UBR2

Targeting a specific enzyme in the muscle could help cancer patients preserve muscle mass and potentially prolong their survival, according to new research. Targeting a specific enzyme in the muscle could help cancer patients preserve muscle mass and potentially prolong their survival, according to research from UTHealth Houston. A study led by Yi-Ping Li, PhD, professor in the Department of Integrative Biology and Pharmacology with McGovern Medical School at UTHealth Houston, found that an enzyme known as UBR2 plays a critical role in cancer-induced muscle wasting, also called cancer cachexia. The results were published today in the scientific journal PNAS. "The findings will fill a key gap in understanding how cancer causes muscle mass and function loss," said Li, senior author of the study and a faculty member with The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences. Cancer cachexia is a complication developed in the late stages of cancer in roughly 60% of all cancer patients. Cachexia patients waste away by losing body weight, primarily due to progressive loss of muscle mass, causing respiratory and heart failure. Approximately 30% of all cancer patients die of cachexia, making the complication a major determinant of cancer survival. Historically, there has been no treatment of cancer cachexia due to poor understanding of its origins. Therefore, a key focus of Li's lab over the past two decades has been to decipher the molecular mechanisms through which cancer causes cachexia. Building upon a series of discoveries in mice, his lab recently identified the role of the enzyme UBR2. This is the key enzyme in muscle that seeks out subtypes of the contractile protein myosin heavy chain, a critical component for sustaining muscle contraction, for destruction in response to cancer. Cancer causes an increase of UBR2 in muscle, and blocking the increase of or removing UBR2 spares mice from tumor-caused muscle mass and function loss. By examining the muscle of cancer patients, researchers obtained evidence that UBR2 is increased, which is associated with loss of the specific subtype of myosin heavy chain preferentially lost in cachexia. Li said this discovery is significant for the future of cancer cachexia therapy. "We have learned in animal studies that muscle wasting in cancer hosts can be ameliorated by blocking UBR2 increase through repurposing some existing drugs," he said. "Based on the findings, we plan to conduct clinical trials for the therapy of cancer cachexia." Song Gao, PhD, former postdoctoral research fellow with McGovern Medical School, was the first author of the study. Co-authors with the Department of Integrative Biology and Pharmacology at McGovern Medical School included Yong Zhou, PhD, assistant professor, as well as former faculty members Guohua Zhang, PhD; Zicheng Zhang, MD, PhD; James Z. Zhu; and Li Li, PhD. Other co-authors were George G. Rodney Jr., PhD, and Reem S. Abo-Zahrah, PhD, both with Baylor College of Medicine in Houston; Lindsey Anderson, PhD, and Jose M. Garcia, MD, PhD, both with VA Puget Sound Health Care System in Seattle; and Yong Tae Kwon, PhD, with Seoul National University in South Korea.

Obesity is implicated in multiple diseases that send health care costs skyrocketing. It’s not just a problem for the U.S. or Western society, either. Obesity is a global epidemic affecting adults and children alike. A recent study in Science shed new light on the issue by evaluating nearly 650,000 exomes from the U.K., United States and Mexico and identifying those with strong implications for body mass or obesity. Specifically, the research team uncovered 16 rare coding variants that were highly associated with obesity (a Body Mass Index of 30 or higher) and identified one – GPR75 – as a potential target for obesity-inhibiting therapies. GPR75 is one of five G protein-coupled receptors that are expressed in the brain and affect body mass or obesity. (The others are CALCR, MC4R, GIPR, GPR151.) Although the researchers noted an overrepresentation of genes highly expressed in the hypothalamus, the protein-truncating variants in GPR75 were prevalent at a ratio of only 4 per 10,000 people sequenced, making them rather rare. Digging deeper, the researchers found that GPR75 was associated with a 54% lower risk of obesity. People in whom it was highly expressed had a BMI that was 1.8kg/m2 lower and weighed 5.3 kg (nearly 11.7 pounds) less than those without this receptor. (BMI is calculated by determining a person's weight in kilograms divided by the square of his or her height in meters.) In mice with a high-fat diet, knocking out GPR75 resulted in weight gains that were 44% less than in wild-type mice. The knockout mice also had better glycemic control and insulin sensitivity than the wild-type. Protein-truncating variants of GIPR and two missense alleles also were linked to a resistance to obesity. In terms of increasing obesity risk, the researchers identified protein-truncating variants in CALCR. The risk of obesity more than doubled for protein-truncating variants of UBR2, ANO4, and PCSK1, they found. The research team was composed of 62 scientists from throughout the world, and was led by Parsa Akbari of Regeneron and Ankit Gilani of New York Medical College. The repercussions of these findings could one day be profound, given the enormity of the situation. The World Health Organization (WHO) says obesity has tripled since 1975, for children as well as adults. Globally, nearly half the obese children under age five live in Asia. Even in Africa, obesity has increased almost 24% among children under age five. In the next older group, those between ages 5 and 19, incidence of obesity has increased globally from less than 1% in 1975 to 6% of girls and 8% of boys in 2016, according to the WHO. For adults, it reported, “About 13% of the world’s adult population (11% of men and 15% of women) were obese in 2016.” In the U.S., according to the Centers for Disease Control & Prevention (CDC), more than 43% of adults were considered obese in 2018. Like waistlines, the trend toward fattiness appears to be growing, and contributes to increases in heart disease, stroke, type 2 diabetes and certain cancers. In fact, the CDC says obesity is the leading cause of preventable, premature death in the U.S. It also accounts for a hefty chunk of health care costs. Current data is scarce, but one headline-grabbing estimate in 2012 from the Journal of Health Economics attributed total spending on obesity-related health care – including time lost from work – at $190 billion. That’s double the 2005 estimates. For individuals, obesity increases annual health care costs by 14.3%, according to research in the Journal of General Internal Medicine. By 2030, unless obesity trends decline, obesity could cost the U.S. healthcare system between $48 billion and $66 billion per year, according to a 2011 projection in Lancet. With such predictions, obesity is a particularly relevant topic of research as researchers seek ways to regulate fat production in the body. For example, another recent report in Science focused on energy storage within cells. A study led by Nehemiah Cox at Memorial Sloan Kettering Cancer Center found that adipose-resident macrophages appear to use a conserved mechanism to regulate energy storage in adipocytes. His team found that “a macrophage-derived growth factor, Pvf3, and its receptor on fat body cells are needed for lipid storage in fruit fly larvae.” That finding also applied to mice and the Pvf3 ortholog, PDGFcc. When PDGFcc (which mice need to store fat) was blocked, the mice ate and absorbed food normally, but they used more energy. The reason, Cox and colleagues wrote, was partially because of enhanced brown adipose tissue thermogenesis. This finding ultimately may contribute to research on ways to combat obesity. Commenting on the implications of this work, Conan J.O. O’Brien and Ana Domingoes, both of Oxford University, explained that, “Recruited monocyte-derived macrophages have long been implicated in promoting the adipose tissue inflammation and metabolic diseases associated with obesity…but a defined role for adipose tissue–resident macrophages in energy storage has remained elusive. This study introduces a new, macrophage-centered paradigm in metazoan energy storage.” Given the global population’s trending fattiness and the ensuing health problems, it’s no wonder researchers are eager to understand the role of genetics in affecting obesity.