Consumption of a Western-style diet during pregnancy impairs offspring islet vascularization in a Japanese macaque model

Abstract

Children exposed to a maternal Western-style diet in utero have an increased risk of developing type 2 diabetes. Understanding the mechanisms and an investigation of possible interventions are critical to reversing this phenomenon. We examined the impact of maternal Western-style diet consumption on the development of islet vascularization and innervation, both of which are critical to normal islet function, in fetal and juvenile offspring. Furthermore, we assessed whether improved dietary intake or resveratrol supplementation could ameliorate the harmful consequences of Western-style diet consumption during pregnancy. Adult female Japanese macaques were maintained on a control or Western-style diet for 4-7 yr. One cohort of dams was switched back onto a control diet, whereas another cohort received resveratrol supplementation throughout gestation. Pregnancies were terminated in the early third trimester by C-section, or offspring were born naturally and sent to necropsy at 1 yr of age. Western-style diet consumption resulted in impaired fetal islet capillary density and sympathetic islet innervation. Furthermore, this reduction in vascularization persisted in the juvenile offspring. This effect is independent of changes in the expression of key angiogenic markers. Diet reversal normalized islet vascularization to control offspring levels, whereas resveratrol supplementation caused a significant increase in capillary density above controls. These data provide a novel mechanism by which maternal Western-style diet consumption leads to increased susceptibility to type 2 diabetes in the offspring. Importantly, an improved maternal diet may mitigate these harmful effects. However, until the long-term consequences of increased vascularization can be determined, resveratrol use during pregnancy is not advised.

Keywords: high fat diet; nonhuman primate; pregnancy; resveratrol; vascularization.

Fig. 1.

Normal vascularization of the nonhuman primate (NHP) adult islet. A: representative immunohistochemical (IHC) image of endocrine and exocrine vascularization in the adult control (CTR) pancreas. B: quantification of capillary area, capillary density, and area per capillary in endocrine (ENDO) and exocrine (EXO) pancreatic tissue (n = 5 males). Data are expressed as means ± SE. Different supercscripted letters indicate a significant difference (P < 0.05). C: representative IHC images of VEGF-A expression in adult CTR pancreas. Scale bars represent 25 μm.

Fig. 2.

Schematic overview of the fetal and juvenile study design. A: fetal CTR and Western-style diet (WSD) exposure in utero with diet reversal (REV) and WSD/resveratrol (RESV) interventions. B: juvenile study design following maternal and postweaning WSD consumption. GD130, gestational day 130.

Fig. 3.

Vascularization of the fetal islet is reduced by maternal WSD consumption and restored by dietary intervention. A: representative IHC images of the vascularization of fetal islets by platelet endothelial cell adhesion molecule 1 (PECAM1) staining. Scale bar represents 25 μm. B–D: quantification of islet PECAM1+ area (B), vascular density (no. of PECAM1+ fibers/islet area; C), and area per vessel in CTR (n = 8; 4 males and 4 females), WSD (n = 9; 3 males and 6 females), REV (n = 6; 2 males and 4 females), and WSD/RESV (n = 6; 4 males and 2 females) offspring (D). E: correlation of maternal insulin secretion during a glucose tolerance test with islet capillary density. F: gene expression of key islet angiogenic factors and their receptors in CTR (n = 13; 6 males and 7 females), WSD (n = 11; 7 males and 4 females), REV (n = 6; 2 males and 4 females), and WSD/RESV (n = 6; 4 males and 2 females) pancreas. Dashed line indicates relative CTR expression. G: quantification of proliferation (Ki67+ cells) within islet capillaries (PECAM1+ cells) in CTR (n = 7; 3 males and 4 females), WSD (n = 7; 2 males and 5 females), REV (n = 7; 2 males and 5 females), and WSD/RESV (n = 6; 4 males and 2 females) pancreas. Data are expressed as means ± SE. Different superscripted letters indicate a significant difference (P < 0.05). *P < 0.05, **P < 0.01 vs. CTR offspring; †P < 0.05, ‡P < 0.01 vs. WSD offspring.

Fig. 4.

Maternal WSD consumption impairs islet vascularization in the juvenile NHP. A: representative IHC images of the vascularization of juvenile islets by PECAM1 staining. Scale bar represents 25 μm. B–D: quantification of islet PECAM1+ area (B), vascular density (no. of PECAM1+ fibers/islet area; C), and area/vessel in CTR/CTR (n = 8; 4 males and 4 females), CTR/WSD (n = 6; 3 males and 3 females), WSD/CTR (n = 8; 3 males and 5 females), and WSD/WSD (n = 11; 6 males and 5 females) juvenile offspring (D). Data are expressed as means ± SE. Different superscripted letters indicate a significant difference (P < 0.05). Significant effect of maternal diet by 2-way ANOVA is indicated.

Fig. 5.

In utero WSD exposure results in impaired fetal islet innervation. A: representative IHC images of the innervation of fetal islets by tyrosine hydroxylase (TH) staining. Scale bar represents 25 μm. B: quantification of islet innervation by TH staining in CTR (n = 9; 4 males and 5 females), WSD (n = 11; 3 males and 8 females), REV (n = 7; 2 males and 5 females), and WSD/RESV (n = 5; 3 males and 2 females) offspring. Data are expressed as means ± SE. Different superscripted letters indicate a significant difference (P < 0.05).

Fig. 6.

Islet innervation in the juvenile NHP is not affected significantly by maternal WSD consumption. Quantification of islet innervation by TH staining in CTR/CTR (n = 7; 3 males and 4 females), CTR/WSD (n = 6; 3 males and 3 females), WSD/CTR (n = 5; 1 male and 4 females), and WSD/WSD (n = 8; 6 males and 2 females) juvenile offspring. Data are expressed as means ± SE. Different letters indicate a significant difference (P < 0.05).