News & Research

    University of Michigan, Ann Arbor, Michigan

Regulation of adipocyte differentiation and metabolism

General Research Subject: Type 2 Diabetes

Focus: Adipocytes

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: July 1, 2008

Project End Date: June 30, 2012

Research Description

Obesity is associated with resistance to insulin and diabetes. Thus, furthering our molecular understanding of how fat cells develop, and how their regulation is controlled will ultimately lead to additional therapeutic targets to improve treatments for obesity and diabetes. The MacDougald lab uses cell culture and animal models to analyze molecular regulatory mechanisms, mainly in adipocytes and adipose tissue. In this proposal, three research projects are proposed as potential projects for a postdoctoral fellow supported by the American Diabetes Association. These projects are focused on regulation of adipocyte differentiation and metabolism by 1) microRNAs, 2) phosphorylation of C/EBPα, and 3) Wnt signaling. Completion of these projects will provide important insight into the medical problems of obesity and diabetes, two major health risks in the United States.

Reseacher Profile

Mentor: Ormond A. MacDougald, PhD   Postdoctoral Fellow: Hiroyuki Mori, MD, PhD

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

The postdoctoral fellow will choose from several diabetes-related projects ongoing within my laboratory. These projects utilize molecular techniques to enhance our understanding of how microRNAs, Wnt signaling and C/EBP  regulate adipocyte development and metabolism. Project 1: One of our new areas of research that promises to be important for understanding adipocyte biology is regulation of gene expression by microRNAs. These small, non-protein-coding ~22-base RNA products modulate post-transcriptional gene repression by inhibiting protein translation and by destabilizing target transcripts. We have screened for microRNAs expressed in adipose tissue, with regulated expression during adipogenesis in vitro. Of the nine that we are pursuing further, two of these, miRNA378 and 422b are located in the first intron of PGC-1  and are highly induced during adipocyte differentiation in vitro and in vivo. Project 2: Based upon dramatic upregulation of secreted Frizzled-Related Protein 5 (sFRP5), a Wnt inhibitor, in adipocytes from obese mice, we will use in vitro methods and mouse models to test the hypothesis that in response to increasing adipocyte size, sFRP5 feeds-back to stimulate differentiation of new adipocytes to help store excess energy. 

Experiments will determine expression and regulation of sFRP5 during adipogenesis and under conditions that adipocyte size is altered in adipose tissue. Our analysis of sFRP5 -/- mice indicates that these mice are resistant to diet-induced obesity and adipocyte hypertrophy. Project 3: C/EBP  is an important transcription for adipocyte differentiation and metabolism and we are investigating how C/EBP  is regulated by phosphorylation. We will continue to investigate the adipose, liver and metabolic phenotypes of mice with mutated sites of C/EBP  phosphorylation . Body composition and tissue weights do not appear to be different in these mice; however, S21A mice have impaired glucose tolerance. To determine the mechanism, we will be perform euglycemic-hyperinsulinemic clamp studies, and determine flux of glucose into peripheral tissues. Completion of these projects focusing on molecular and physiological mechanisms of action for miRNAs, C/EBP , and Wnt signaling will provide important insight into the medical problems of obesity and type II diabetes, two major health risks in the United States and industrialized world.

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

This research, in itself ,will not improve the prognosis of diabetic patients. However, we study proteins and signaling pathways and processes that play very important roles in the development of fat cells, and in the ability of fat cells to respond to insulin and other metabolic stimuli. Our research into the basic mechanisms by which precursor cells turn into fat cells, and mechanisms whereby mature fat cells function within the context of the body will help pharmacologists develop drugs to improve insulin action and reduce formation of fat cells.

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

 I have had a long-standing and innate interest in metabolism, its control by hormones, and the dysregulation of metabolism associated with diabetes. Although my initial forays into this line of research followed this interest, the fact that my grandfather developed diabetes, and that a friend was recently diagnosed with type II diabetes affirms to me the importance of this research and my need to work hard and find ways to improve treatments for this disease. This award plays a critical role in the building of my research program since it allows me to pursue questions that I believe are important for our understanding of C/EBP , adipogenesis, and insulin-action.

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

Our understanding of insulin action, signal transduction, and regulation of gene expression improves almost every day. This will allow us eventually to precisely identify defects associated with diabetes and then use gene therapy and targeted designer drugs to correct the defect. In addition, we will increasingly appreciate the crosstalk between organs and tissues, and the role that this communication plays in maintaining glucose homeostasis.