Michael J. Griffin, Ph.D.

Assistant Professor of Biochemistry


Midwestern University

Arizona College of Osteopathic Medicine
Department of Biochemistry
Agave 201-X4
19555 N. 59th Ave
Glendale, AZ 85308
Office: (623)-572-3707
E-mailmgriffin@midwestern.edu

EDUCATION

RESEARCH SUMMARY

Obesity continues to represent a major health issue in the US and other developed countries, and often goes hand-in-hand with a state of chronic inflammation in the adipose tissue. This inflammation is thought to be directly responsible for precipitating many of the diseases associated with obesity, especially insulin resistance, diabetes, and coronary heart disease. Understanding the mechanisms through which chronic over nutrition leads to inflammation in fat cells is a major topic in the field and the major interest of the lab. I have discovered that a single gene, called Early B-Cell Factor-1 (Ebf1), appears to promote broad inflammatory signaling in cultured fat cells in vitro; adipocytes deficient in Ebf1 have a severely impaired response to an inflammatory stimulus. This suggests that Ebf1 could eventually represent a therapeutic target for the treatment of obesity-associated chronic inflammation. However, numerous questions remain, including 1) What is the effect of Ebf1 deletion on fat cell inflammation in vivo (i.e., in a living animal consuming a high-fat diet? 2) What proteins does Ebf1 interact with to regulate inflammatory gene expression? And 3) What is/are the mechanism(s) through which Ebf1 regulates target gene expression (since previous data suggests that Ebf1 does not bind directly to major loci involved in inflammation).

In addition, our lab is interested in identifying phytonutrients that can potentially inhibit adipocyte inflammation in a cell-autonomous manner. Several cell culture and animal models have suggested that various phytonutrients can inhibit inflammation in other systems, and we aim to determine whether they can attenuate adipose inflammation in the context of high-fat diet-induced obesity in animal models. Examples of phytonutrients that we are planning on studying include sulforaphane (found in broccoli), EGCG (found in Green Tea), and bromelain (found in pineapple). The hope is that eventually our findings may lead to intervention trials in humans, such that supplementation of phytonutrients may be able to ease adipose inflammation in the obese even without significant weight loss.

Research projects

Project I: Role of Ebf1 In Adipocyte Inflammation. This project is divided into three specific aims:

1)  Determine the role of Ebf1 in adipose tissue inflammation in vivo-here, we will use mice that are deficient in Ebf1, but only in fat cells. We call these Adipose-Specific Ebf1-KnockOut (ASEKO) animals. (Whole-body Ebf1 knockouts are perinatal lethal on the C57/Bl6 background). Our working hypothesis is that these mice will be protected from high-fat diet-induced adipose inflammation during obesity, in an adiposity-independent manner (i.e., without significant weight loss). To examine our hypothesis, we will perform a variety of tests on these mice, including adipose expression of inflammatory cytokines, glucose and insulin tolerance tests, insulin signaling in liver, muscle, and fat, and macrophage infiltration assays.

2)  Identify the interaction partners of Ebf1 in adipocytes. This aim is a discovery-driven, unbiased approach towards 'fishing out' Ebf1-interacting proteins in adipocytes. Although the function of Ebf1 as a transcriptional regulator has been well-described, very little is known about its interaction partners, especially in mature adipocytes. This approach could yield novel, adipocyte-Ebf1 protein complexes and will help to gain insight into how Ebf1 regulates gene transcription in fat cells. 3)     

3)  Identify the mechanism(s) through which Ebf1 regulates inflammatory gene transcription. Although the expression of inflammatory signaling genes in Ebf1-deficient adipocytes are severely reduced, curiously, Ebf1 does not appear to bind directly to most of these loci (as evidenced by global ChIP-Seq analysis), suggesting that Ebf1 works through one or more unknown downstream transcriptional regulators. To identify such proteins in an unbiased manner, we will examine open chromatin regions in a genome-wide manner (using a technique called FAIRE-Seq), comparing 'normal' vs. 'Ebf1-deficient' adipocytes. This is expected to identify several transcriptional regulators that mediate the action of Ebf1 on inflammatory gene expression, and will shed light on the epistatic mechanisms through which Ebf1 regulates gene expression in adipocytes.

Project II: Identification of phytonutrients that can attenuate adipocyte inflammation. This is a de novo project designed to determine whether certain phytonutrients can inhibit lipopolysaccharide (LPS)- or Tumor Necrosis Factor-α (TNF-α)-induced inflammation in cultured 3T3-L1 adipocytes. If positive results are obtained, we will move forward with diet studies in mice to determine whether supplementation of the selected phytonutrient can attenuate inflammation in the context of high-fat diet-induced obesity. We will also attempt to determine the mechanisms of action for these compounds; for instance, by covalently linking the phytonutrient molecule to a solid-state resin (i.e., agarose beads), 'fishing-out' interacting proteins, and determining their identities by mass spectrometry. Eventually, this data could be used to design or make recommendations for human intervention trials, and could be a useful adjunct therapy for obese individuals who experience difficulty with sustained exercise and/or weight loss. 

RECENT PUBLICATIONS

Identification of nuclear hormone receptor pathways causing insulin resistance by transcriptional and epigenomic analysis.
Kang S, Tsai LT, Zhou Y, Evertts A, Xu S, Griffin MJ, Issner R, Whitton HJ, Garcia BA, Epstein CB, Mikkelsen TS, Rosen ED.Nat Cell Biol. 2015 Jan;17(1):44-56

Early B-cell factor-1 (EBF1) is a key regulator of metabolic and inflammatory signaling pathways in mature adipocytes.
Griffin MJ, Zhou Y, Kang S, Zhang X, Mikkelsen TS, Rosen ED.J Biol Chem. 2013 Dec 13;288(50):35925-39.

Regulation of early adipose commitment by Zfp521.
Kang S, Akerblad P, Kiviranta R, Gupta RK, Kajimura S, Griffin MJ, Min J, Baron R, Rosen ED.PLoS Biol. 2012;10(11)

OTHER PUBLICATIONS