Lifetime Exposure to a Constant Environment Amplifies the Impact of a Fructose-Rich Diet on Glucose Homeostasis during Pregnancy

Abstract

The need to refine rodent models of human-related disease is now being recognized, in particular the rearing environment that can profoundly modulate metabolic regulation. Most studies on pregnancy and fetal development purchase and transport young females into the research facility, which after a short period of acclimation are investigated (Gen0). We demonstrate that female offspring (Gen1) show an exaggerated hyperinsulinemic response to pregnancy when fed a standard diet and with high fructose intake, which continues throughout pregnancy. Markers of maternal hepatic metabolism were differentially influenced, as the gene expression of acetyl-CoA-carboxylase was raised in Gen1 given fructose and controls, whereas glucose transporter 5 and fatty acid synthase expression were only raised with fructose. Gen1 rats weighed more than Gen0 throughout the study, although fructose feeding raised the percent body fat but not body weight. We show that long-term habituation to the living environment has a profound impact on the animal’s metabolic responses to nutritional intervention and pregnancy. This has important implications for interpreting many studies investigating the influence of maternal consumption of fructose on pregnancy outcomes and offspring to date.

High Fructose Intake During Pregnancy in Rats Influences the Maternal Microbiome and Gut Development in the Offspring

“…The present study extends our previous findings that increased consumption of fructose negatively impacts on lipid and carbohydrate metabolism due to insulin resistance ( Lineker et al, 2016 ; Song et al, 2017 ). Importantly, this adverse adaptation only becomes apparent during pregnancy and is amplified in the next generation.…”

“…We have recently shown that although feeding a high fructose diet modulates the mother’s metabolism, it has little impact on the offspring ( Lineker et al, 2016 ) despite being smaller at birth. However, the maternal response appears to be amplified in the next generation when maintained on the same fructose supplemented diet ( Song et al, 2017 ). Other groups have demonstrated that a high fructose intake during pregnancy will affect fetal endocrine function ( Vickers et al, 2011 ) and lipid metabolism ( Clayton et al, 2015 ).…”

Potential Crosstalk between Fructose and Melatonin: A New Role of Melatonin—Inhibiting the Metabolic Effects of Fructose

“…Besides, fructose increases the circulating levels of glucose, insulin, free fatty acids, triglycerides, cholesterol, lipase, insulin, TNF α , and IL- β . In the liver, fructose induces hepatic steatosis by overexpression of the SREBP-1c and FASN and a decrease in the expression of PGC1 α , PPAR α , and phosphoenolpyruvate carboxykinase [ 26 , 29 ]. Also in the liver, fructose induces mRNA expression from Glut-2, Glut-5, fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC1) [ 29 ].…”

“…In the liver, fructose induces hepatic steatosis by overexpression of the SREBP-1c and FASN and a decrease in the expression of PGC1 α , PPAR α , and phosphoenolpyruvate carboxykinase [ 26 , 29 ]. Also in the liver, fructose induces mRNA expression from Glut-2, Glut-5, fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC1) [ 29 ]. Those metabolic symptoms are more severe in ovariectomized animals where the triglyceride levels are three times higher than the control diet.…”

“… Potential crosstalk between melatonin hormone and fructose. Fructose induces lipogenesis via SREBP-1c stimulation [ 26 , 29 ], hypertension [ 8 , 10 , 25 – 27 , 33 , 34 ], gluconeogenesis [ 23 , 29 ], hyperuricemia, and reactive oxygen species (ROS) [ 8 , 28 ]. Besides, it induces chrono-disruption [ 67 , 68 ], and the impairment expression of clock genes modifies the circadian output of PGC1 α , PPAR α , NRF, SIRT1, and UCP1 [ 1 , 48 – 50 ].…”