Research on genetic, hormonal and microbial mechanisms pave the way toward new prevention and treatment strategies

Obesity Illustration

How do genetics, hormones, and the microbes in the gut contribute to obesity and metabolic syndrome? At a time when more than one-third of U.S. adults are obese and effective long-term therapies for obesity and fatty liver disease are lacking, cutting edge research being pursued in the UCLA Vatche and Tamar Manoukian Division of Digestive Diseases into the contributing mechanisms carries major public health implications.

A group headed by Drs. Joseph Pisegna and Yvette Taché, professors in the division, is funded by the U.S. Department of Veterans Affairs for research looking at the potential for diets high in protein to positively affect metabolism and therefore be used to treat obesity and fatty liver disease. Dr. Pisegna, an expert in how gastrointestinal hormones regulate physiologic function, currently heads industry-funded clinical trials on drugs for treating fatty liver; his group also conducts parallel studies in mouse models of obesity and fatty liver disease.

In the laboratory, Dr. Pisegna and colleagues have found that a high-protein diet regulates certain hormones involved in satiety, including vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide. “We think that the high-protein diet turns on hormones that lead to satiety, but that these hormones may also have a direct effect on adipose tissue and the liver,” Dr. Pisegna explains. “They are operating through two different mechanisms — one through the brain and how it sends out signals for satiety, and the other more directly, either on the liver or adipose cells.”

In addition to studying these questions at the hormone level in humans and mouse models, Dr. Pisegna is looking into the genetic signatures of obesity and fatty liver in collaboration with a member of UCLA’s Department of Human Genetics faculty, Dr. Paivi Pajukanta. Their study utilizes the Million Veteran Program cohort, a U.S. Department of Veterans Affairs-funded population study that has thus far collected full-exome sequencing data on approximately 400,000 veterans.

Dr. Pisegna and other faculty in the division are part of the UCLA Center for Obesity and METabolic Health (COMET), a leader in clinical and basic research on obesity and metabolic syndrome. COMET’s investigative efforts are directed by a member of the division faculty, Dr. Simon Beaven, who focuses on how alterations of lipid metabolism promote liver damage and diabetes. Dr. Beaven and his colleagues are examining the role of endogenous nutrient receptors, called nuclear receptors, in the development of the component conditions of the metabolic syndrome — fatty liver, diabetes, high cholesterol, obesity, and atherosclerosis. They recently made a major discovery with the observation that lipid metabolism, through liver X receptor signaling, plays an important role in the activation of hepatic stellate cells and contributes to liver fibrosis susceptibility. 

Investigators in the Ingestive Behavior and Obesity Program of the G. Oppenheimer Center for Neurobiology of Stress and Resilience (CNSR) are focusing on identifying the role of brain gut interactions in obesity. Dr. Arpana Gupta is studying structural and functional brain changes associated with early adverse life events, socioeconomic status and obesity. She found that certain brain characteristics predispose individuals to obesity, and that traumatic early life events lead to brain changes that can lead to dysregulated eating behaviors (“food addiction”), increasing obesity risk. Based on these findings, she is now studying the effectiveness of cognitive behavioral therapy in reversing altered ingestive behavior and promoting weight loss.

The CNSR Obesity Research Program is investigating the connection between the brain and the gut microbiome in obesity, particularly after weight loss and bariatric surgery. Research involving identical twins has shown that when the stools from an obese donor and a lean donor are transplanted into germ-free mice, the mice that receive the obese donor’s stool tend to subsequently gain more weight. Moreover, patients who undergo bariatric surgery experience a marked reduction in appetite and changes in food preferences that have not been explained, and fecal transplant from post-bariatric surgery donors results in weight loss in animal models. These and other findings led to the exploration of the role of gut microbial metabolites in the control of food preference and weight control. The gut microbiome is certainly not the only player in the field of obesity, but it definitely plays an important role.

In an effort to learn more about that role, our team is collaborating with a group that includes Dr. Erik Dutson, COMET’s surgical director, to study appetite and behavioral changes in patients following bariatric surgery. The ongoing study has found an association between gut metabolites and changes in appetite and food preferences after the surgery, along with resulting changes in brain function. These are preliminary findings with a small sample size, but we are seeing profound changes in appetite, food preferences and brain structure in the first months after surgery, then over time the appetite and food cravings tend to return.

The group is continuing to examine how the gut microbiome contributes to the changes in brain structure and function seen immediately after the surgery that can promote reduced appetite and increased satiety. We have found that some of the products of the gut microbiome affect hunger, satiety levels, and weight loss, and also that certain characteristics of the gut microbiome before surgery can predict who is going to be most successful in losing weight after the surgery. We are hopeful that the research will contribute to a better understanding of which patients are most likely to benefit from bariatric surgery — and, ultimately, to new treatments that could achieve the same effect on appetite and satiety without the operation.