Insights began with mouse models
To explore the role of HDAC3 in obesity, the team fed a high-fat diet to healthy control mice and to mice missing HDAC3 in their intestinal epithelial cells. As expected, the controls became obese. Their responses to sugar weakened as well.
However, the HDAC3-deficient mice stayed lean despite the high-fat diet. They also had less fat circulating in their blood, less liver fat, and smaller fat-storing adipocytes.
“Future studies will explore how to regulate the enzyme in the gut without disturbing its beneficial functions.”
The team went on to demonstrate that butyrate levels were low in the intestinal epithelial cells (IECs) of obese mice. Giving these mice butyrate significantly decreased HDAC3 enzymatic activity, altered expression of core metabolic genes, and led to weight loss.
The team also used tamoxifen to inhibit HDAC3 activity in a group of control mice after they became obese. Inhibition of HDAC3 in the intestinal epithelial cells of adult obsese mice led to decreased weight. They also showed decreased serum triglycerides, reduced fasting glucose levels, and improved glucose tolerance, much like the mice that were bred to lack HDAC3 activity in their intestinal cells from birth.
These findings suggest that decreasing HDAC3 levels may reset the body’s metabolism rate for higher energy expenditure.
“Taken together, these data indicate that butyrate promotes leanness by inhibiting IEC-intrinsic HDAC3 activity and suggests that loss of intestinal butyrate with HFD may relieve HDAC3 inhibition in IECs and promote weight gain,” Alenghat says.
Achieving these results required contributions from several core research services at Cincinnati Children’s, including Veterinary Services, the Pathology Research Core, and the NMR-based Metabolomics Core. The project also received support from the University of Cincinnati Genomics, Epigenomics and Sequencing Core, and the Mouse Metabolic Phenotyping Center.