Immunobiology

Similar to the hereditary nature of epigenetics, obese mothers can pass along the bacterial mix in their gut in a way that also makes their children prone to obesity. Now a team of researchers at Cincinnati Children’s reveals a critical mechanism involved—and a potential treatment to control it.

“We wanted to understand what might enable the gut microbiome to affect obesity,” says senior author Theresa Alenghat, VMD, PhD, “and we already knew from our previous research that this particular enzyme, HDAC3, is sensitive to the microbiota.”

In a groundbreaking study, published in Gastroenterology, Alenghat and colleagues reveal that the short-chain fatty acid (SCFA) butyrate plays a critical role in regulating HDAC3 activity in the gut.

The study suggests that decreased butyrate levels in mice fed high-fat diets leads to increased weight gain and susceptibility to obesity-associated sequelae. This systemic effect seems to reflect a loss of intestinal inhibition of the HDAC3 epigenetic-modifying enzyme in intestinal epithelial cells.

“Targeting intestinal HDAC3 directly or through microbiota-based strategies may represent a potential mechanism for specifically preventing obesity and tackling sequelae associated with obesity,” the study states.

The Cincinnati Children’s team included first author Jordan Whitt and co-authors Vivienne Woo, Patrick Lee, Jessica Moncivaiz, Yael Haberman Ziv, MD, PhD, Lee Denson, MD, and Patrick Tso, PhD.

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.

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.

Does this mechanism occur in humans?

To determine whether the mouse findings might translate to humans, the team worked with Lee Denson to examine HDAC3 levels in pediatric control patient ileal biopsies that had been collected during a Crohn’s disease study. Indeed, they found that HDAC3 levels in the tissue samples correlated with body weight.

This in turn raises several implications that have yet to be tested in clinical trials in the years ahead.

The HDAC3-driven pathways that promote obesity may also predispose offspring to development of obesity and diabetes later in life, Alenghat and colleagues say. In addition, early antibiotic exposures that already are known to alter the intestinal microbiome may trigger early obesity by affecting HDAC3 activity in the intestine.

Thus, regulating HDAC3 could be an important treatment target in obese individuals—particularly if blocking the enzyme can be limited to the gut.

“HDAC3 plays roles crucial to health in many tissues so future studies will explore how to regulate the enzyme in the gut without disturbing its beneficial functions locally and outside the intestine,” Alenghat says.

Citation

Whitt J, Woo V, Lee P, Moncivaiz J, Haberman Y, Denson L, Tso P, Alenghat T. Disruption of Epithelial HDAC3 in Intestine Prevents DietInduced Obesity in Mice. Gastroenterology. 2018 Aug;155(2):501-513.