Exposure to maternal obesityper seprograms sex-differences in pancreatic islets of the offspring

Abstract

Maternal obesity increases type 2 diabetes (T2D) risk in the offspring. 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. Using a well-established mouse model of diet-induced obesity, we examined offspring islets before the onset of metabolic dysfunction. This allowed us to determine inherent changes, in males and females, which are distinct from the response of islets to an existing obesogenic, insulin resistant milieu hence identifying islet dysregulation reflecting very early manifestation of the disease before the onset of disrupted glucose homeostasis. Female offspring of obese dams displayed higher glucose-stimulated insulin secretion and mitochondrial respiration, increased expression of estrogen receptor α and decreased cleaved-caspase 3 and Bax:Bcl-2 reflecting reduced susceptibility to apoptosis. In contrast, male offspring of obese dams displayed compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration and increased "uncoupled" respiration and reduced docked insulin granules in β-cells. Thus, maternal obesity "programs" sex-differences in offspring islet function. Islets of female but not male offspring appear primed to cope with a nutritionally-rich postnatal environment, which may reflect differences in future T2D risk.

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)(14)(15)(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)(18)(19).…”

“…However, the sexspecific 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)(29)(30), increased adiposity (31,32), and decreased insulin sensitivity (31).…”

“…In regard to pancreatic islet b cell health, a number of preclinical studies reported an altered islet architecture and b cell mass in offspring of obese dams (26,(33)(34)(35)(36). In contrast, only two studies evaluated insulin secretion of both male and female young adult (8-weeks) offspring (16,27). These studies found that male offspring of obese dams have a lower capability of maintaining insulin secretion (16,27).…”

“…In contrast, only two studies evaluated insulin secretion of both male and female young adult (8-weeks) offspring (16,27). These studies found that male offspring of obese dams have a lower capability of maintaining insulin secretion (16,27). Interestingly, Zambrano et al suggested the presence of islet insulin secretory defects in offspring at a much younger age (5 weeks) (26).…”