LA JOLLA (January 3, 2023): Obesity and metabolic diseases, such as diabetes, are extremely common in the United States. Small proteins called microproteins have been overlooked in research, but new evidence shows they play an important role in metabolism. Salk scientists have discovered that both brown and white fat are filled with thousands of previously unknown microproteins and show that one of these microproteins, called Gm8773, can increase appetite in mice.
These findings, published in Cell Metabolism on January 3, 2023, could lead to the development of a therapeutic to help people gain weight in certain disease situations, such as during chemotherapy for cancer. Furthermore, by establishing the existence of these microproteins, the team provides a valuable resource for the scientific community to study microproteins as well.
“It is vital to better understand the processes that regulate obesity and metabolic health in order to provide improved therapies for the future,” says Salk Professor Alan Saghatelian, co-author of the study and holder of the Dr. Frederik Paulsen. “Having this list of microproteins will help the field of metabolism identify new players in a variety of metabolic diseases. And we have shown a biologically active microprotein that promotes feeding, as well as other microproteins that are involved in fat metabolism.”
Adipose tissue secretes many different proteins to regulate feeding, energy balance and heat production. White fat, known as “bad fat”, is often found just under the skin and in the abdominal region. This type of fat acts as an energy reservoir and is linked to obesity and other diseases caused by excess weight. In contrast, brown fat or “good fat” is found around the shoulders and along the spinal cord. Brown fat is associated with proper diet, exercise and health.
In this study, scientists used innovative genomics technologies to examine brown, white, and beige fat (another type of fat with similar characteristics to white and brown fat) in mouse cells. They discovered 3,877 genes that produce microproteins in both white and brown fat. In addition, they explored the levels of these genes in mice fed a high-fat Western diet and linked hundreds of microproteins to changes in fat tissue metabolism. Overall, the analysis highlights many metabolically relevant microproteins for the first time.
“We have provided a roadmap for how best to use our data to link and ultimately characterize the roles of microproteins in fundamental metabolic pathways,” says first author Thomas Martinez, a former postdoctoral fellow in Saghatelian’s lab who now is an assistant professor at the UC. Irvine.
The team also focused on a microprotein called Gm8773, located in the brain’s feeding center, called the hypothalamus. The microprotein’s location in the brain suggested it might play a role in appetite. In fact, when the scientists administered Gm8773 to obese mice, the mice consumed more food. There is also a human gene similar to Gm8773 called FAM237B, and this gene could act similarly in humans to promote feeding. According to the researchers, this microprotein could eventually become a therapeutic to promote weight gain in those suffering from extreme weight loss.
“The new microproteins presented in our study are exciting discoveries for the field of metabolism and for the study of fat biology,” says co-corresponding author Chris Barnes, formerly of the Novo Nordisk Research Center Seattle, Inc., now head of proteomics in Velia. therapeutic “We hope that this resource will be used to generate numerous new experimental hypotheses for the scientific community to test in their own laboratories, and that this work will lead to the identification of new mechanisms in biology.”
In the future, the scientists plan to develop tools to investigate the roles of Gm8773 and FAM237B with the goal of eventually developing a therapeutic that could increase appetite in humans.
Other authors include Cynthia Donaldson, Joan M. Vaughan, Calvin Lau, and Maxim N. Shokhirev of Salk; Brian C. Searle of Ohio State University; Lindsay K. Pino and Michael J. MacCoss of the University of Washington; Eduardo V. De Souza, and Cristiano V. Bizarro from the Pontifcia Universidade Catolica do Rio Grande do Sul in Brazil; and Sally Lyons-Abbott, Angie L. Bookout, Ariel Abramov, Arian F. Baquero, Karalee Baquero, Dave Friedrich, Justin Huard, Ray Davis, Bong Kim, Ty Koch, Aaron J. Mercer, Ayesha Misquith, Sara A. Murray, Sakara Perry, Christina Sanford, Alex Simon, Yu Zhang, Garrett Zipp, and Andrew J. Whittle of Novo Nordisk Research Center Seattle, Inc.
The work was supported by the National Institutes of Health (R01 GM133981, P41 GM103533, R24
GM141156, U19 AG065156, P30CA014195, R01GM102491, RC2DK129961 and K01CA249038), Frederick Paulsen and the Ferring Foundation, a sponsored research agreement with Novo Nordisk Research Center Seattle,
Inc., National Institute of Science and Technology of Tuberculosis, Brazil (421703-2017-2/17-1265-8/14.2.0914.1), National Council for Scientific and Technological Development of Brazil (310344/2016-6), and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brazil.
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