Abstract
BackgroundMaternal overnutrition including pre-pregnancy, pregnancy and lactation promotes a lipotoxic insult leading to metabolic dysfunction in offspring. Diet-induced obesity models (DIO) show that changes in hypothalamic mitochondria fusion and fission dynamics modulate metabolic dysfunction. Using three selective diet formula including a High fat diet (HFD), Cafeteria (CAF) and High Sugar Diet (HSD), we hypothesized that maternal diets exposure program leads to selective changes in hypothalamic mitochondria fusion and fission dynamics in male offspring leading to metabolic dysfunction which is exacerbated by a second exposure after weaning.MethodsWe exposed female Wistar rats to nutritional programming including Chow, HFD, CAF, or HSD for 9 weeks (pre-mating, mating, pregnancy and lactation) or to the same diets to offspring after weaning. We determined body weight, food intake and metabolic parameters in the offspring from 21 to 60 days old. Hypothalamus was dissected at 60 days old to determine mitochondria-ER interaction markers by mRNA expression and western blot and morphology by transmission electron microscopy (TEM). Mitochondrial-ER function was analyzed by confocal microscopy using hypothalamic cell line mHypoA-CLU192.ResultsMaternal programming by HFD and CAF leads to failure in glucose, leptin and insulin sensitivity and fat accumulation. Additionally, HFD and CAF programming promote mitochondrial fusion by increasing the expression of MFN2 and decreasing DRP1, respectively. Further, TEM analysis confirms that CAF exposure after programing leads to an increase in mitochondria fusion and enhanced mitochondrial-ER interaction, which partially correlates with metabolic dysfunction and fat accumulation in the HFD and CAF groups. Finally, we identified that lipotoxic palmitic acid stimulus in hypothalamic cells increases Ca2+ overload into mitochondria matrix leading to mitochondrial dysfunction.ConclusionsWe concluded that maternal programming by HFD induces hypothalamic mitochondria fusion, metabolic dysfunction and fat accumulation in male offspring, which is exacerbated by HFD or CAF exposure after weaning, potentially due to mitochondria calcium overflux.
Highlights
Maternal overnutrition including pre-pregnancy, pregnancy and lactation promotes a lipotoxic insult leading to metabolic dysfunction in offspring
Selective nutritional programming alters pregnancy ratio, body weight and food intake in offspring Our aim was to evaluate the effect of nutritional programming by maternal hypercaloric diets in mitochondrial dynamics in the hypothalamus of the offspring and evaluate if this effect is exacerbated when offspring is exposed to these formula after weaning
Female rats were fed with hypercaloric formula (HFD, CAF or High Sugar Diet (HSD)) do not modify body weight before mating; there was a significant decrease in female body weight during CAF exposure at 5–7 weeks and there were no changes during High fat diet (HFD) and HSD exposure (Fig. 1b)
Summary
Maternal overnutrition including pre-pregnancy, pregnancy and lactation promotes a lipotoxic insult leading to metabolic dysfunction in offspring. Diet-induced obesity models (DIO) show that changes in hypothalamic mitochondria fusion and fission dynamics modulate metabolic dysfunction. Using three selective diet formula including a High fat diet (HFD), Cafeteria (CAF) and High Sugar Diet (HSD), we hypothesized that maternal diets exposure program leads to selective changes in hypothalamic mitochondria fusion and fission dynamics in male offspring leading to metabolic dysfunction which is exacerbated by a second exposure after weaning. Maternal nutritional programming by hypercaloric diets exposure that simulate Western diets, such as high fat diet (HFD), cafeteria diet (CAF) or high sugar diet (HSD) in murine models, change offspring metabolism leading to insulin resistance, type 2 diabetes mellitus (T2DM) [5,6,7], cardiovascular diseases and hypertension [8], non-alcoholic liver diseases and steatohepatitis [9, 10]. In humans, placentas of obese mothers show a decrease in mtDNA and mitochondrial dysfunction which correlate with metabolic dysfunction in offspring [17]
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