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Effects of PPARGC1A gene polymorphism on metabolism and obesity

Hjelt Grant Holder 2022, Sebastian Kalamajski
Anja Schmidt-Christensen
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Sebastian Kalamajski,
Hjelt Grant Holder 2022,
Lund University.

Background
Our health relies on a proper balance between energy intake, storage, and expenditure. To accomplish that, a number of genes act as responders to the continuously changing calorie intake, and can direct our fat cells to either store or degrade the calories, depending on our needs. One of those genes is called PPARGC1A, and an estimated 43% of the people globally carry a genetic variant of PPARGC1A that associates with obesity and diabetes. Our goal is to investigate whether this variant not merely correlates, but causes changes in fat cells that make them more or less responsive to calorie intake. Why this is of concern is that a disturbed fat storage capacity leads to insulin resistance and diabetes. In the end, our aim is to create guidelines for precision medicine treatment of obesity and diabetes, based on what genetic variants the individuals are carrying in their DNA.

Hypothesis
We think the genetic variant in the PPARGC1A gene somehow alters the production and/or degradation of the protein (called PGC-1alpha), which in turn would affect how fast a cell can respond to calorie intake or fasting. This would effectively change how much fat is being stored or removed from a fat cell, and would help predict the effect of the genetic variants on obesity and diabetes.

Methods
We can genomically edit fat cells for the different genetic variants using CRISPR-Cas9 toolkit. The edited cells are then analyzed for their specialized fat cell properties, including capacity to store and release fat under different environmental changes, including calorie restriction or cold exposure. Our results will later guide us in the design of clinical studies where we can assess the combined influence of the different environmental factors and genetic variation on e.g. weight loss.

Results
We have genomically edited several cell populations for the obesity-associated genetic variant of PPARGC1A. We have also generated cells that allow us to follow the turnover of the PGC-1alpha protein over time, under different environmental conditions. So far, we have observed rather dramatic effects of one of the genetic variants on the fat cell lipid storage capacity, and also a clear effect of the variant on PGC-1alpha protein stability.

Conclusions
To this end, we have observed clear causal effects of the genetic variants in the PPARGC1A gene on the produced PGC-1alpha protein stability, and on overall fat cell properties. More studies are underway with regards to the effects of different environmental factors and PPARGC1A variants on the fat cell lipid storage and release.

Importance

Almost half of the human population is carrying a genetic variant in PPARGC1A that seems to cause profound effects on fat cell capacity of storing or releasing lipids. This information could guide future precision medicine-based treatments of obesity and diabetes.

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