High-fat diets and obesity prompt the accumulation of fat in the liver, which is becoming an increasingly prevalent global health concern.
Excessive fat buildup in the liver, known as fatty liver disease, poses severe risks for metabolic disorders. While most research has concentrated on how fat is processed in the liver, new studies highlight the gut’s critical role in this process.
Proglucagon-derived peptides (PGDPs), like glucagon, GLP-1, and GLP-2, are essential hormones that help regulate fat metabolism in the liver. They come from the same precursor, proglucagon. While earlier studies suggest that GLP-1 and GLP-2 play a role in liver fat accumulation, their exact contributions still need to be understood entirely.
A new study from Fujita Health University explores how PGDPs impact fat absorption and liver fat buildup. Scientists used genetically modified mice that lack PGDPs (GCGKO mice) to determine their response to a high-fat diet (HFD) for seven days.
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Associate Professor Yusuke Seino from Fujita Health University said, “When we subjected both GCGKO mice and control mice to an HFD for one week, the GCGKO mice exhibited a significantly lower increase in hepatic free fatty acid (FFA) and triglyceride levels, along with reduced adipose tissue weight. These effects were attributed to decreased lipid absorption via the CD36 pathway in the intestinal tract, despite a reduced fat-burning capacity (β-oxidation) in the liver.”
The study found that mice lacking proglucagon-derived peptides (GCGKO) showed lower gene expression for fatty acid oxidation, particularly for Pparα and Cd36 in the duodenum. This reduction is linked to decreased fat absorption in the intestines and higher fecal cholesterol, suggesting that without PGDPs, diet-induced fatty liver is prevented by lowering intestinal fat uptake.
Interestingly, although fat-burning in the liver was reduced, the main reason for less fat accumulation was decreased fat absorption from the intestines. These GCGKO mice also had lower plasma triglyceride levels during fat tolerance tests, confirming reduced lipid absorption.
The research highlights the complex interplay between diet, hormones, and gut bacteria. The HFD-fed GCGKO mice showed significant changes in their gut microbiota, with more Parabacteroides and fewer Lactobacillus, which are associated with obesity resistance. This suggests potential dietary and hormonal strategies to improve gut health and metabolic function.
Dr. Seino notes, “If we can examine in more detail how PGDPs specifically regulate lipid absorption in the gut, we hope to clarify the relationship between diet, hormones, and intestinal bacteria sufficiently to recommend a diet less conducive to obesity and fatty liver disease.”
Regarding the long-term implications of the study, the oral dual antagonists of GLP-2 and glucagon could emerge as potential therapies for obesity and fatty liver.
Journal Reference:
- Koki Nishida, Shinji Ueno et al. Impaired Fat Absorption from Intestinal Tract in High-Fat Diet Fed Male Mice Deficient in Proglucagon-Derived Peptides. Nutrients. DOI: 10.3390/nu16142270
