News & Research

    Texas AgriLIFE Research, College Station, Texas

microRNA regulation of insulin resistance: a miR-223-PPARgamma circuit regualted adipose tissue macrophage polarization

General Research Subject: Insulin Resistance Pre Diabetes

Focus: Immunology, Insulin Action\Insulin Resistance, Obesity\Animal Models

Type of Grant: Junior Faculty

Project Start Date: January 1, 2013

Project End Date: December 31, 2015

Research Description

Macrophage-mediated adipose tissue inflammation critically contributes to the development of insulin resistance, which is a causal factor of a wide variety of metabolic diseases including type 2 diabetes and cardiovascular diseases. Compelling evidences suggest that miRNAs, a group of small non-coding RNAs, are key regulators for cell fate determination and contribute to the pathogenesis of complex diseases including obesity-associated metabolic diseases. Therefore, targeting the miRNAs in macrophages to inhibit macrophage-mediated inflammation could offer a novel approach to preventing and/or treating insulin resistance and insulin resistance-associated diseases, such as type 2 diabetes and various cardiovascular diseases.

Dr. Zhou's group recently identified a novel regulator of adipose tissue macrophage activation, miR-223. However, it is completely unknown about how miR-223 regulates macrophage activation, specifically inflammatory or anti-inflammatory responses, which is a crucial factor modulating systemic insulin resistance. Recent preliminary results obtained by Zhou's group suggest an important regulatory circuit consisting of miR-223 and PPARgamma, a master regulatory signaling pathway in insulin resistance, in controlling macrophage functions in the context of obesity associated adipose tissue inflammation and insulin sensitivity. Thus, it is of great importance to determine the exact role of miR-223 and to dissect the networks governing by this microRNA in macrophage function and subsequent obesity-associated adipose tissue inflammation.

The proposed study will illustrate a new microRNA-based paradigm of the regulation of insulin sensitivity and provide the basis for using miR-223 analogs/mimetics for development of novel therapeutic strategies to treat insulin resistance-related diseases, such as type 2 diabetes and atherosclerosis.

Research Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?

My project will elucidate a novel mechanism of how immune cells, such as macrophages, contributing to the development of type 2 diabetes. Adipose tissue macrophages regulated adipose tissue inflammation is an important factor to the development of insulin resistance, which is the hallmark of type 2 diabetes and a causal factor of a wide variety of metabolic diseases. Compelling evidences suggest that miRNAs, a group of small non-coding RNAs, are key regulators for cell fate determination and contribute to the pathogenesis of complex diseases including obesity-associated metabolic diseases. Therefore, targeting the miRNAs in macrophages to inhibit macrophage-mediated inflammation could offer a novel approach to preventing and/or treating insulin resistance and insulin resistance-associated diseases, such as type 2 diabetes and various cardiovascular diseases.

This project will determine the exact role of miR-223 and to dissect the networks governing by this microRNA in macrophage function and subsequent obesity-associated adipose tissue inflammation.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

My group recently identified a novel regulator of adipose tissue macrophage activation, miR-223. (how did your study show or how your study would show that miR-223 has the potential to treat type 2 diabetes?) However, it is completely unknown how miR-223 regulates macrophage activation, specifically inflammatory or anti-inflammatory responses, which is a crucial factor modulating systemic insulin resistance.

This project will illustrate a new microRNA-based paradigm of the regulation of insulin sensitivity and provide the basis for the development of novel therapeutic strategies to treat insulin resistance-related diseases, such as type 2 diabetes and atherosclerosis.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?

Diabetes is one of the leading causes of mortality in the United States and worldwide. The prevalence of type 2 diabetes is tightly correlated with obesity. Immune cells, especially macrophages, play crucial roles not only to change the microenvironment of host tissues, but also directly contribution to how the whole metabolic system responding to nutrients. My group has extensive experience in the regulatory role of miRNAS in immune cells.  We recently identified that a microRNA, miR-223, is a potent regulator for adipose tissue macrophage activation and subsequent insulin resistance. This finding suggests that microRNAs regulated macrophage function is a crucial regulator in the obesity associated metabolic disorders, including type 2 diabetes. My long-term career goal in research is to elucidate the interaction between leukocyte mediated inflammation and diabetes development so that evidence-based novel approaches can be applied to develop new therapeutic methods to treat metabolic related diseases, including diabetes.

With the support of the Junior Faculty Award (JFA) from ADA, I will be able to investigate the unique effects of microRNAs in controlling macrophage activity and determining the interaction of macrophage and adipocytes in the context of diabetes development and insulin sensitivity.  Moreover, this award will also enable me to work closely with experts in the fields to discover new answers to what control the development of diabetes and how we can find new solutions to fight again it efficiently.

In what direction do you see the future of diabetes research going?

A major question we are facing is to understand how obesity contributes to the development of type 2 diabetes and how obesity induces tissue inflammation, which in turn leads to insulin resistance. The answer to this question requires our in-depth understanding of how exactly immune cells function and how they interact with host tissues. Most of current insulin-sensitizers and anti-diabetic drugs focus on improving diabetic symptoms, but not curing diabetes. Understanding how insulin resistance development is regulated with the respect of obesity induced inflammation will provide new direction for the design of new preventative and therapeutic strategies against this most prevalent disease.