Exposure to maternal obesity programs sex differences in pancreatic islets of the offspring in mice

Abstract

Aims/hypothesis Obesity during pregnancy increases offspring type 2 diabetes risk. Given that nearly half of women of child-bearing age in many populations are currently overweight/obese, it is key that we improve our understanding of the impact of the in utero/early life environment on offspring islet function. Whilst a number of experimental studies have examined the effect of maternal obesity on offspring islet architecture and/or function, it has not previously been delineated whether these changes are independent of other confounding risk factors such as obesity, postnatal highfat-feeding and ageing. Thus, we aimed to study the impact of exposure to maternal obesity on offspring islets in young, glucose-tolerant male and female offspring. Methods Female C57BL/6J mice were fed ad libitum either chow or obesogenic diet prior to and throughout pregnancy and lactation. Offspring were weaned onto a chow diet and remained on this diet until the end of the study. An IPGTT was performed on male and female offspring at 7 weeks of age. At 8 weeks of age, pancreatic islets were isolated from offspring for measurement of insulin secretion and content, mitochondrial respiration, ATP content, reactive oxygen species levels, beta and alpha cell mass, granule and mitochondrial density (by transmission electron microscopy), and mRNA and protein expression by real-time RT-PCR and Western blotting, respectively. Results Glucose tolerance was similar irrespective of maternal diet and offspring sex. However, blood glucose was lower (p < 0.001) and plasma insulin higher (p < 0.05) in female offspring of obese dams 15 min after glucose administration. This was associated with higher glucose-(p < 0.01) and leucine/glutamine-stimulated (p < 0.05) insulin secretion in these offspring. Furthermore, there was increased mitochondrial respiration (p < 0.01) and density (p < 0.05) in female offspring of obese dams compared with same-sex controls. Expression of mitochondrial and nuclear-encoded components of the electron transport chain, L-type Ca 2+ channel subtypes that play a key role in stimulus-secretion coupling [Cacna1d (p < 0.05)], and oestrogen receptor α (p < 0.05) was also increased in islets from these female offspring of obese dams. Moreover, cleaved caspase-3 expression and BAX:Bcl-2 were decreased (p < 0.05) reflecting reduced susceptibility to apoptosis. In contrast, in male offspring, glucose and leucine/glutamine-stimulated insulin secretion was comparable between treatment groups. There was, however, compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration (p < 0.05) and increased uncoupled respiration (p < 0.01), reduced docked insulin granules (p < 0.001), decreased Cacna1c (p < 0.001) and Cacna1d (p < 0.001) and increased cleaved caspase-3 expression (p < 0.05).

Obese mother offspring have hepatic lipidic modulation that contributes to sex-dependent metabolic adaptation later in life

“…M displayed higher insulin levels than F but fasting insulin levels and the ratio of AUCins:AUCglc during the OGTT were reduced between MID and END in M. This demonstrate an improved liver metabolism in M between MID and END and would suggest that diet reversal post-weaning could partly rescue M from in utero changes. However, peripheral IS remained impaired in HF/C M at END, which could explain common diabetic phenotypes later in life, in line with the recent study 28 .…”

Offspring of Obese Dams Exhibit Sex-Differences in Pancreatic Heparan Sulfate Glycosaminoglycans and Islet Insulin Secretion

“…Human and animal studies have demonstrated the important role of in-utero and early postnatal environments in modulating offspring islet insulin secretion ( 13 – 16 ). This concept of the developmental origin of health and diseases (DOHaD) was first described by Dr. Barker and Dr. Osmond, where adults that experienced growth restriction during fetal life were found to have a higher rate of cardiovascular diseases during adulthood ( 17 – 19 ).…”

“…However, the sex-specific impact of maternal obesity exposure on insulin secretion in human offspring has not been studied extensively. Therefore, animal models have been used to delineate the specific impact of maternal obesity on offspring islet insulin secretion ( 16 , 26 , 27 ).…”

“…Diet-induced obesity is a commonly used approach to model maternal obesity ( 16 ). While varying in diet compositions and duration of exposure, many studies have reported relatively consistent findings where offspring born to dams with pregestational obesity have hypertension, endothelial dysfunction ( 28 – 30 ), increased adiposity ( 31 , 32 ), and decreased insulin sensitivity ( 31 ).…”

The effects of maternal obesity during gestation and lactation and orange juice intake on the metabolic profile of male offspring exposed to control and obesogenic diets and breast cancer risk of female offspring

“…Even though there are numerous studies on the metabolic parameters of offspring of obese mothers (SAMUELSSON et al, 2007;DE OLIVEIRA ANDRADE et al, 2014;RIBAROFF et al, 2017;LOCHE et al, 2018;NICHOLAS et al, 2019), not many studies have explored the effect of maternal obesity in offspring weaned into an obesogenic diet (DE ALMEIDA FARIA et al, 2017; HUANG et al, 2020). There is, experimental studies have focused on the mismatch conceptthe effects of maternal obesity during gestation and lactation on offspring fed a control diet.…”