Researchers at Baylor College of Medicine have found that the interaction between genetics and diet plays a significant role in regulating daily patterns of gene activity in the liver, particularly those related to fat metabolism. The study, published in Cell Metabolism, indicates that these interactions add another layer to how circadian rhythms—natural 24-hour cycles influencing sleep and metabolism—are regulated.
“Our study provides new insights into the question, ‘Why do some people gain weight more easily or develop liver problems while others don’t, even when they eat similar diets?’” said Dr. Dongyin Guan, assistant professor of medicine – endocrinology, diabetes and metabolism and molecular and cellular biology at Baylor. Guan is also a member of Baylor’s Dan L Duncan Comprehensive Cancer Center.
“We found that individual genetic differences affect the timing of gene activity in the liver in response to food,” said Dr. Ying Chen, postdoctoral fellow in the Guan lab. “Genes and diet work together to shape the liver’s daily rhythm, which in turn can affect how fats are processed and stored.”
The research team examined both human liver samples and two strains of mice with different genetic backgrounds. They observed how genes turned on and off throughout the day and tracked changes when mice were fed a high-fat diet.
To understand how genetics and diet interact at a molecular level, researchers studied three-dimensional interactions between DNA regions. They looked specifically at enhancers—which boost gene activity—and promoters—which start gene activity—and how their connections varied over time.
Guan noted that genetic variation affects daily patterns of gene activity in both humans and mice. In human subjects, thousands of genes showed rhythmic activity only among individuals with certain gene variants.
“We also found that diet changes the rhythm of gene expression in mouse liver, but differently for different genes,” said Dishu Zhou, research assistant in the Guan lab. “When mice were fed a high-fat diet, their liver gene activity changed, but not in the same way for all genes. Some genes kept their rhythm, some lost it, and others gained it.”
The study determined that genetics and nutrition jointly control more than 80% of rhythmic enhancer-promoter interactions within cells. “We identified gene ESRRγ as a noncanonical clock regulator, meaning that it is not part of the core circadian clock gene family but still plays a significant role in regulating daily rhythms,” Guan said. “Mice lacking ESRRγ lost many of these rhythmic connections in the liver and showed disrupted fat metabolism.”
The findings suggest that fat metabolism depends on both timing (circadian rhythm) and genetic background. For example, only mice with active ESRRγ experienced daily changes in fat droplet size within their livers.
While this research focused on fat metabolism within the liver, authors propose similar principles could apply to other organs or diseases. The results support further exploration into personalized chronotherapy—aligning mealtimes or treatments with an individual’s genetic profile—to optimize health outcomes.
Study collaborators included researchers from Baylor College of Medicine as well as Xiamen University; University of Pennsylvania; Case Western Reserve University School of Medicine; University of California Irvine School of Medicine; University of Texas Health Science Center at Houston; and Princeton University.
Funding was provided by organizations including American Liver Foundation Postdoctoral Research Fellowship Award NIH K01-DK125602; CPRIT Scholar in Cancer Research (RR210029); V Foundation (V2022-026); pilot award NIH R37CA296577; DK056338; P30-CA125123; TRISH NNX16AO69A; H-NORC; R01AG069966; R01ES034768; NIH R01DK111495; U54HL165442; U01HL166058; SVRF grant from Additional Ventures; NIH/NCI R00 CA237618 & R01-AA029124; USDA/ARS grant 58-3092-5-001 & CPRIT Scholar Award (PR210056); Pew Foundation & Fundamental Research Funds for Central Universities China-Xiamen University (20720180048).
