Glucose is an important nutrient that dictates the development, fertility and lifespan of all organisms. In humans, a deficit in its homeostatic control might lead to hyperglucemia and the development of obesity and type 2 diabetes, which show a decreased ability to respond to and metabolize glucose. Previously, we have reported that high-glucose diets (HGD) induce alterations in triglyceride content, body size, progeny, and the mRNA accumulation of key regulators of carbohydrate and lipid metabolism, and longevity in Caenorhabditis elegans (PLoS ONE 13(7): e0199888). Herein, we show that increasing amounts of glucose in the diet induce the swelling of both mitochondria in germ and muscle cells. Additionally, HGD alter the enzymatic activities of the different respiratory complexes in an intricate pattern. Finally, we observed a downregulation of ceramide synthases (hyl-1 and hyl-2) and antioxidant genes (gcs-1 and gst-4), while mitophagy genes (pink-1 and dct-1) were upregulated, probably as part of a mitohormetic mechanism in response to glucose toxicity.

Thiamine is one of several essential cofactors for ATP generation. Its deficiency, like in beriberi and in the Wernicke-Korsakoff syndrome, has been studied for many decades. However, its mechanism of action is still not completely understood at the cellular and molecular levels. Since it acts as a coenzyme for dehydrogenases of pyruvate, branched-chain keto acids, and ketoglutarate, its nutritional privation is partly a phenocopy of inborn errors of metabolism, among them maple syrup urine disease. In the present paper, we report metabolic and genomic findings in mice deprived of thiamine. They are similar to the ones we have previously found in biotin deficiency, another ATP generation cofactor. Here we show that thiamine deficiency substantially reduced the energy state in the liver and activated the energy sensor AMP-activated kinase. With this vitamin deficiency, several metabolic parameters changed: blood glucose was diminished and serum lactate was increased, but insulin, triglycerides, and cholesterol, as well as liver glycogen, were reduced. These results indicate a severe change in the energy status of the whole organism. Our findings were associated with modified hepatic levels of the mRNAs of several carbon metabolism genes: a reduction of transcripts for liver glucokinase and fatty acid synthase and augmentation of those for carnitine palmitoyl transferase 1 and phosphoenolpyruvate carboxykinase as markers for glycolysis, fatty acid synthesis, beta-oxidation, and gluconeogenesis, respectively. Glucose tolerance was initially increased, suggesting augmented insulin sensitivity, as we had found in biotin deficiency; however, in the case of thiamine, it was diminished from the 3rd week on, when the deficient animals became undernourished, and paralleled the changes in AKT and mTOR, 2 main proteins in the insulin signaling pathway. Since many of the metabolic and gene expression effects on mice deprived of thiamine are similar to those in biotin deficiency, it may be that they result from a more general impairment of oxidative phosphorylation due to a shortage of ATP generation cofactors. These findings may be relevant to energy-related disorders, among them several inborn errors of metabolism, as well as common energy disorders like obesity, diabetes, and neurodegenerative illnesses.

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Several studies have shown that pharmacological concentrations of biotin decrease serum lipid concentrations and the expression of lipogenic genes. Previous studies on epididymal adipose tissue in mice revealed that 8 weeks of dietary biotin supplementation increased the protein abundance of the active form of AMPK and the inactive forms acetyl CoA carboxylase (ACC)‐1 and − 2, and decreased serum free fatty acid concentrations but did not affect lipolysis. These data suggest that pharmacological concentrations of the vitamin might affect fatty acid metabolism. In this work, we investigated the effects of pharmacological biotin concentrations on fatty acid synthesis, oxidation, and uptake in 3T3‐L1 adipocytes. Similar to observations in mice, biotin‐supplemented 3T3‐L1 adipose cells increased the protein abundance of active T172‐AMPK and inactive ACC‐1 and ‐2 forms. No changes were observed in the expression of the transcriptional factor PPARα and carnitine‐palmitoyltransferase‐1 (CPT‐1). Radiolabeled assays indicated a decrease in fatty acid synthesis; an increase in fatty acid oxidation and fatty acid incorporation rate into the lipid fraction between control cells and biotin‐supplemented cells. The data revealed an increase in the mRNA abundance of the fatty acid transport proteins Fatp1 and Acsl1 but not Cd36 or Fatp4 mRNA. Furthermore, the abundance of glycerol phosphate acyl transferase‐3 protein was increased. Triglyceride content was not affected. Lipid droplet numbers showed an increase and their areas were smaller in the biotin‐supplemented group. In conclusion, these data indicate that biotin supplementation causes a decrease in fatty acid synthesis and an increase in its oxidation and uptake. © 2018 BioFactors, 45(2):259–270, 2019

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