(HOUSTON) — Through a series of recent studies, researchers at the Texas A&M Health Science Center (TAMHSC) Institute of Biosciences and Technology have demonstrated that fat cells are the specific target of an anti-stress, anti-obesity liver hormone – a finding that could help in the development of treatments for obesity.
Wallace McKeehan, Ph.D.
The three studies in Nutrition and Metabolism, Molecular Metabolism and Science Translational Medicine involved a research team coordinated by Wallace McKeehan, Ph.D., John S. Dunn Regents and Distinguished Professor in the Center for Cancer and Stem Cell Biology (CCSCB). The focus was on adipocytes, specialized cells throughout the body that store fat.
By specifically making adipocytes in mice deficient in a widely expressed tyrosine kinase receptor called FGFR1, researchers learned that the adipocytes and a specific receptor in them is the sole target of the circulating liver hormone FGF21. This hormone has potential anti-obesity and anti-diabetic effects.
It was previously believed that similar to insulin, FGF21 acts directly on receptors in diverse tissues, including the liver, due to its dramatic effects on metabolism in the entire body. Instead, the TAMHSC-Institute of Biosciences and Technology researchers showed that the diverse effects of the hormone on tissues other than fat cells is indirect and due to its direct effects only in adipocytes that trigger signals from the fat cells affecting other organs.
Once thought of as simply a dispensable fat storage organ, adipose tissue is now believed to be an important endocrine organ in its own right that communicates with other organs throughout the body. More importantly, it indirectly affects metabolic parameters governed by the liver to maintain the metabolic balance essential for good health.
In the October 2012 Nutrition and Metabolism study, the normal physiological role of the FGF21 receptor FGFR1 in adipocytes was shown to underlie communication between liver cells and fat cells during starvation. Liver cells via FGF21 instruct fat cells to not send all of their lipid reserves at once to the liver for conversion to carbohydrates. In turn, the fat cells signal the liver that they received the message and to not convert the carbohydrates needed for brain food back into lipids.
“This communication enables the body to stretch out its lipid reserves as long as possible for critical carbohydrates needed to maintain brain function in order that eating can resume when food becomes available,” Dr. McKeehan said. “Under normal dietary conditions, lipids and carbohydrates are exquisitely balanced. When one is too high, it is converted to the other and vice versa.”
The liver converts excess fat or carbohydrates into the other form while fat tissue converts and stores any excess to lipid reserves. Liver FGF21 signaling to adipocyte FGFR1 seems to uncouple the process by slowing down the breakdown of lipids in the fat reserves and the synthesis of lipids in the liver in response to starvation and other conditions causing metabolic stress, Dr. McKeehan said.
Eating too much – whether carbohydrates or fat – results in obesity characterized by an increase in fat tissue far beyond what ever would be needed during periods without food. Remarkably, when FGF21 is provided externally at pharmacological levels, it causes weight loss and relieves consequences of obesity as diabetes, even when individuals continue eating too much.
Meanwhile, the August 2012 Molecular Metabolism study, in collaboration with researchers from Eli Lilly, Inc., examined mice deficient specifically in adipocyte FGFR1. Researchers learned the adipocytes – through their FGFR1 receptor and its signaling – accounts for the alleviation of obesity and its symptoms in obese mice. In addition, similar to FGF21 effects during starvation conditions, the adipocytes that comprise fat tissue account for the myriad of pharmacological benefits of FGF21 on the obese in vivo, and other effects may be an indirect consequence of signals to other tissues from the adipocytes.
“This exciting and somewhat unexpected finding of the specificity of adipocytes and its FGFR1 in alleviation of obesity suggests that adipocyte FGFR1 may be the specific and direct target of choice to stimulate with drug mimics of FGF21,” said Chaofeng Yang, former TAMHSC-Institute of Biosciences and Technology graduate student and study lead author. “These are desirable since native FGF21 has a short life in vivo when injected in primates and humans. Activating the adipocyte FGFR1 receptor with the right drugs may work even better than FGF21 in alleviating obesity.”
In the November 2012 Science Translational Medicine study, TAMHSC-Institute of Biosciences and Technology researchers, in collaboration with researchers from Amgen, Inc., showed FGFR1 together with a specific partner called beta-klotho in adipocytes is activated by a monoclonal antibody (mimAb1) developed by the Amgen group. The drug mimics the metabolic benefits of FGF21 in obese cynomolgus monkeys, which are more like humans than fat mice. The fat monkeys lost weight and body mass without reduction in their high calorie diet.
This unique drug appears highly specific for only FGFR1 complexed with beta-klotho in adipocytes, which should minimize side effects in other tissues that might contain FGFR1, Dr. McKeehan said.
“It may be the same mechanism of action by the stress-induced liver FGF21 acting on specifically FGFR1 in adipocytes during prolonged fasting that accounts for its pharmacologic benefit during obesity,” said Dr. McKeehan about the studies collectively. “During long periods between meals as in prolonged fasting or starvation, the uncoupling of the strict inverse relationship between lipid and carbohydrate extends lipid reserves without using them all up at once to maintain carbohydrates essential for brain function at peak normal levels. In contrast, under conditions of constant overeating, the uncoupling somehow prevents the continuous buildup of lipid by liver cells and adipocytes that ends up as excessive fat.”
Additional institute researchers included Fen Wang, Ph.D., CCSCB director, and Yongde Luo, Ph.D., CCSCB assistant professor.
