Excess maternal fructose intake and the developmental programming of mitochondrial function and lipid metabolism in adult offspring

Author: Smith, Erin Vanessa La Rae

Date: 2021

Publisher: University of Otago

Type: Thesis

Link to this item using this URL: http://hdl.handle.net/10523/11963

Abstract

Excess dietary fructose is a major public health concern. Evidence shows increased fructose intake can cause insulin resistance, hepatic de novo lipogenesis, hypertriglyceridemia, obesity and non-alcoholic fatty liver disease (NAFLD). However, little is known about the effects of fructose during pregnancy and its influence on offspring development and predisposition to later-life disease. To determine whether moderately increased maternal fructose intake could have health future consequences on offspring, we have investigated the effects of 10% w/v fructose water intake during preconception and pregnancy in guinea pigs. Female Dunkin Hartley guinea pigs were fed a control diet (CD) or fructose diet (FD; 10% kcal from fructose) ad-libitum 60 days prior to mating and throughout gestation. Weanling Offspring were culled at weaning, day 21 (d21) and adolescent offspring at 4-months (4M). Compared to CD dams, FD dams had altered glucose metabolism and increased milk free fatty acid content. Matsuda-DeFronzo insulin sensitivity index (M-ISI) from OGTT plasma showed no significant difference in whole-body insulin sensitivity between FD and CD dams 60 days post-dietary intervention and during mid-gestation. Fetal exposure to increased maternal fructose resulted in offspring with significantly altered serum free fatty acids at day 0, 7, 14 and 21 (including pentadecanoic acid (15:0), dma16:0, margaric acid (17:0) palmitoleic acid, total omega-7 and total saturates), increased levels of uric acid and triglycerides were also observed at d21. In male and female fructose offspring, proteomic analysis revealed that key markers of mitochondria function, oxidative phosphorylation, NRF-2 pathways were significantly altered. Western blot analysis confirmed these findings by increased protein abundance in complex II & IV and key enzymes involved in hepatic de novo lipogenesis (FAS, SREBP-1C). In adult male and female fructose offspring (4 month) were observed to also have very similar changes in pathways involved in fatty acid B-oxidation, oxidative phosphorylation and mitochondrial function. Similar to d21 fructose offspring, adults also displayed programmed increases in key enzymes of de novo lipogenesis (FAS and SREBP-1c), mitochondrial function (Complex II & IV) and consistently increased palmitoleic acid at all time-points (day 0 to 4 month of age). We have demonstrated that excess maternal fructose intake during pregnancy and not lactation can cause significant changes in maternal metabolic function and milk composition, which programmes weanling and adult offspring hepatic mitochondrial function, de novo lipogenesis and metabolism. Taken together, these changes in pregnancy outcomes and feto-maternal condition may underlie their offspring’s predisposition to metabolic dysfunction during later-life.

Subjects: developmental programming, maternal fructose, milk composition, palmitoleic acid, free fatty acids, hepatic lipids, hepatic function, omega-7, hepatic metabolic function, hepatic mitochondrial function, de novo lipogenesis, beta-oxidation, oxidative phosphorylation, complex II, complex IV, SREBP-1c, FAS, VDAC1, fructose, mitochondria

Citation: ["Smith, E. V. L. R. (2021). Excess maternal fructose intake and the developmental programming of mitochondrial function and lipid metabolism in adult offspring (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/11963"]

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