How the Gut Decides Fat Storage

On September 4th, 2024, the Storelli lab at the CECAD Research Center at the University of Cologne published groundbreaking findings in Cell Reports on how the gut regulates fat storage. In collaboration with researchers from the University Hospital of Cologne, the University of Münster, and the University of Utah School of Medicine, the study offers key insights into intestinal lipid metabolism, with implications for the treatment of metabolic disorders such as obesity, type 2 diabetes, and inflammatory bowel disease (IBD).

Enterocytes, the primary cells of the intestine, play a pivotal role in managing dietary fats after digestion, either storing them as lipid droplets or exporting them into the bloodstream as lipoproteins. Until now, the mechanisms governing this decision were poorly understood. Using the fruit fly Drosophila as a model, the researchers identified hepatocyte nuclear factor 4 (HNF4) as a key transcription factor coordinating lipid balance in the gut.

“HNF4 works like a switch,” explains Dr. Storelli. “In enterocytes, it activates enzymes that break down lipid droplets, releasing fats to be converted into exportable lipoproteins. At the same time, in hepatocyte-like oenocytes, HNF4 promotes the production of an insulin antagonist, which remotely inhibits lipid storage in enterocytes. This interplay ensures proper lipid distribution in the body.”

Disruption of this crosstalk between enterocytes and oenocytes leads to abnormal lipid retention in the gut, inflammation, and symptoms of IBD in fruit flies. Mutations in the human HNF4A gene, already associated with IBD, suggest that the mechanisms uncovered in Drosophila may have direct relevance to human health. Using advanced tools such as CRISPR gene editing, lipidomics, transcriptomics, and imaging, the team gained unprecedented insights into real-time lipid storage and export pathways in the gut.