Changed mitochondrial function by pre- and/or postpartum diet alterations in sheep

Abstract

In a sheep model, we investigated diet effects on skeletal muscle mitochondria to look for fetal programming. During pregnancy, ewes were fed normally (N) or were 50% food restricted (L) during the last trimester, and lambs born to these ewes received a normal (N) or a high-fat diet (H) for the first 6 mo of life. We examined mitochondrial function in permeabilized muscle fibers from the lambs at 6 mo of age (adolescence) and after 24 mo of age (adulthood). The postpartum H diet for the lambs induced an ϳ30% increase (P Ͻ 0.05) of mitochondrial V O2max and an ϳ50% increase (P Ͻ 0.05) of the respiratory coupling ratio (RCR) combined with lower levels of UCP3 and PGC-1␣ mRNA levels (P Ͻ 0.05). These effects proved to be reversible by a normal diet from 6 to 24 mo of age. However, at 24 mo, a long-term effect of the maternal gestational diet restriction (fetal programming) became evident as a lower V O2max (ϳ40%, P Ͻ 0.05), a lower state 4 respiration (ϳ40%, P Ͻ 0.05), and lower RCR (ϳ15%, P Ͻ 0.05). Both PGC-1␣ and UCP3 mRNA levels were increased (P Ͻ 0.05). Two analyzed muscles were affected differently, and muscle rich in type I fibers was more susceptible to fetal programming. We conclude that fetal programming, seen as a reduced V O2max in adulthood, results from gestational undernutrition. Postnatal high-fat diet results in a pronounced RCR and V O2max increase in adolescence. However, these effects are reversible by diet correction and are not maintained in adulthood. metabolic syndrome; high-fat diet; nutrient restriction; maternal diet; respiratory coupling ratio EPIDEMIOLOGICAL STUDIES IN HUMANS since the 1980s and subsequent clinical studies have revealed that small size or thinness at birth is associated with increased risk of developing metabolic dysfunctions like obesity, type 2 diabetes, and abnormal lipid and carbohydrate metabolism, leading to coronary heart disease and elevated blood pressure in adulthood (2, 21). This has spurred an increasing interest in the long-term consequences of maternal nutrition during pregnancy and early postnatal nutrition, a phenomenon first described by Hales and Barker (22) and termed metabolic programming. Although this concept is now widely accepted, the mechanisms behind it remain poorly understood. The observed effects reflect phenotypical alterations, probably established through epigenetic mechanisms, which occur as a result of fetal adaptations to intrauterine and probably early postnatal influences (23, 38). Maternal low-protein diet during pregnancy in rats may in adulthood result in reduced glucose tolerance and high blood pressure, evidently due to a prenatally programmed tendency to dysfunction of small arteries and abnormal pancreatic development (9, 17, 25). Likewise, maternal low-protein diets may result in very significantly shortened life span in mice offspring (44). Thus, both the type of malnutrition and the time of exposure during pregnancy appear to influence the programming effects observed later in life (21, 23). Furthermore, the potentially de...

Prenatal undernutrition and postnatal overnutrition alter thyroid hormone axis function in sheep

“…In fact, only two significant results were found and both regarded THRA, which was downregulated in both BF muscle and subcutaneous adipose tissue. The different responses in muscles to pre-and postnatal dietary exposure could not be related to whether the muscles contained predominantly glycolytic (LD) or oxidative (cardiac and BF) muscle fibers (Jørgensen et al 2009). …”

“…After killing, thyroids and target organs were quickly excised and weighed and tissue samples were snap-frozen for later RNA extraction. Target tissues included liver (left lobe), two different skeletal muscles (the longissimus dorsi dominated by glycolytic type II fibers and biceps femoris dominated by oxidative type I fibers; Jørgensen et al (2009), cardiac muscle (central part of ventriculus sinister cordis), and two adipose tissues (visceral and subcutaneous sampled above the central part of longissimus dorsi).…”

Effects of high-fat overfeeding on mitochondrial function, glucose and fat metabolism, and adipokine levels in low-birth-weight subjects

“…The link between increased mitochondrial function and insulin resistance could be mediated via increased generation of reactive oxygen species (7), perhaps as a consequence of reduced state 4 respiration, as proposed in a recent study of sheep exposed to the combination of fetal under-and postnatal overnutrition (17).…”

Skeletal muscle mitochondrial uncoupling, adaptive thermogenesis and energy expenditure

“…In addition to total caloric intake [39,40], the magnitude of diet-induced thermogenesis has been determined to be dependent on the macronutrient composition of the diet [41] and previous obesity status [42]. Interestingly, it has been demonstrated that maternal energy restriction, as well as postnatal high-fat feeding, alters mitochondrial oxidative capacity and respiratory coupling ratio in sheep [43], suggesting that dietary composition may be able to directly alter muscle mitochondrial function.…”