Oxidative and endoplasmic reticulum stress develop adverse metabolic effects due to the high-fat high-fructose diet consumption from birth to young adulthood

Life Sci. 2022 Nov 15;309:120924. doi: 10.1016/j.lfs.2022.120924. Epub 2022 Sep 5.


Aims: The early postnatal dietary intake has been considered a crucial factor affecting the offspring later life metabolic status. Consistently, this study investigated the oxidative and endoplasmic reticulum (ER) stress interventions in the induction of adverse metabolic effects due to the high-fat high-fructose diet (HFHFD) consumption from birth to young adulthood in rat offspring.

Materials and methods: After delivery, the dams with their pups were randomly allocated into the normal diet (ND) and HFHFD groups. At weaning, the male offspring were divided into ND-None, ND-DMSO, ND-4-phenyl butyric acid (4-PBA), HFHFD-None, HFHFD-DMSO, and HFHFD-4-PBA groups and fed on their respected diets for five weeks. Then, the drug was injected for ten days. Subsequently, glucose and lipid metabolism parameters, oxidative and ER stress markers, and Wolfram syndrome1 (Wfs1) expression were assessed.

Key findings: In the HFHFD group, anthropometrical parameters, plasma high-density lipoprotein (HDL), and glucose-stimulated insulin secretion and content were decreased. Whereas, the levels of plasma leptin, low-density lipoprotein (LDL) and glucose, hypothalamic leptin, pancreatic catalase activity and glutathione (GSH), pancreatic and hypothalamic malondialdehyde (MDA), binding immunoglobulin protein (BIP) and C/EBP homologous protein (CHOP), and pancreatic WFS1 protein were increased. 4-PBA administration in the HFHFD group, decreased the hypothalamic and pancreatic MDA, BIP and CHOP levels, while, increased the Insulin mRNA and glucose-stimulated insulin secretion and content.

Significance: HFHFD intake from birth to young adulthood through the development of pancreatic and hypothalamic oxidative and ER stress, increased the pancreatic WFS1 protein and impaired glucose and lipid homeostasis in male rat offspring.

Keywords: 4-phenylbutyric acid; Endoplasmic reticulum stress; High-fat high-fructose diet; Oxidative stress; Wolfram syndrome 1.

Publication types

  • Randomized Controlled Trial, Veterinary

MeSH terms

  • Animals
  • Butyric Acid / pharmacology
  • Catalase / metabolism
  • Diet, High-Fat* / adverse effects
  • Dimethyl Sulfoxide / pharmacology
  • Endoplasmic Reticulum Stress*
  • Fructose* / adverse effects
  • Glucose / pharmacology
  • Glutathione / metabolism
  • Insulin / metabolism
  • Leptin / metabolism
  • Lipoproteins, HDL / metabolism
  • Lipoproteins, LDL / metabolism
  • Male
  • Malondialdehyde / pharmacology
  • Oxidative Stress*
  • RNA, Messenger / metabolism
  • Rats
  • Tungsten / pharmacology


  • 4-phenylbutylamine
  • Butyric Acid
  • Catalase
  • Dimethyl Sulfoxide
  • Fructose
  • Glucose
  • Glutathione
  • Insulin
  • Leptin
  • Lipoproteins, HDL
  • Lipoproteins, LDL
  • Malondialdehyde
  • RNA, Messenger
  • Tungsten
  • WFS1 protein, rat