Fasting with ProLon

 Introducing Metabolic Elasticity

Hi Friend,

You might have heard of the term metabolic flexibility

– the ability to efficiently switch between carbohydrates and fatty acids, depending on nutrient availability – but a new term has recently been introduced: metabolic

elasticity.

This refers to an organism’s ability to “bounce back” from metabolic fluctuations that occur with fasting and feeding, or changes to diet composition – i.e. to switch effectively to an adaptive metabolic state when nutrient conditions changes, and then to normalize when conditions revert back. It was recently introduced in a paper by Zhou et al (2023).

According to Zhou et al., metabolic elasticity is underpinned by “gene elasticity” – the ability of tissues to modulate gene expression in response to metabolic challenges. This is done mostly via transcription factors – proteins that regulate the expression of genes. For example, tissues need to upregulate transcription of genes involved in carbohydrate metabolism during a period of high carbohydrate feeding, and then switch back to genes involved in lipid metabolism during a period of fasting.

To establish gene elasticity they performed RNA sequencing (RNAseq) on four major metabolic organs in healthy young mice, during an ad libitum feeding-refeeding cycle. The organs were adipose tissue (epididymal and subcutaneous), liver and muscle.

They developed a scoring system based on gene expression dynamics, restorability and statistical significance to represent metabolic elasticity at the gene level. Genes with a low score change little during fasting/refeeding; genes with a high score change a lot and were restored back to their fasting level (their expression is “dynamic”).

The authors then ranked genes according to their score, and looked at what the genes did. They found that the genes were mostly enriched in lipid and carbohydrate metabolism, showing that expression of these genes is highly elastic.

In a series of elegant further experiments, they also found:

The findings were recapitulated in non-human primates.

Gene elasticity is impaired during aging. Genes that were more elastic tended to show the biggest shifts with aging.

Gene elasticity is also impaired during diet-induced obesity in mice.

Mice on a six week intermittent fasting (IF) regime showed improvements in weight and insulin sensitivity. In addition, the expression of metabolic genes in adipose tissue and liver became more elastic.

Treatment with a PPARy-agonist (PPARy is a transcription factor that coordinates genes involved in glucose and lipid metabolism) improved gene elasticity.

Overall, this study provides a new angle on metabolic physiology that overlaps with but is distinct from, metabolic flexibility. One of the most striking findings was the loss of gene elasticity with both aging and obesity. Interventions that improve gene elasticity, such as fasting, may help to mitigate declines in elasticity with aging (and obesity).

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