Abstract
We previously reported that undernutrition in late fetal life reduced whole-body insulin sensitivity in adult sheep, irrespective of dietary exposure in early postnatal life. Skeletal muscle may play an important role in control of insulin action. We therefore studied a range of putative key muscle determinants of insulin signalling in two types of skeletal muscles (longissimus dorsi (LD) and biceps femoris (BF)) and in the cardiac muscle (ventriculus sinister cordis (VSC)) of sheep from the same experiment. Twin-bearing ewes were fed either 100% (NORM) or 50% (LOW) of their energy and protein requirements during the last trimester of gestation. From day-3 postpartum to 6-months of age (around puberty), twin offspring received a high-carbohydrate-high-fat (HCHF) or a moderate-conventional (CONV) diet, whereafter all males were slaughtered. Females were subsequently raised on a moderate diet and slaughtered at 2-years of age (young adults). The only long-term consequences of fetal undernutrition observed in adult offspring were lower expressions of the insulin responsive glucose transporter 4 (GLUT4) protein and peroxisome proliferator-activated receptor gamma, coactivator 1α (PGC1α) mRNA in BF, but increased PGC1α expression in VSC. Interestingly, the HCHF diet in early postnatal life was associated with somewhat paradoxically increased expressions in LD of a range of genes (but not proteins) related to glucose uptake, insulin signalling and fatty acid oxidation. Except for fatty acid oxidation genes, these changes persisted into adulthood. No persistent expression changes were observed in BF and VSC. The HCHF diet increased phospholipid ratios of n-6/n-3 polyunsaturated fatty acids in all muscles, even in adults fed identical diets for 1½ years. In conclusion, early postnatal, but not late gestation, nutrition had long-term consequences for a number of determinants of insulin action and metabolism in LD. Tissues other than muscle may account for reduced whole body insulin sensitivity in adult LOW sheep.
Highlights
A rapid burst of fetal growth takes place during late-gestation, and maternal nutritional restriction during this period can reduce fetal growth rate and result in low birth weight (LBW) of the newborns [1,2]
From the STRING gene/ protein network analyses, it is clear that more molecular markers very strongly interact with the target genes/markers we studied here and it includes, for example, Insulin-like growth factor 1 receptor (IGF1R), forkhead box protein O1 (FOXO1), growth factor receptor-bound protein 2 (GRB2), lymphocyte cytosolic protein 2 (LCP2), son of sevenless homolog 1 (SOS1), target of rapamycin complex subunit LST8 (MLST8) and mammalian target of rapamycin (MTOR)
For the results reported in the present paper on muscle specific traits for molecular metabolism and lipid composition, it must be born in mind that we are not able to separate the effects of gender and ageing, since lambs slaughtered at 6-months of age were predominantly males, and the 2-years old adult sheep were exclusively females
Summary
A rapid burst of fetal growth takes place during late-gestation, and maternal nutritional restriction during this period can reduce fetal growth rate and result in low birth weight (LBW) of the newborns [1,2] It is well-known that LBW is associated with increased risk of type II diabetes, obesity, and other metabolic disorders later in life [3,4,5,6]. The molecular-biological mechanisms which are linking a LBW phenotype to increased risk of developing metabolic disorders in later life, are only partially understood [9] Both human and rat studies have shown that LBW is associated with distinct changes in protein expression patterns with down-regulation of key markers of skeletal muscle insulin sensitivity, such as glucose transporter 4 (GLUT4), phosphatidylinositol 3-kinases (PI3Ks) and protein kinase C zeta (PKCf) [10]. Muscle is believed to be a key target organ for fetal programming, which contributes to the development of whole-body insulin resistance later in life in LBW subjects
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