You are exactly right! More works needed to understand how all these diets change your physiology. Thank you!

Weight loss is generally associated with reduced liver fat. So if IF leads to weight loss in someone, likely their total liver fat has gone down too. It would be interesting to see long term if persistent fasting hormones reprogram the fasting response in liver.

I think there’s a lot we still need to know. Is glucagon signaling persistent in IF and does it desensitize? How do other fasting hormones factor in (like cortisol and adrenaline).

I would love to see a longitudinal study on liver fat changes over the course of different IF protocols.

This research is the result of over 10 years of work, numerous collaborations and the tireless efforts of many people in my lab. Thank you to everyone!! In particular, first author Dr Aysim Gunes, and Clemence Schmitt whose talents allow us to tell our story in pictures. 6/6

In mice, high PGC-1A4 causes accumulation of large lipid droplets, drives a MASLD-like lipid signature, and worsens liver disease with a western diet.

In people living with MASLD, high levels of PGC-1A4 in liver correlate with more steatosis and larger lipid droplets. 5/6

Fasting increases PPARγ levels in liver, facilitating lipid uptake and allowing lipid droplets to expand by increasing levels of Fsp27/Cidec. 4/6

How does the liver know when to burn or store?

We found this is driven by glucagon and PPARγ, and coordinated by the PGC-1A family of co-activators.

One family member (PGG-1A1) drives lipid catabolism, while another (PGC-1A4) promotes lipid storage, at different times. 3/6

Why is this important?
The liver burns lipids during fasting for energy. But the liver accumulates fat during fasting, which may seem paradoxical. The lipids it stores are needed when other energy sources become scarce, especially if the fast goes on for a long time. 2/6

🧵(3/3) Cont' beginning of Sept 2025:
1) www.cell.com/cell-stem-ce...
2) academic.oup.com/edrv/advance...
3) www.nature.com/articles/s41...

🧵(2/3) Cont' beginning of Sept 2025:
2) “Glycerol and glycerol-3-phosphate: multifaceted metabolites in metabolism, cancer and other diseases” PMID: 40927981
3) “Osteocalcin has many tricks to get γ-carboxylated” PMID: 40913186
Links in last thread