabetes remain poorly understood. Intermittent fasting (IF) is known to improve glucose homeostasis and insulinresistance. However, the effects of IF on fat in the pancreas and ß-cell function remain largely unknown. Our aim was to evaluate the impact of IF on pancreatic fat accumulation and its effects on islet function. METHODS: New Zealand Obese (NZO) mice were fed a high-fat diet ad libitum (NZO-AL) or fasted every other day (intermittent fasting, NZO-IF) and pancreatic fat accumulation, glucose homoeostasis, insulin sensitivity, and islet function were determined and compared to ad libitum-fed B6.V-Lepob/ob (ob/ob) mice. To investigate the crosstalk of pancreatic adipocytes and islets, co-culture experiments were performed. RESULTS: NZO-IF mice displayed better glucose homeostasis and lower fat accumulation in both the pancreas (-32%) and the liver (-35%) than NZO-AL mice. Ob/ob animals were insulin-resistant and had low fat in the pancreas but high fat in the liver. NZO-AL mice showed increased fat accumulation in both organs and exhibited an impaired islet function. Co-culture experiments demonstrated that pancreatic adipocytes induced a hypersecretion of insulin and released higher levels of free fatty acids than adipocytes of inguinal white adipose tissue. CONCLUSIONS: These results suggest that pancreatic fat participates in diabetes development, but can be prevented byIF.

Maternal exercise before and during gestation modifies liver and muscle mitochondria in rat offspring.

It is now well established that the intrauterine environment is of major importance for offspring health during later life. Endurance training during pregnancy is associated with positive metabolic adjustments and beneficial effects on the balance between pro-oxidants and antioxidants (redox state) in the offspring. Our hypothesis was that these changes could rely on mitochondrial adaptations in the offspring due to modifications of the fetal environment induced by maternal endurance training. Therefore, we compared the liver and skeletal muscle mitochondrial function and the redox status of young rats whose mothers underwent moderate endurance training (treadmill running) before and during gestation (T) with those of young rats from untrained mothers (C). Our results show a significant reduction in the spontaneous H2O2 release by liver and muscle mitochondria in the T versus C offspring (P<0.05). These changes were accompanied by alterations in oxygen consumption. Moreover, the percentage of short-chain fatty acids increased significantly in liver mitochondria from T offspring. This may lead to improvements in the fluidity and the flexibility of the membrane. In plasma, glutathione peroxidase activity and protein oxidation were significantly higher in T offspring than in C offspring (P<0.05). Such changes in plasma could represent an adaptive signal transmitted from mothers to their offspring. We thus demonstrated for the first time, to our knowledge, that it is possible to act on bioenergetic function including alterations of mitochondrial function in offspring by modifying maternal physical activity before and during pregnancy. These changes could be crucial for the future health of the offspring.

Impact of maternal low-level cadmium exposure on glucose and lipid metabolism of the litter at different ages after weaning.

Cadmium (Cd) is a metal which may participate in the development of type II diabetes even if Cd exposure levels are mild. However, experimental studies focusing on daily environmentally relevant doses are scarce, particularly for glucose metabolism of the offspring of chronically exposed mothers. The aim is to measure the impact of maternal low level Cd exposure on glucose and lipid metabolism of offspring. Female rats were exposed to 0, 50 or 500 µg.kg-1.d-1 of CdCl2, 21 days before mating and during 21 days of gestation and 21 days of lactation. Pups exposure was organized in 3 groups (control, Cd1, Cd2) according to renal dams' Cd burden. Parameters of glucose and lipid metabolisms were measured for the pups on post-natal day 21, 26 and 60. Maternal Cd exposure led to significant amounts of Cd in the liver and kidney of pups. At weaning, insulin secretion upon glucose stimulation was unchanged, but the removal of circulating glucose was slower for pups born from the lowest impregnated dams (Cd1). Five days after, glucose tolerance of all groups was identical. Thus, this loss of insulin sensitivity was reversed, in part by increased adiponectin secretion for the Cd1 group. Furthermore, pups from dams accumulating the highest levels of Cd (Cd2) exhibited a compensatory increased insulin pancreatic secretion, together with increased circulating non-esterified fatty acids, indicating the establishment of insulin resistance, 2 months after birth. This study has demonstrated the influence of maternal exposure to low levels of Cd on glucose homeostasis in the offspring that might increase the risk of developing type II diabetes later in life.

