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

Abstract

Offspring of obese mothers suffer higher risks of type 2 diabetes due to increased adiposity and decreased β cell function. To date, the sex-differences in offspring islet insulin secretion during early life has not been evaluated extensively, particularly prior to weaning at postnatal day 21 (P21). To determine the role of maternal obesity on offspring islet insulin secretion, C57BL/6J female dams were fed chow or western diet from 4 weeks prior to mating to induce maternal obesity. First, offspring of chow-fed and obese dams were evaluated on postnatal day 21 (P21) prior to weaning for body composition, glucose and insulin tolerance, and islet phasic insulin-secretion. Compared to same-sex controls, both male and female P21 offspring born to obese dams (MatOb) had higher body adiposity and exhibited sex-specific differences in glucose tolerance and insulin secretion. The male MatOb offspring developed the highest extent of glucose intolerance and lowest glucose-induced insulin secretion. In contrast, P21 female offspring of obese dams had unimpaired insulin secretion. Using SAX-HPLC, we found that male MatOb had a decrease in pancreatic heparan sulfate glycosaminoglycan, which is a macromolecule critical for islet health. Notably, 8-weeks-old offspring of obese dams continued to exhibit a similar pattern of sex-differences in glucose intolerance and decreased islet insulin secretion. Overall, our study suggests that maternal obesity induces sex-specific changes to pancreatic HSG in offspring and a lasting effect on offspring insulin secretion, leading to the sex-differences in glucose intolerance.

Vascular Heparan Sulfate and Amyloid-β in Alzheimer’s Disease Patients

“…These structurally distinct forms of male and female liver HS exert differential effects on human mesenchymal cell proliferation and subsequent osteogenic differentiation [71]. In a recent study of a type 2 diabetes rat model, lower HS intensity was reported in male animals, potentially contributing to glucose intolerance and decreased islet insulin secretion in the disease [72,73]. Currently, it remains unknown whether HS levels and structure differ between male and female individuals under normal physiological conditions and in AD patients.…”

RISING STARS: Mechanistic insights into maternal–fetal cross talk and islet beta-cell development

“…Animal models of a maternal obesogenic diet have demonstrated this link between overnutrition and offspring beta-cell programming. Different models of maternal high-fat diet in rodents report altered islet morphology, beta-cell mass, and function ( Han et al 2005 , Nicholas et al 2020 , Akhaphong et al 2021 b , Casasnovas et al 2021 ). However, recapitulating human pathophysiology by modeling maternal obesity through dietary alterations is difficult and varying, due to differences in the composition of diet, length of diet fed prior to pregnancy to mimic obesity, and diet change post birth.…”

Maternal obesity and the impact of associated early-life inflammation on long-term health of offspring

“…In a diet-induced maternal obesity murine model, Samuelsson et al showed that offspring exposed to maternal obesity had increased adiposity, impaired lipid and glucose metabolism and higher blood pressures months after birth (Samuelsson et al, 2008). Several studies showed that maternal obesity induces sex-specific effects on glucose metabolism and the cardiometabolic profiles of offspring in favor of male sex (Sun et al, 2012;Lecoutre et al, 2016;Kulhanek et al, 2020;Casasnovas et al, 2021). One theory is that the sex-differences in pancreatic b-cell function may be partially due to increased oxidative stress in male islets (Yokomizo et al, 2014).…”