Maternal Overnutrition Programs Changes in the Expression of Skeletal Muscle Genes That Are Associated with Insulin Resistance and Defects of Oxidative Phosphorylation in Adult Male Rat Offspring

Abstract

Children of obese mothers have increased risk of metabolic syndrome as adults. Here we report the effects of a high-fat diet in the absence of maternal obesity at conception on skeletal muscle metabolic and transcriptional profiles of adult male offspring. Female Sprague Dawley rats were fed a diet rich in saturated fat and sucrose [high-fat diet (HFD): 23.5% total fat, 9.83% saturated fat, 20% sucrose wt:wt] or a normal control diet [(CD) 7% total fat, 0.5% saturated fat, 10% sucrose wt:wt] for the 3 wk prior to mating and throughout pregnancy and lactation. Maternal weights were not different at conception; however, HFD-fed dams were 22% heavier than controls during pregnancy. On a normal diet, the male offspring of HFD-fed dams were not heavier than controls but demonstrated features of insulin resistance, including elevated plasma insulin concentration [40.1 ± 2.5 (CD) vs 56.2 ± 6.1 (HFD) mU/L; P = 0.023]. Next-generation mRNA sequencing was used to identify differentially expressed genes in the offspring soleus muscle, and gene set enrichment analysis (GSEA) was used to detect coordinated changes that are characteristic of a biological function. GSEA identified 15 upregulated pathways, including cytokine signaling (P < 0.005), starch and sucrose metabolism (P < 0.017), inflammatory response (P < 0.024), and cytokine-cytokine receptor interaction (P < 0.037). A further 8 pathways were downregulated, including oxidative phosphorylation (P < 0.004), mitochondrial matrix (P < 0.006), and electron transport/uncoupling (P < 0.022). Phosphorylation of the insulin signaling protein kinase B was reduced [2.86 ± 0.63 (CD) vs 1.02 ± 0.27 (HFD); P = 0.027] and mitochondrial complexes I, II, and V protein were downregulated by 50-68% (P < 0.005). On a normal diet, the male offspring of HFD-fed dams did not become obese adults but developed insulin resistance, with transcriptional evidence of muscle cytokine activation, inflammation, and mitochondrial dysfunction. These data indicate that maternal overnutrition, even in the absence of prepregnancy obesity, can promote metabolic dysregulation and predispose offspring to type 2 diabetes.

Mitochondrial biogenesis is decreased in skeletal muscle of pig fetuses exposed to maternal high-energy diets

“…Consistently, decreased activities of antioxidative enzymes (SOD, GPx and CAT) and increased MDA levels were also observed in skeletal muscle of HE fetuses, suggesting the failure of ROS defense system and more, which is probably one of the major determinants of mitochondrial function alterations (Bonnard et al, 2008). In addition, several studies have shown mitochondrial dysfunction can affect whole-body metabolism and play an important in the pathophysiology of insulin resistance in offspring of high-fat diet-fed dams (Bonnard et al, 2008;Latouche et al, 2014). In accordance with previous work (Raipuria et al, 2015), in the current study the fetuses from HE sows had a potential risk for metabolic disorder with higher insulin and triglyceride concentrations in umbilical vein serum compared with fetuses from NE sows.…”

“…Here, we use pig as model based on the higher similarities of pig to human in physiology and genome (Merrifield et al, 2011). Cumulative evidence strongly indicates that reduction in mitochondrial function and oxidative metabolism in skeletal muscle during critical period of fetus growth and development was associated with the greater incidence of T2D and insulin resistance in later life (Shelley et al, 2009;Latouche et al, 2014). In the present study, the intriguing findings were that HE fetuses exhibited High-energy diet affects mitochondrial biogenesis decreased skeletal muscle mitochondrial biogenesis in response to maternal HE intake on day 90 of gestation compared with NE fetuses.…”

“…Decreases in mtDNA copy number have been reported in kidney and liver of offspring of rat dams fed a high-fat diet during gestation (Taylor et al, 2005;Burgueño et al, 2013). In addition, it has been reported that increased maternal nutrition in pigs and rats did not provide advantageous effects on offspring muscle growth and mtDNA copy number (McNamara et al, 2011;Latouche et al, 2014).…”

“…Mitochondrial dysfunction in skeletal muscle has been associated with metabolic diseases in human and animal models (Pagel-Langenickel et al, 2010). Likewise, decreased oxidative phosphorylation, antioxidative capacity and mitochondrial electron transport chain enzyme activities in the liver and skeletal muscle have been observed in the offspring subjected to maternal overnutrition and diabetes (Bruce et al, 2009;Zhang et al, 2011;Latouche et al, 2014). In mammals, muscle fibers are formed prenatally, and subsequent skeletal muscle development depends largely on muscle fiber hypertrophy (Nissen et al, 2003;Zou et al, 2016).…”

Decreased basal insulin secretion from pancreatic islets of pups in a rat model of maternal obesity

“…Insulin resistance or deficiency alters the regulation of these processes and causes elevated fasting and postprandial levels of glucose and lipids. Maternal obesity (MO) is increasing worldwide and is an important risk factor contributing to type 2 diabetes in offspring (Wang & Lobstein 2006, Samuelsson et al 2008, Gonzalez et al 2013, Latouche et al 2014. Type 2 diabetes is polygenic and may involve polymorphisms in multiple genes encoding proteins involved in 231:1 insulin signaling, insulin secretion and intermediary metabolism (Stern 2000, Kahn et al 2006.…”