Early maternal undernutrition programs increased feed intake, altered glucose metabolism and insulin secretion, and liver function in aged female offspring

Abstract

Insulin resistance and obesity are components of the metabolic syndrome that includes development of cardiovascular disease and diabetes with advancing age. The thrifty phenotype hypothesis suggests that offspring of poorly nourished mothers are predisposed to the various components of the metabolic syndrome due to adaptations made during fetal development. We assessed the effects of maternal nutrient restriction in early gestation on feeding behavior, insulin and glucose dynamics, body composition, and liver function in aged female offspring of ewes fed either a nutrient-restricted [NR 50% National Research Council (NRC) recommendations] or control (C: 100% NRC) diet from 28 to 78 days of gestation, after which both groups were fed at 100% of NRC from day 79 to lambing and through lactation. Female lambs born to NR and C dams were reared as a single group from weaning, and thereafter, they were fed 100% NRC recommendations until assigned to this study at 6 yr of age. These female offspring were evaluated by a frequently sampled intravenous glucose tolerance test, followed by dual-energy X-ray absorptiometry for body composition analysis prior to and after ad libitum feeding of a highly palatable pelleted diet for 11 wk with automated monitoring of feed intake (GrowSafe Systems). Aged female offspring born to NR ewes demonstrated greater and more rapid feed intake, greater body weight gain, and efficiency of gain, lower insulin sensitivity, higher insulin secretion, and greater hepatic lipid and glycogen content than offspring from C ewes. These data confirm an increased metabolic "thriftiness" of offspring born to NR mothers, which continues into advanced age, possibly predisposing these offspring to metabolic disease.

Fig. 1.

Body weight (BW) of aged control (C, solid circles; n = 4) and nutrient restricted (NR) female offspring (open circles; n = 4) during ad libitum feeding. Both treatment groups increased in BW over time (P = 0.001), but NR offspring had greater overall BW than C (P = 0.002), and there was no significant interaction between week and treatment on BW (P > 0.50).

Fig. 2.

Body fat % (A) and lean mass (B) from dual-energy X-ray absorptiometry in aged female offspring of control (C; white bars; n = 4) and nutrient restricted (NR; gray bars, n = 4) ewes. ^a,b,cLetters that differ show significant difference, P < 0.05.

Fig. 3.

Plasma glucose (A), insulin (B), insulin to glucose ratio (C), cortisol (D), and leptin (E) of control (C) female offspring (closed circles; n = 4) and nutrient restricted (NR) offspring (open circles; n = 4) during ad libitum feeding. Baseline plasma glucose concentrations were not different between treatment groups, and there was no interaction of week and treatment on glucose concentrations (P > 0.50). Insulin and insulin:glucose ratio were greater overall in NR than C offspring (P = 0.001). However, there was no significant interaction of week and treatment for insulin or insulin:glucose ratio (P > 0.50). Plasma cortisol and leptin were greater (P < 0.0001 and P < 0.001, respectively) in NR offspring compared with C offspring.

Fig. 4.

Relative mRNA expression (A) and protein levels (B) of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6 phosphatase (G-6P) to 18s RNA and β-actin expression, respectively, in livers from aged female offspring of control (C, white bars; n = 4) and nutrient-restricted (NR, gray bars; n = 4) dams. *P < 0.05.

Fig. 5.

Relative mRNA expression (A) and protein levels (B) of peroxisome proliferator-activated receptor-γ (PPARγ) to 18s RNA and β-actin expression, respectively, in livers from aged female offspring of control (C, white bars; n = 4) and nutrient-restricted (NR, gray bars; n = 4) dams. *P < 0.05.