January 24, 2005
Plant protein mimics hormone that mitigates diabetes and obesity
WEST LAFAYETTE, Ind. - A common protein that protects plants from fungal infection mimics the activity of a hormone in mammals that is linked to weight loss and is believed to play a role in mitigating heart disease, obesity and diabetes, according to a team of researchers at Purdue University and several collaborating institutions.
The research has the potential to lead to a simple screening system for developing new drugs to treat these and several other human diseases, including some forms of cancer, said Ray Bressan, distinguished professor of horticulture and one of the study's authors.
The study also raises questions about the human health role of this type of plant protein, found in many fruits, seeds and vegetables such as grapes, oats and tomatoes.
The protein, called osmotin, belongs to a large, diverse family of proteins that defend plants from fungal pathogens. Bressan and his colleagues report in the current issue (Friday, Jan. 21) of Molecular Cell that a protein in mammal muscle cells called a receptor, which normally binds to the hormone adiponectin, also binds osmotin.
They also found that the plant-derived osmotin activates the receptors in mammals in the same manner as adiponectin.
"We've found that this plant protein mimics the behavior of adiponectin in muscle cells," Bressan said. "It's very possible that the plant protein could play a role in the prevention of diseases like diabetes as well, because it has the same target as adiponectin in mammal cells - the adiponectin receptor."
The binding of hormones and other proteins to receptors activates specific responses. For example, when the hormone oxytocin binds to cells in the uterus, contractions - and childbirth - begin.
When bound to its receptor, adiponectin regulates sugar uptake and, in mouse models, prevents the development of diabetes and atherosclerosis, or the hardening of the arteries associated with heart disease. Previous studies have shown that people with diabetes tend to have lower levels of adiponectin in their blood than non-diabetics. In addition, adiponectin levels tend to be lower in the obese and in patients with heart disease than in healthier individuals.
Whether the beneficial effects of adiponectin can be induced by osmotin is currently unknown.
"We've shown the connection between adiponectin and the plant protein osmotin," Bressan said. "That connection is that the same protein in animal cells recognizes both osmotin and adiponectin and responds to them in the same way. There's an inference that the plant protein very possibly could have a similar protective connection to those diseases, but we don't yet know that."
In the current study, researchers looked at how osmotin functions in yeast, a fungus often used as a model organism in molecular and biochemical experiments. They also assessed how osmotin acts in adiponectin receptors in a culture of mouse muscle cells.
The yeast system they developed hints at the possibility of using yeast to screen for new pharmaceutical products to target diabetes, heart disease and obesity, Bressan said. Running a screen in yeast is a highly efficient first step in looking for potentially therapeutic agents because yeast is easy to grow and is very well understood at the cellular and molecular genetic levels.
"It may be possible to expose different drug candidates to the receptor in yeast that recognizes osmotin and see which compounds activate this receptor," he said. "Another approach would be to take the gene for the animal receptor, insert it into yeast, and start asking those same questions - what other compounds does the receptor recognize?"
In their study, the researchers determined that activation of the osmotin receptor in yeast kills yeast cells by inducing a phenomenon called "apoptosis," or programmed cell death. Thus, a screen to look for compounds that activate this receptor could simply rely on finding out which compounds kill yeast cells by the same process.
This study also shows that we need to look more closely at the way our bodies use the foods we eat, especially plant-based foods such as fruits, nuts and vegetables.
"Proteins like osmotin are consumed by people all the time," Bressan said. "Yet no studies have been done to determine how the presence or absence of these proteins in the diet affects us."
Osmotin is a stable protein that is resistant to heat, acidity and enzymes, meaning it could circulate through the body without being broken down by digestion, he said.
Whether osmotin plays any role in the health benefits attributed to diets high in fruits and vegetables is a tantalizing possibility, and this research opens the door to that question, Bressan said.
"We know that osmotin is an active protein in many of the plants we eat," he said. "We control and label nutrients like fats, carbohydrates and protein - but the really active materials in the foods we eat are the ones we know the least about and don't label in our foods."
Both adiponectin and osmotin jump-start a process called "AMP kinase phosphorylation," which increases both sugar and fat use by muscle cells.
"By binding to the adiponectin receptor, osmotin, like adiponectin, can control the energy status of muscle cells, " said Meena Narsimhan, research scientist at Purdue's Bindley Bioscience Center and a study co-author.
Curiously, adiponectin also can kill some types of mammalian cells, Narsimhan said.
"Other research has shown a strong correlation between low levels of adiponectin and increased risk of breast cancer," she said.
Whether osmotin also has a similarly lethal effect on any types of mammalian cells remains to be seen; however, osmotin, when bound to its receptor on yeast cells, does kill those cells, Narsimhan said.
"What's interesting about this research is that is raises so many questions," she said.
Collaborating researchers in this study include Maria A. Coca, who first isolated the yeast receptor gene, at the Instituto de Biologia Molecular, Barcelona, Spain; Dae-Jin Yun of the Environmental Biotechnology National Core Research Center at Gyeongsang National University, Korea; Jingo Jin, Barbara Damsz and Paul Hasegawa at Purdue's Center for Plant Environmental Stress Physiology; Toshimasa Yamauchi, Yusuke Ito and Takashi Kadowaki at the University of Tokyo Graduate School of Medicine and CREST, Japan Science and Technology Agency; Jose Pardo with the Instituto de Recuersos Naturales y Agrobioloia in Seville, Spain; and Kyeong Kyu Kim with the Sungkyunkwan University School of Medicine, Suwon, Korea.
Funding was provided by the National Science Foundation, the Korean Ministry of Science and Technology, the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research of Japan, and the Korea Science and Engineering Foundation.
Writer: Jennifer Cutraro, (765) 496-2050, email@example.com
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Meena Narsimhan, (765)-494-0152, email@example.com
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Osmotin is a Homolog of Mammalian Adiponectin and Controls Apoptosis in Yeast Through a Homolog of Mammalian Adiponectin Receptor
The antifungal activity of the PR-5 family of plant defense proteins has been suspected to involve specific plasma membrane component(s) of the fungal target. Osmotin is a tobacco PR-5 family protein that induces apoptosis in the yeast Saccharomyces cerevisiae. We show here that the protein encoded by ORE20/PHO36 (YOL002c), a seven transmembrane domain receptor-like polypeptide that regulates lipid and phosphate metabolism, is an osmotin-binding plasma membrane protein that is required for full sensitivity to osmotin. PHO36 functions upstream of RAS2 in the osmotin-induced apoptotic pathway. The mammalian homolog of PHO36 is a receptor for the hormone adiponectin and regulates cellular lipid and sugar metabolism. Osmotin and adiponectin, the corresponding 'receptor'-binding proteins, do not share sequence similarity. However, the beta barrel domain of both proteins can be overlapped and osmotin, like adiponectin, activates AMP kinase in C2C12 myocytes via adiponectin receptors.
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