Investigators have discovered a pathway between the “anti-hunger” molecule N-lactoyl phenylalanine (Lac-Phe) and the widely prescribed diabetes drug metformin. The researchers hope that controlling this pathway will lead to viable strategies to reduce body mass and improve health of millions of people.
Their study, published in Nature Metabolism, included basic science research led by Lydia Lynch, PhD, (conducted while her lab was part of Brigham and Women’s Hospital) and clinical work led by Marie E. McDonnell, MD, director of the Brigham’s Diabetes Management Program.
‘Our Research Took a Left Turn’
Dr. Lynch did not set out to study appetite control. Instead, she was investigating how obesity affects the immune system.
“People living with obesity are much more susceptible to infection and certain cancers, suggesting that there may be something wrong or different about their immune system,” she says. “As we started to study this connection by collecting patient samples from Brigham patient volunteers in Dr. McDonnell’s clinic, we discovered that Lac-Phe was increased in patients with type 2 diabetes [T2D] who were taking metformin. At that point, our research took a left turn.”
The dataset from Brigham patients reflected findings from the much larger TwinsUK dataset and other datasets worldwide, providing robust support for the researchers’ hypothesis. The patient data, coupled with prior research published in Nature showing that Lac-Phe production during and after vigorous exercise can benefit metabolism and appetite suppression, suggested that the anti-hunger molecule can produce weight-loss benefits.
“Controlling appetite has long been a goal in the management of T2D,” Dr. McDonnell says. “The better we can understand the link between appetite, feeding, and blood sugar, the closer we will get to more precise treatments for the disease.”
Significant Increase in Lac-Phe Levels Observed
The study compared metabolic profiling among individuals who were lean non-T2D, lean pre-T2D, obese non-T2D, obese pre-T2D, or obese T2D. Lac-Phe levels were found to be 5.7-fold higher in obese T2D individuals compared to obese non-T2D control volunteers. A significant increase also was observed between obese T2D and pre-diabetic individuals.
Considering the prevalence of metformin use in individuals with T2D, the researchers hypothesized that serum levels of Lac-Phe were linked with metformin treatment. They found a strong correlation between Lac-Phe and metformin concentrations among individuals with T2D in the Brigham cohort.
The TwinsUK dataset allowed researchers to observe metabolic changes over time, during a period in which metformin’s role in T2D management expanded considerably. They found that patients newly diagnosed with T2D and starting metformin treatment exhibited a significant elevation in Lac-Phe levels. Meanwhile, those newly diagnosed but not initiating metformin therapy did not show a significant elevation in Lac-Phe levels.
A similar rise in Lac-Phe levels was detected in metformin-taking patients consistently diagnosed with T2D over successive blood draws. In contrast, those who were consistently diagnosed with T2D but did not initiate metformin therapy did not show a significant change.
The Feeding and Fasting Effect on Lac-Phe Levels
One of the study’s surprising findings, according to Dr. Lynch, was the high correlation between Lac-Phe levels and being “non-fasted.” While most patient samples in the TwinsUK cohort were collected under a fasted condition, a subset of T2D patients had eaten within six hours of sample collection. A trend toward increased Lac-Phe levels was observed in the fed volunteers, suggesting that serum Lac-Phe levels are controlled by food intake.
“Given Lac-Phe’s appetite-suppressing properties, we speculated that its elevation post-meal could act as a feedback mechanism in appetite regulation,” Dr. Lynch says. “Interestingly, this is the case when solid food is consumed. However, the increase is much less when liquid food, like smoothies, is consumed. Therefore, digestion factors likely play a role in maximizing that impact and the resulting appetite-suppression feedback to the brain.”
“We have long thought that metformin had, at best, a mild anorexigenic effect, especially once it reaches the bloodstream,” Dr. McDonnell adds. “However, if we can optimize the way metformin works in the gut, it may open the possibility of using it as a safe and effective weight-loss drug.”
The study’s findings have prompted Dr. Lynch to investigate other metabolites and metabolic pathways that may play a role in appetite suppression and other functions related to immuno-metabolism.
“So much of the metabolome is uncharacterized,” she says. “About 70% of metabolites are unidentified, just like Lac-Phe was until recently.”
The Bridge Between Basic Science and Clinical Innovation
As a clinician, Dr. McDonnell relies on the Brigham’s strength in basic science and the collaboration between Brigham scientists and clinicians. Without the latter of these factors, she would not have been able to link observations in the clinic around metformin to their underlying mechanisms.
“The Brigham encourages clinicians to go across the hallway to our basic science colleagues and epidemiologists and ask the really hard questions, then answer those questions together,” she says. “Collaborative work like this study with Dr. Lynch is one of the many things that makes the Brigham a truly rewarding place to practice.”