by UT Southwestern Medical Center
Secondary structure of long non-coding RNA Snhg9. (A) Secondary structure of Snhg9 RNA predicted by RNAfold (49) with nucleotide positions indicated. (B) Locations of nucleotide deletions analyzed in Fig. 2E. Credit: Science (2023). DOI: 10.1126/science.ade0522
Bacteria that live in the intestines inhibit a molecule that limits the amount of fat absorbed, increasing weight gain in mice fed a high-sugar, high-fat diet, researchers from UT Southwestern Medical Center report. The findings, published in Science, could eventually lead to new ways to combat obesity, diabetes, and malnutrition—health problems that plague hundreds of millions worldwide.
"We know that there are big differences in the composition of the gut microbiome between lean and obese mice, as well as lean and obese people. The question we've been grappling with is, does our microbiome cause metabolic changes that promote obesity, and if so, what are the molecular causes? This study paints part of that picture," said Lora Hooper, Ph.D., Professor and Chair of Immunology, Professor of Microbiology, a member of the Center for the Genetics of Host Defense at UT Southwestern, and a Howard Hughes Medical Institute Investigator. Dr. Hooper co-led the study with Yuhao Wang, Ph.D., a former UTSW graduate student and postdoctoral researcher in the Hooper lab who is now a faculty member at Zhejiang University in Hangzhou, China.
Researchers have long known that "germ-free" mice, which have no gut microbiome and are maintained in sterile colonies, tend to be leaner than mice with gut microbes, especially when fed a Western-style high-sugar, high-fat diet. Searching for reasons why, Drs. Hooper and Wang and their colleagues used RNA sequencing to compare gene expression in the small intestines of germ-free mice and "conventional" counterparts with typical gut bacteria.
The team homed in on a gene called Snhg9, which produces a long, noncoding RNA whose function was unknown. A series of experiments showed that the RNA molecule produced by Snhg9 binds to a protein called CCAR2, setting off a molecular cascade that prevents dietary fats from being absorbed by the cells that line the intestine. Additional investigation showed that the intestinal cells that produced this RNA decreased its synthesis when they were alerted to the presence of gut microbes through a feedback loop governed by the immune system.
In germ-free mice and mice genetically altered to produce extra Snhg9 RNA, the process kicked off by this molecule protected them from becoming obese, even on a Western-style diet. Additional tests showed these animals weren't absorbing as much dietary fat as wild-type mice. However, mice genetically altered to lack Snhg9 gained excess weight on the high-sugar, high-fat diet, even when their gut microbes were killed off with antibiotics.
Together, the findings—which follow a 2017 paper led by Drs. Hooper and Wang that identified a molecular "accelerator" for lipid absorption and metabolism—help solve the mystery of how the microbiome regulates metabolism in host organisms. The discovery could eventually lead to ways to manipulate this interaction to prevent or treat metabolic diseases. For example, Dr. Hooper said, researchers may eventually be able to treat malnutrition by inhibiting Snhg9 or treat obesity by mimicking Snhg9 function with pharmaceuticals.
More information: Yuhao Wang et al, The gut microbiota reprograms intestinal lipid metabolism through long noncoding RNA Snhg9, Science (2023). DOI: 10.1126/science.ade0522
Journal information: Science
Provided by UT Southwestern Medical Center
by Yale University
Cancer-related fatigue (CRF) is a debilitating yet all-too-common condition, which can severely affect quality of life for patients undergoing treatment. For those struggling with CRF, there have been no effective pharmaceutical treatments for the constellation of symptoms that together define the syndrome.
In a new study led by Yale Cancer Center researchers at Yale School of Medicine, the team found that a metabolism-targeting drug called dichloroacetate (DCA) helped alleviate CRF in mice, without interfering with cancer treatments. The findings are a pathway for future CRF research that may someday lead to a new therapy for patients.
The results were published in American Journal of Physiology-Endocrinology and Metabolism on Oct. 2.
"This study identifies dichloroacetate, an activator of glucose oxidation, as the first intervention, and particularly the first metabolism-focused intervention, to prevent the whole syndrome of cancer-related fatigue in preclinical models," said senior author Rachel Perry, who is a member of Yale Cancer Center.
Researchers used tumor-bearing mouse models to investigate the effectiveness of DCA in treating cancer-related fatigue for patients living with melanoma. The group found that DCA did not affect the rates of tumor growth or compromise the effectiveness of immunotherapy or chemotherapy in two mouse cancer models. DCA also significantly preserved physical function and motivation in mice with late-stage tumors.
The data suggests that DCA treatment may have several positive effects, including reducing oxidative stress in muscle tissue of tumor-bearing mice. The researchers said DCA could be a practice-changing approach in the future, when used as an adjuvant therapy to treat cancer-related fatigue.
"We hope that this research will provide the bedrock for future clinical trials using dichloroacetate—an FDA-approved drug for another indication (lactic acidosis)—to treat the debilitating syndrome of cancer-related fatigue," said Perry, who is also an assistant professor of medicine (endocrinology) and of cellular and molecular physiology at Yale School of Medicine.
Perry was joined by Yale first author Xinyi Zhang.
More information: Xinyi Zhang et al, Dichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma, American Journal of Physiology-Endocrinology and Metabolism (2023). DOI: 10.1152/ajpendo.00105.2023
Provided by Yale University
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