Maternal exercise modifies body composition and energy substrates handling in male offspring fed a high-fat/high-sucrose diet.

KEY POINTS: Maternal training during gestation enhances offspring body composition and energy substrates handling in early adulthood. Offspring nutrition also plays a role as some beneficial effects of maternal training during gestation disappear after consumption of a high-fat diet. ABSTRACT: Maternal exercise during gestation has been reported to modify offspring metabolism and health. Whether these effects are exacerbated when offspring are receiving a high-fat diet remains unclear. Our purpose was to evaluate the effect of maternal exercise before and during gestation on the offspring fed a high-fat/high-sucrose diet (HF) by assessing its body composition, pancreatic function and energy substrates handling by two major glucose-utilizing tissues: liver and muscle. Fifteen-week-old nulliparous female Wistar rats exercised 4 weeks before as well as during gestation at a constant submaximal intensity (TR) or remained sedentary (CT). At weaning, pups from each group were fed either a standard diet (TRCD or CTCD) or a high-fat/high-sucrose diet (TRHF or CTHF) for 10 weeks. Offspring from TR dams gained less weight compared to those from CT dams. Selected fat depots were larger with the HF diet compared to control diet (CD) but significantly smaller in TRHF compared to CTHF. Surprisingly, the insulin secretion index was higher in islets from HF offspring compared to CD. TR offspring showed a higher muscle insulin sensitivity estimated by the ratio of phosphorylated protein kinase B to total protein kinase B compared with CT offspring (+48%, P < 0.05). With CD, permeabilized isolated muscle fibres from TR rats displayed a lower apparent affinity constant (Km ) for pyruvate and palmitoyl coenzyme A as substrates compared to the CT group (-46% and -58%, respectively, P < 0.05). These results suggest that maternal exercise has positive effects on young adult offspring body composition and on muscle carbohydrate and lipid metabolism depending on the nutritional status.

Short-term and long-term effects of submaximal maternal exercise on offspring glucose homeostasis and pancreatic function.

Only a few studies have explored the effects of maternal exercise during gestation on adult offspring metabolism. We set out to test whether maternal controlled submaximal exercise maintained troughout all gestational periods induces persistant metabolic changes in the offspring. We used a model of 15-wk-old nulliparous female Wistar rats that exercised (trained group) before and during gestation at a submaximal intensity or remained sedentary (control group). At weaning, male offspring from trained dams showed reduced basal glycemia (119.7 ± 2.4 vs. 130.5 ± 4.1 mg/dl, P < 0.05), pancreas relative weight (3.96 ± 0.18 vs. 4.54 ± 0.14 g/kg body wt, P < 0.05), and islet mean area (22,822 ± 4,036 vs. 44,669 ± 6,761 µm(2), P < 0.05) compared with pups from control dams. Additionally, they had better insulin secretory capacity when stimulated by 2.8 mM glucose + 20 mM arginine compared with offspring from control dams (+96%, P < 0.05). At 7 mo of age, offspring from trained mothers displayed altered glucose tolerance (AUC = 15,285 ± 527 vs. 11,898 ± 988 mg·dl(-1)·120 min, P < 0.05) and decreased muscle insulin sensitivity estimated by the phosphorylated PKB/total PKB ratio (-32%, P < 0.05) and tended to have a reduced islet insulin secretory capacity compared with rats from control dams. These results suggest that submaximal maternal exercise modifies short-term male offspring pancreatic function and appears to have rather negative long-term consequences on sedentary adult offspring glucose handling.