Boston University Medical Campus
Medicine

The Obesity Research Center comprises faculty members from the Department of Medicine and several basic science departments at BUSM. Barbara Corkey, Ph.D., Professor of Medicine and Biochemistry, continues to serve as Director of the Obesity Research Center (ORC) at BUSM and the NIH-funded Boston Obesity Nutrition Research Center (BONRC). Center members include Stephen Farmer, Ph.D., Professor of Biochemistry and Medicine; Paul Pilch, Ph.D., Professor of Biochemistry and Biophysics; and Keith Tornheim, Ph.D., Associate Professor of Biochemistry, from the Department of Biochemistry. James Hamilton, Ph.D., Professor of Biophysics, represents the Department of Biophysics and Physiology. James Kirkland, M.D., M.Sc., Ph.D., Associate Professor of Medicine and Biochemistry, is from the Section of Geriatrics.

Dr. Corkey’s laboratory focuses on the metabolic regulation of signal transduction and energy metabolism in fat cells, β-cells, and human fibroblasts. She and her colleagues have been studying fuel-stimulated insulin secretion by the pancreatic β-cell; fuel partitioning in rat adipocytes; cytokine signaling; and Ca²⁺ transients in human fibroblasts from patients with inborn errors of fatty acid oxidation and Type 1 diabetes.

Research being conducted by Jude Deeney, Ph.D., Assistant Professor of Medicine, is designed to discern the nutrient-derived metabolic signals leading to glucose- and fatty acid-induced insulin secretion from the pancreatic β-cell. These studies entail the measurement of intracellular calcium, lipids, ATP, and other metabolites, in addition to protein phosphorylation and acylation, which may influence insulin exocytosis.

Wen Guo, Ph.D., Research Assistant Professor of Medicine, is researching the effects of fatty acids on adipocyte metabolism, including fat storage, membrane lipid modification, and preadipocyte differentiation. At the current stage, both 3T3L1 adipocytes and primary rat preadipocytes are used as fat cell models to determine the regulatory effects of dietary medium-chain and polyunsaturated long-chain (w-3/w-6) fatty acids on fat cell development. Findings from cell culture studies will be used as guidance for dietary treatment with rats as animal models. The study’s ultimate goal is to seek dietary manipulations and the underpinning mechanisms for the regulation of body weight gain.

Lina Moitoso de Vargas, Ph.D., Research Assistant Professor of Medicine, is studying pancreatic islet biology and function, particularly the role of calcium influx through voltage-dependent calcium channels in secretagogue-induced insulin secretion. Research has been, and continues to be, aided by recent developments in adenoviral gene transfer technology and the ability to express the green fluorescent protein (GFP) of the jellyfish Aequora victoria in cells, tissues, and organisms to monitor fluorescence in situ. Distinct GFP variants have been used to allow the visualization of differential gene expression by fusing them to two of the protein subunits of the voltage-dependent calcium channel that mediates the glucose-induced insulin release. New multiple-insert adenoviral vectors have been constructed; these allow the delivery and co-expression of the two differentially fluorescent-tagged channel subunits. Present studies utilize the fluorescent-tagged subunits in heterologous expression systems to conduct a thorough investigation of their functional role, as well as the molecular mechanisms underlying some of the secretagogue-induced insulin secretion pathways.

Gordon Yaney, Ph.D., Assistant Professor of Medicine, is pursuing research that deals with the generation of lipid-signaling molecules arising from the metabolism of glucose and/or complex lipids within the β-cell and their action on various cellular effect systems including protein kinase C and exocytosis.

Dr. Kirkland is focusing his research on the effects of age and fat deposit sites on adipose function. Dr. Kirkland has shown that accumulation of lipid, increases in lipogenic enzyme activities, and changes in differentiation-dependent gene expression are blunted during differentiation of preadipocytes cultured from fat deposits of old compared with young individuals, even after several generations ex vivo. Recently, he has found that expression of C/EBPα and PPARγ, key transcription factors in the preadipocyte differentiation program, declines with donor age. Overexpression of C/EBPα or PPARγ by transient DNA transfection in preadipocytes from old animals restored their capacity to differentiate.

While expression of C/EBPβ does not change with age, expression of the dominant negative inhibitor LIP isoform of C/EBPβ, which reduces expression of C/EBPα and PPARγ, increases. The goal of current work in Dr. Kirkland’s laboratory is to understand the mechanism underlying these changes in transcription factor expression with age. These studies will contribute to understanding about mechanisms of age-related changes in fat tissue function and cell differentiation.

Dr. Tornheim’s research deals with regulation of glycolysis and energy metabolism in mammalian systems. The current major project is focused on elucidating the biochemical basis of the oscillatory pattern of insulin secretion that is normally seen in vivo and in vitro and that is lost or impaired in non-insulin-dependent diabetes. The hypothesis being tested is that oscillations of glycolysis and the ATP/ADP ratio underlie the observed oscillations in intracellular free Ca²⁺ and insulin release in pancreatic islets, and that this involves the muscle isoform of the key glycolytic enzyme phosphofructokinase. In addition, Dr. Tornheim collaborates with Neil Ruderman, M.D., D.Phil., Director of the Diabetes and Metabolism Unit, and Professor of Medicine and Physiology, and his group on studies of vascular metabolism and the effects of diabetes.

The NIH-funded, multi-institutional BONRC has continued to offer educational programs and support to junior investigators. Ongoing programs include the Boston Nutrition Seminar Series, travel scholarship awards, and a pilot & feasibility program. The Center’s accomplishments culminate with a half-day program that includes a plenary session and a poster session. This year’s program was held on June 28, 2002.