Neil Ruderman, M.D., D.Phil.

Fuel Sensing, Signaling, and Metabolic Syndrome Associated Diseases

Dr. Ruderman’s research deals with the effects of insulin, exercise, and fuels on cellular metabolism, signal transduction and, most recently, gene expression.  Its focus in the past twenty years has been on their regulation by AMPK and, more recently, by the sirtuins, a group of NAD-dependent histone/protein deacetylases that have many of the same biological actions as AMPK.  His group has proposed that dysregulation of the AMPK fuel-sensing mechanism is both a pathogenetic factor for many metabolic syndrome-associated disorders and a target for their therapy.  Prior studies from his laboratory have tested this theory in skeletal muscle, liver, keratinocytes, and adipose tissue using cultured cells, incubated tissues and intact animals as models.  In addition, his group is examining whether a similar dysregulation of AMPK underlies the endothelial cell dysfunction that leads to accelerated atherosclerosis and the microvascular cell dysfunction that underlies diabetic retinopathy.  Also, it has been testing the existence of a SIRT1/AMPK cycle that regulates multiple cellular functions (e.g., growth, inflammation, aging) and whether such a cycle links cellular redox and energy state.  Most recently, they have carried out an investigation that demonstrated for the first time that AMPK activity is decreased by 30-60% in adipose tissue depots of the 75% of bariatric surgery patients who are insulin resistant (but not the remaining 25% who are insulin sensitive).  In addition, they are presently carrying out serial studies of the effects of bariatric surgery on these and other parameters, including gene expression by RNA seq in the various depots.  Finally, in a collaborative effort with colleagues of East Carolina University, they are examining whether distinctive metabolic and genetic markers distinguish the offspring of insulin sensitive and resistant bariatric surgery patients and two lean control parents from each other.

The techniques employed by the Ruderman laboratory include reporter gene assays, adenoviral, lentiviral, and retroviral gene transfer (cultured vascular and other cells), immunoflouresence microscopy, protein separation, enzyme analysis, gradient PCR and real time PCR, and metabolite determination by spectrophotometric and chromatographic methods.  The models used include incubated tissues, cultured cells, intact rodents (including transgenic mice) and, as already noted, humans.  Many Boston University faculty are co-investigators in this work including Drs. Kenneth Walsh and Richard Cohen (vascular cell studies).  Collaborators from other institutions include Drs. Marc Prentki, University of Montreal (malonyl CoA and AMPK regulation); E.W. Kraegen, Garvan Institute, Australia (insulin resistance in rodents in vivo); David Sinclair, Harvard (the sirtuins); David Carling, Hammersmith Hospital, U.K. (molecular biological approaches to study AMPK action in vascular cells); Tarjei Mikkelsen, Broad Institute, Harvard (RNA seq of human adipose tissue); Joseph Houmard, Walter Pories, East Carolina (bariatric surgery patients and their offspring). The studies with Dr. Mikkelsen are supported by a BADERC grant.

References.

1. Nelson LE, Valentine RJ, Cacicedo JM, Gauthier MS, Ido Y, Ruderman NB. A novel inverse relationship between metformin-triggered AMPK-SIRT1 signaling and p53 protein abundance in high glucose-exposed HepG2 cells. Am J Physiol Cell Physiol. 2012 Jul 1;303(1):C4-C13. PMCID:PMC3404529

 

2. Ido Y, Duranton A, Lan F, Cacicedo JM, Chen TC, Breton L, Ruderman NB. Acute activation of AMP-activated protein kinase prevents H2O2-induced premature senescence in primary human keratinocytes. PLoS One. 2012;7(4):e35092. PMCID: PMC3325987

 

3. Xu XJ, Pories WJ, Dohm LG, Ruderman NB.What distinguishes adipose tissue of severely obese humans who are insulin sensitive and resistant? Curr Opin Lipidol. 2013 Feb;24(1):49-56.PMCID:PMC3575680

 

4. Laurent G, German NJ, Saha AK, de Boer VC, Davies M, Koves TR, Dephoure N, Fischer F, Boanca G, Vaitheesvaran B, Lovitch SB, Sharpe AH, Kurland IJ, Steegborn C, Gygi SP, Muoio DM, Ruderman NB, Haigis MC.SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell. 2013 Jun 6;50(5):686-98.PMCID:PMC3721068 [Available on 2014/6/6]

 

5. Ruderman NB, Carling D, Prentki M, Cacicedo JM.AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 2013 Jul 1;123(7):2764-72.PMCID:PMC3696539

 

6. Krasner NM, Ido Y, Ruderman NB, Cacicedo JM.Glucagon-Like Peptide-1 (GLP-1) Analog Liraglutide Inhibits Endothelial Cell Inflammation through a Calcium and AMPK Dependent Mechanism. PLoS One. 2014 May 16;9(5):e97554. PMCID: PMC4023984

 

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