Diabetes Genetics
Domenico Accili, MD, Director
Dr. Accili’s research is focused on the pathogenesis of insulin resistance and its role in type 2 diabetes. The laboratory currently utilizes transgenesis, targeted mutagenesis in embryonic stem cells and gene transfer techniques to study the complex genetics of type 2 diabetes and insulin resistance. The Accili lab is located in the newly established Naomi Berrie Diabetes Center, a highly interactive scientific environment for care, prevention and research of type 1 and type 2 diabetes. The laboratory has extensive research collaborations with other research groups in the Diabetes Center, and is currently funded by the National Institutes of Health, the Juvenile Diabetes research Foundation and the American Diabetes Association. Current interests include the role of the forkhead transcription factor Foxo1 in insulin action, and especially in linking peripheral insulin action and b-cell function. Accili’s lab has recently shown that Foxo1haploinsufficiency reverses b-cell failure in mice through partial restoration of b-cell proliferation and increased expression of the pancreatic transcription factor Pdx1. Foxo1 is also emerging as the insulin-regulated transcription factor that regulates glucose-6-phosphatase, a key enzyme in the pathogenesis of diabetes.

Moreover, this laboratory is interested in examining the role of different tissues in insulin action and insulin resistance. Accili’s lab was the first to draw attention to the apparent paradox that impairment of insulin action in skeletal muscle is not sufficient to set in motion the complex metabolic abnormalities that eventuate in type 2 diabetes. To examine this aspect of insulin resistance, the laboratory is using tissue-specific rescue of insulin receptor knockout mice by transgenesis and conditional knock-ins.
Other projects in the laboratory include the role of Insulin-like growth factors in pancreatic development and b-cell function. Conditional mutagenesis using the cre-loxP system has been extensively used to address these questions.

The group has many interactions with other members of the training program. Accili and Tall have an ongoing collaboration to study insulin resistance in peripheral macrophages and how it affects foam cell formation, a key step in the progression of the atherosclerotic lesion. Similarly, Accili and Ginsberg are studying the consequences of hepatic insulin resistance on lipid metabolism, using both cultured cell line sand genetically engineered mice. The mouse models developed by the Accili lab have are also being used in studies by the Deckelbaum and Goldberg laboratories to understand the mechanisms of insulin resistance-induced lipid abnormalities. The long-term goal of this work is to examine the mechanism of insulin resistance-induced vascular abnormalities that predispose to macrovascular diseases.

Neuroendocrinology
Sharon Wardlaw, MD, Director
The basic research program focuses on the neuroendocrine control of pituitary function by the hypothalamic neuropeptides proopiomelanocortin (POMC) and corticotropin-releasing hormone (CRH) and on the regulation of POMC and CRH in the hypothalamus. Our studies on POMC regulation in the hypothalamus are proving very relevant to the obesity field as it is becoming increasing clear that obesity is a neuroendocrine disease. Recent studies show that brain POMC is an important target for leptin, which is produced by fat cells and regulates appetite and energy expenditure. The POMC-derived peptide, ?-MSH, and the melanocortin receptors have also been shown to play an important role in regulating feeding behavior and body weight. One project, therefore, focuses on the regulation of POMC gene expression, peptide processing and peptide release in the arcuate nucleus of the hypothalamus by leptin and insulin and on its interaction with the newly discovered a-MSH antagonist, agouti-related protein, which is also highly expressed in the arcuate nucleus. Transgenic mice which overexpress a-MSH and y-MSH have also been developed to further understand the role that these neuropeptides play in modulating feeding behavior, metabolic and endocrine responses. These studies are being performed in collaboration with Drs. Rudolph Leibel and Streamson Chua in the Division of Molecular Genetics. Another area of research focuses on neuroendocrine-immune interactions. Studies have been designed to elucidate how cytokines act within the brain to control pituitary and peripheral immune responses and how the neuroendocrine and immune systems interact when activated by stress or infection. A major focus is on the inflammatory cytokines and mechanisms of hypothalamic-pituitary-adrenal (HPA) activation, and on the modulation of cytokine and HPA responses to inflammation by leptin and the melanocortin system.