Diet reduction to requirements in obese/overfed ewes from early gestation prevents glucose/insulin dysregulation and returns fetal adiposity and organ development to control levels

Abstract

Obesity at conception and excess gestational weight gain pose significant risks for adverse health consequences in human offspring. This study evaluated the effects of reducing dietary intake of obese/overfed ewes beginning in early gestation on fetal development. Sixty days prior to conception, ewes were assigned to a control diet [CON: 100% of National Research Council (NRC) recommendations], a diet inducing maternal obesity (MO: 150% of NRC recommendations), or a maternal obesity intervention diet (MOI: 150% of NRC recommendations to day 28 of gestation, then 100% NRC) until necropsy at midgestation (day 75) or late (day 135) gestation. Fetal size and weight, as well as fetal organ weights, were greater (P < 0.05) at midgestation in MO ewes than those of CON and MOI ewes. By late gestation, whereas fetal size and weight did not differ among dietary groups, cardiac ventricular weights and wall thicknesses as well as liver and perirenal fat weights remained elevated in fetuses from MO ewes compared with those from CON and MOI ewes. MO ewes and fetuses exhibited elevated (P < 0.05) plasma concentrations of triglycerides, cholesterol, insulin, glucose, and cortisol at midgestation compared with CON and MOI ewes and fetuses. In late gestation, whereas plasma triglycerides and cholesterol, insulin, and cortisol remained elevated in MO vs. CON and MOI ewes and fetuses, glucose concentrations were elevated in both MO and MOI fetuses compared with CON fetuses, which was associated with elevated placental GLUT3 expression in both groups. These data are consistent with the concept that reducing maternal diet of obese/overfed ewes to requirements from early gestation can prevent subsequent alterations in fetal growth, adiposity, and glucose/insulin dynamics.

Keywords: dietary intervention; fetal growth and metabolism; maternal obesity.

Fig. 1.

Ewe body weights for control (CON; open bars), maternal obese (MO; black bars), and maternal obese intervention (MOI; gray bars) groups at diet initiation 60 days before breeding (start; n = 12/group), at conception (day 0; n = 12/group), at midgestation (day 75; n = 12/group), and at late gestation (day 135; n = 6/group). ^a,b,cMeans ± SE within a time point with different letters differ (P < 0.01); ^α,β,γ,δmeans ± SE within a dietary group across all time points with different Greek letters differ (P < 0.01).

Fig. 2.

Ewe %body fat determined by dual-energy X-ray absorptiometry for CON (open bars), MO (black bars), and MOI (gray bars) groups at diet initiation 60 days before breeding (start; n = 6/group), at midgestation (day 75; n = 6/group), and at late gestation (day 135; n = 6/group). ^a,b,cMeans ± SE within a time point with different letters differ (P < 0.01); ^α,β,γmeans ± SE within a dietary group across all time points with different Greek letters differ (P < 0.01).

Fig. 3.

Plasma glucose (A) and insulin (B) dynamics of CON (n = 4; ○), MO (n = 4; ●), and MOI (n = 4; ▼) during an intravenous glucose tolerance test (IVGTT) at midgestation. Area under the curve (AUC) is shown as a bar graph at right for each dietary group. Means ± SE; differences are noted compared with CON group; *P < 0.05; **P < 0.0001.

Fig. 4.

Maternal plasma glucose (n = 6; A), maternal plasma insulin (n = 6; B), fetal plasma glucose (n = 6; C), and fetal plasma insulin levels (n = 6; D) of CON (open bars), MO (black bars), and MOI (gray bars) dietary groups at midgestation. ^a,b,cMeans ± SE within a measurement with different letters differ (maternal, P < 0.05; fetal, P < 0.01).

Fig. 5.

Plasma glucose (A) and insulin dynamics (B) of CON (n = 4; ○), MO (n = 4; ●), and MOI (n = 4; ▼) during an IVGTT at late gestation. AUC is shown as a bar graph at right for each dietary group. Means ± SE differences are noted compared with CON group. *P < 0.05; **P < 0.0001.

Fig. 6.

Maternal plasma glucose (n = 6/group; A), maternal plasma insulin (n = 6/group; B), fetal plasma glucose (n = 6/group; C), and fetal plasma insulin levels (n = 6/group; D) in CON (open bars), MO (black bars), and MOI (gray bars) dietary groups in late gestation. ^a,b,cMeans ± SE within a measurement with different letters differ (P < 0.05).

Fig. 7.

Baseline cortisol levels at midgestation (day 75; n = 6) and late gestation (day 135; n = 6) in maternal (A) and fetal plasma (B) for CON (open bars), MO (black bars), and MOI (gray bars) dietary groups. ^a,bMeans ± SE within animal type and stage of gestation with different letters differ; *P < 0.05; **P < 0.0001.

Fig. 8.

Protein expression of glucose transporter 1 (GLUT1), glucose transporter 3 (GLUT3), fatty acid transport protein 1 (FATP1), fatty acid transport protein 4 (FATP4), and cluster of differentiation 36 (CD36) in cotyledonary tissue for CON (open bars), MO (black bars), and MOI (gray bars) dietary groups at late gestation (day 135). ^a,bMeans ± SE with different letters differ. P < 0.05.