Maternal obesity characterized by gestational diabetes increases the susceptibility of rat offspring to hepatic steatosis via a disrupted liver metabolome

Abstract

Key pointsr Gestational diabetes mellitus is a common complication of pregnancy, but its effects on the offspring are poorly understood.r We developed a rat model of diet-induced gestational diabetes mellitus that recapitulates many of the clinical features of the disease, including excessive gestational weight gain, glucose intolerance, hyperinsulinaemia and mild hyperglycaemia.r Compared to the offspring of lean dams, exposure to gestational diabetes mellitus during the prenatal period resulted in obesity, hepatic steatosis and insulin resistance in young rat offspring that consumed a postnatal diet that was low in fat.r The combination of maternal gestational diabetes mellitus and the postnatal consumption of a high-fat diet by the offspring caused a more severe metabolic phenotype.r Metabolomic profiling of the liver tissues of the offspring of gestational diabetic dams revealed accumulation of lipotoxic lipids and reduced phosphatidylethanolamine levels compared to the offspring of lean dams.r The results establish that gestational diabetes mellitus is a driver of hepatic steatosis and insulin resistance in the offspring.Abstract Maternal obesity is associated with a high risk for gestational diabetes mellitus (GDM), which is a common complication of pregnancy. The influence of maternal obesity and GDM on the metabolic health of the offspring is poorly understood. We hypothesize that GDM associated with maternal obesity will cause obesity, insulin resistance and hepatic steatosis in the offspring. Female Sprague-Dawley rats were fed a high-fat (45%) and sucrose (HFS) diet to cause maternal obesity and GDM. Lean control pregnant rats received low-fat (LF; 10%) diets. To investigate the interaction between the prenatal environment and postnatal diets, rat offspring were assigned to LF or HFS diets for 12 weeks, and insulin sensitivity and hepatic steatosis were evaluated. Pregnant GDM dams exhibited excessive gestational weight gain, hyperinsulinaemia and hyperglycaemia. Offspring of GDM dams gained more weight than the offspring of lean dams due to excess adiposity. The offspring of GDM dams also developed hepatic steatosis and insulin resistance. The postnatal consumption of a LF diet did not protect offspring of GDM dams against these metabolic disorders. Analysis of the hepatic metabolome revealed increased diacylglycerol and reduced phosphatidylethanolamine in the offspring of GDM dams compared to offspring of lean dams. Consistent with altered lipid metabolism, the expression of CTP:phosphoethanolamine cytidylyltransferase, and peroxisomal proliferator activated receptor-α mRNA was reduced in the livers of GDM offspring. GDM exposure programs gene expression and hepatic metabolite levels and drives the development of hepatic steatosis and insulin resistance in young adult rat offspring.

Exposure to gestational diabetes mellitus induces neuroinflammation, derangement of hippocampal neurons, and cognitive changes in rat offspring

“…Rats were given ad libitum access to food and water and were housed two per cage. As described previously [25], GDM was induced in female Sprague-Dawley rats using a high-fat and sucrose diet (HFS; 45% fat, 4.73 kcal/gm, Research Diets D12451; New Brunswick, NJ, USA) for 6 weeks prior mating, throughout gestation and lactation, while lean control dams were fed a low-fat diet (LF, 10% fat, 3.85 kcal/gm, Research Diets D12450B). All females were mated with lean males.…”

“…The dams experienced increased weight gain during pregnancy and starting mid-gestation developed hyperinsulinemia and moderate hyperglycemia (Table 1). This model mimics clinical symptoms of GDM seen in mothers as well as their offspring that developed obesity and insulin resistance [2, 25]. Litters were randomly reduced to eight pups in order to avoid competition for food.…”

“…We utilized a high-fat and sucrose (HFS) diet-induced GDM model [19, 25] to evaluate the effects of GDM exposure and postnatal diets on cognitive abilities and neuroinflammation in the offspring. In this GDM model, hyperglycemia is observed in mid-gestation and resolves after the dam litters out, thus mimicking some features of the clinical presentation of GDM in overweight and obese women [19, 25].…”

“…In this GDM model, hyperglycemia is observed in mid-gestation and resolves after the dam litters out, thus mimicking some features of the clinical presentation of GDM in overweight and obese women [19, 25]. We determined that GDM exposure impaired recognition memory in the offspring and when combined with postnatal HFS diet, resulted in atypical inattentive behavior.…”

Targeting skeletal muscle mitochondria to prevent type 2 diabetes in youth

“…How these observations relate to muscle insulin resistance and mitochondrial function, remain largely unknown at present; however, diacylglycerols can be converted to phospholipids through CTP:phosphoethanolamine cytidylyltransferase (Singh et al 2012) and disruption of this pathway has been implicated in diacylglycerol accumulation, hepatic steatosis, and insulin resistance in rodents exposed to gestational diabetes during fetal development (Pereira et al 2015). In addition, in vitro studies suggest that arachidonic acid containing diacylglycerols are more potent activators of down-stream For personal use only.…”