Novel studies identify small RNAs connecting inflammation and obesity

Obesity, a prevalent threat among one-third of the adult population in the United States, is associated with cardiovascular disease and metabolic disorders such as diabetes.  A major contributor to this danger is inflamed adipose tissue, or body fat.  A recent study by a team at the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM) indicates that small RNAs, or microRNAs (miRNAs), which are part of a person's genetic code, can guide inflammatory or anti-inflammatory action of macrophages - a special type of cell - in the adipose tissue that are crucial for our immune defense and important regulators once permeated into tissues. The study, led by Dr. Beiyan Zhou, assistant professor of physiology and pharmacology at the CVM, was recently accepted for publication by Circulation, the leading journal of the American Heart Association (AHA).

Macrophages are a type of immune cell which often responds to infections or wound repairings.  Zhou said the study focuses on understanding how microRNA influences these cells when regulating the "good" and "bad" fat cells.

Cong Meng, a graduate student in Zhou's laboratory and the co-first author of the article, said  adipose tissue infiltrated by macrophages can be polarized to M1,"bad," and M2,"good," macrophages.

Zhou said macrophages in fat tissues act in a protective, anti-inflammatory role in people who are not obese.  For those that are obese, or have plaque on their blood-vessel walls, macrophages infiltrate the tissues, try to correct the problem, and become inflamed.

"Both M1 and M2 macrophages are regulators in atherosclerotic lesions that play a critical role in the development of cardiovascular diseases. One miRNA can regulate many genes simultaneously. By harnessing one-crucial miRNA, you can shift the network to either direction: inflammatory or anti-inflammatory," said Guoqing Zhuang, the co-first author for this study and postdoctoral fellow in Zhou's lab.

Xin Guo, a graduate student in Assistant Professor Chaodong Wu's laboratory in the Department of Nutrition and Food Sciences at Texas A&M College of Agriculture and Life Sciences, validated the adipose tissue signaling pathways.

"In this study, we demonstrated that miR-223 is a novel and crucial regulator of macrophage polarization and is indicated for suppressing pro-inflammatory and enhancing anti-inflammatory responses," Guo said.

Dr. Stephen Safe, collaborator on the study and professor at the CVM, said the results hold great promise in the development of treatments for metabolic disorders.

"This study has identified a new microRNA-based paradigm for regulation of insulin sensitivity," Safe said. "The results may ultimately provide the basis for using microRNA analogs or chemicals for microRNA regulated genes to treat insulin resistance-related diseases," he added.

While this study represents a starting point in developing new therapeutic drugs for diabetes, Dr. Robert Chapkin, collaborator on the study and a Regent Professor in the Department of Nutrition and Food Sciences, explained there is currently a need for new drugs since most are no longer sold due to severe side effects.

"Their highly novel finding suggests that because macrophages play an important role in mediating metabolic disorders including obesity-induced insulin resistance, that microRNA-223 may be a metabolic target for therapies designed to regulate systemic inflammation and energy metabolism," he added.

The paper sparked positive feedback from the science community including an editorial introduction (published on the same issue of Circulation) by Dr. Jiandie Lin from the University of Michigan.

"Previous studies have implicated different miRNA members in the regulations of innate and adaptive immune responses as well as immune cell differentiation," Lin said. "However, a role for miRNA in macrophage polarization has not been explored and this research is the first one to link macrophage function and obesity related diseases."

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