Researchers at the University of Cincinnati (UC) and the Helmholtz Center in Munich, Germany, have found that the hormones glucagon and fibroblast growth factor 21 (FGF21), two of the most promising signaling pathways currently targeted for the treatment of diabetes and obesity, may interact to promote weight loss.
The study, which appears in the May 2013 print edition of Diabetes, was led by Kirk Habegger, PhD, research assistant professor in the endocrinology, diabetes and metabolism division at UC, and Matthias Tschöp, MD, adjunct professor at UC and director of the Institute for Diabetes and Obesity at the Helmholtz Center.
"The report provides the first evidence that glucagon controls body weight and lipid metabolism via regulation of FGF21 secretion,” says Habegger.
Glucagon is a naturally occurring hormone known to regulate glucose levels. Considered a "fasting hormone,” glucagon is produced by the islet cells in the pancreas and is released when glucose levels become too low, working in a feedback loop with insulin, which is released when glucose levels rise.
If overproduced, glucagon can lead to high blood sugar and unintentional weight loss. This is evidenced in patients with glucagonoma, a tumor formed of pancreatic islet cells which causes overproduction of glucagon.
A team led by Tschöp from the Helmholtz Center and Technical University in Munich had previously discovered that single molecule combinations between glucagon and glucagon-like-peptides offered superior potential for the treatment of obesity and diabetes.
"What we didn’t know was which signals glucagon controlled to melt the fat,” says Tschöp. "Now we know that FGF21 is at least one of those mediators.”
Together with chemists from Indiana University, the Habegger/Tschöp team developed a stable and soluble glucagon receptor agonist, which allowed for better in vivo dissection of a wide array of glucagon action.
Habegger points out that "while these discoveries were first made in mice, glucagon also increases circulating FGF21 in humans.”
The team of scientists used genetically modified mice (lacking FGF21) to show that its presence was needed to elicit weight loss associated with glucagon. They confirmed their findings in a human study by injecting natural glucagon. Those patients receiving glucagon injections showed an increase of circulating FGF21 within hours.
"This finding provides the first evidence that FGF21 is required for the metabolic benefits of glucagon,” says Habegger, a member of the Cincinnati Diabetes and Obesity Center. "Understanding how glucagon works could help in the long term with the development of therapeutics for metabolic syndrome, diabetes and obesity.”
Co-authors from UC include Kristy Heppner, Nickki Ottaway, Jenna Holland, Jazzmin Hembree, Radha Krishna, PhD, Stephen Woods, PhD, David D’Alessio, MD, Diego Perez-Tilve, PhD, and Randy Seeley, PhD.
Additional co-authors represent the Institute for Diabetes and Obesity and the Institute of Experimental Genetics (Helmholtz Center, Munich); the German Research Center for Environmental Health; Technical University, Munich; Lilly Research Laboratories; Indiana University; Charité University Hospitals, Berlin; F. Hoffmann-La Roche, Ltd., in Basel, Switzerland; and Kyoto University Graduate School of Pharmaceutical Sciences in Japan.
This study was funded by Marcadia Biotech and Roche Pharmaceuticals. Tschöp and several other authors cite consultancy and/or collaborative agreements with Roche. Tschöp has received Roche research funds.