Although Roux-en-Y gastric bypass has been shown to be effective in helping severely obese individuals achieve substantial, long-term weight loss, a group of Mayo Clinic researchers found that the likelihood of benefit may depend on a person’s genetic makeup.
Maria Espinosa, MD, a research fellow in the gastroenterology and hepatology department at Mayo Clinic, in Rochester, Minn., presented a study at DDW 2025 showing that genetic testing can help healthcare professionals identify which patients are most likely to benefit from bariatric procedures and which are at greater long-term risk of regaining weight after surgery.
Genetic Risk Score and Leptin-Melanocortin Mutations
Using the MyPhenome test, which generates a polygenic risk score for calories to satiation (GRS) and identifies variants in the leptin-melanocortin (LMP) pathway, the investigators predicted patients’ obesity phenotypes. The GRS is based on multiple genetic variants that collectively affect appetite regulation and satiety-signaling pathways in the brain and influence how many calories an individual requires to feel full.
“The LMP is a key brain circuit that helps regulate appetite and satiation,” said lead researcher Andres Acosta, MD, PhD, a bariatrician and gastroenterologist at Mayo Clinic and a co-founder of Phenomix Sciences, which developed the MyPhenome test. “Leptin is a hormone produced by fat cells that signals to the brain when the body has enough energy. In a healthy pathway, leptin and other hormones, such as glucagon-like peptide 1, activate melanocortin neurons to suppress appetite.
“However, rare genetic variants can disrupt this signaling, leading to a higher threshold for feeling full, what we refer to as the Hungry Brain phenotype,” Dr. Acosta told Gastroenterology & Endoscopy News. “We examined this pathway because prior studies have shown that disruptions here are strongly linked to obesity, and our goal was to see how these mutations affect long-term weight loss after bariatric surgery.”
For the study, they performed genotyping using blood samples from participants in the Mayo Clinic Biobank with a history of bariatric procedures, focusing on 442 patients who had undergone Roux-en-Y gastric bypass (RYGB), and collected anthropometric data for up to 15 years after RYGB. Using the GRS predictions, they designated patients as either GRS+ or GRS–. The researchers also identified carriers and noncarriers of variants in the LMP pathway, designating them as LMP+ and LMP–, respectively. Based on the GRS and LMP designations, they assigned each patient to one of four groups: LMP+/GRS+, LMP+/GRS–, LMP–/GRS+ and LMP–/GRS–. They conducted multiple regression analysis to analyze total body weight loss percentage (TBWL%) at different time points in the different groups.
“The LMP+/GRS+ group represents the most severe form of the Hungry Brain phenotype, as it combines both rare and common genetic variants that impair satiation,” Dr. Acosta explained. “The LMP+/GRS– and LMP–/GRS+ groups likely represent milder or partial forms of the Hungry Brain phenotype—patients who may still struggle with satiation but not to the same degree. The LMP–/GRS– group is likely not consistent with the Hungry Brain phenotype and may correspond to other obesity phenotypes identified through MyPhenome, like Hungry Gut, Emotional Hunger, and … Slow Burn. However, this study was designed to focus solely on the Hungry Brain phenotype and did not assess the other subtypes.”
There were 47 carriers of LMP genetic variants (LMP+), and 88 patients with high GRS (GRS+). Starting at 10 years after RYGB, the LMP+/GRS+ group had weight regain that was significantly higher than that of the other groups. At 15 years post-RYGB, the mean TBWL% ± SEM (standard error of the mean) was significantly lower for those in the LMP+/GRS+ group (–4.0±5.4) compared with those in the LMP+/GRS– (–20.3±3.2), LMP–/GRS+ (–18.0±3.0) and LMP–/GRS– (–24.8±1.5) groups.
“We’ve known that genetics can impact weight outcomes, but this is the first time we’ve shown that a polygenic risk score, developed with machine learning and used in the MyPhenome test, can predict long-term weight recurrence after Roux-en-Y gastric bypass,” Dr. Acosta said. This “hungry brain phenotype, patients who need more calories to feel full, [is] driven by genetic factors in the leptin-melanocortin pathway,” Dr. Acosta explained.
Early Days for Personalized Obesity Care
Although treatment options for obesity have “evolved at the speed of light” in the last 10 years, “personalized approaches to care are still in their infancy,” Carolyn Newberry, MD, an associate professor of clinical medicine at Weill Cornell Medical College and the director of GI nutrition at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, in New York City, told Gastroenterology & Endoscopy News. “This includes the incorporation of genetic information into care algorithms, which is not currently readily available but of interest to clinicians as a way to risk-stratify patients and determine an effective treatment plan.”
Dr. Newberry said current obesity treatments are provided based on a combination of anthropometric data such as body mass index and waist circumference as well as medical history. Choice of procedure often is based on “shared decision-making between patient and provider in addition to other clinical considerations, such as presence of reflux, (for which a Roux-en-Y gastric bypass may be preferred) or inflammatory bowel disease (for which a sleeve gastrectomy may be a better option),” she added.
A better understanding of the genetic influences for obesity may give clinicians greater insight into the challenges faced by each patient. “Clinically, this means we now have a tool to help identify patients who may be at higher risk for weight regain before they undergo surgery. That gives us the opportunity to personalize care [by] choosing the right procedure, preparing for closer follow-up or considering adjunct therapies,” Dr. Acosta said. “This moves us toward a more biologically informed approach to bariatric treatment, beyond BMI or behavioral factors alone.”
More research is needed to realize the potential of genetic testing in obesity care, Dr. Newberry said. “The ability to use genotypic information to make treatment decisions for patients with obesity is exciting and warrants further exploration,” she added. “If these results are validated in larger, more diverse patient populations and the testing can be scaled so it is accessible, its implications in choosing specific obesity treatments would be significant.”
The MyPhenome test is not FDA approved. Dr. Acosta said that the test predicts obesity phenotype, but it is not a companion diagnostic and does not identify or recommend specific medications or other interventions.
“Our other research has found that patients can have more than one obesity phenotype, which further underscores the complexity of obesity treatment,” Dr. Acosta added. “Our goal is to highlight how MyPhenome can support clinicians in identifying at-risk patients preoperatively to improve surgical planning and long-term care strategies.”
—M.E. Ford, MD, MPH
Dr. Newberry reported no relevant financial disclosures.
This article is from the September 2025 print issue.