Barbara Kahn, M.D.

1.  Retinoid biology, insulin resistance and the “Metabolic syndrome”.  Dr. Kahn’s Lab made mice with “knockout” or overexpression of the GLUT4 glucose transporter selectively in adipose tissue.  Characterization of these mice led to novel insights including the important role of adipocytes in regulating glucose homeostasis and insulin sensitivity through the secretion of hormones, cytokines and other factors. Using DNA array analysis of gene expression in adipocytes from these mice, we identified retinol binding protein 4 (RBP4) as a novel adipocyte-secreted molecule that regulates insulin action in muscle and liver. The lab showed that transgenic or pharmacologic approaches to increase RBP4 in mice cause insulin resistance and lowering RBP4 confers enhanced insulin sensitivity even in obese mice. The lab demonstrated that serum and adipose (especially visceral fat) RBP4 levels are elevated in insulin resistant humans with obesity and type 2 diabetes, and the extent of elevation correlates highly with insulin resistance, intra-abdominal fat mass and cardiovascular risk factors including dyslipidemia and hypertension.  The Kahn lab is now investigating the molecular mechanisms for the effects of RBP4 at the level of gene expression, signal transduction and metabolism.  

2.  Discovering novel adipocyte molecules that alter insulin sensitivity.  From the same DNA array studies described above Dr. Kahn’s lab identified and validated other novel molecules expressed in adipoctyes which could be involved in adipocyte function and systemic insulin sensitivity.  The lab is determining how these novel adipocyte molecules alter insulin action systemically.

3.  Identifying neuronal pathways underlying the effects of Protein Tyrosine Phosphatase 1B (PTP1B) on insulin sensitivity and adiposity.  Protein tyrosine phosphatases attenuate insulin signaling leading to insulin resistance. The Kahn lab with Ben Neel’s lab showed that absence of PTP1B in all tissues or selectively in the brain results in increased insulin and leptin sensitivity and resistance to obesity on a high fat diet. Dr. Kahn’s lab is now studying mice lacking PTP1B in specific hypothalamic neuronal populations to identify the neuronal pathways responsible for the effects of PTP1B on insulin and leptin action, body weight regulation and glucose homeostasis.  These studies will also shed light on recent data indicating that the neural circuitry regulating adiposity may diverge from that controlling glucose homeostasis and insulin sensitivity.

4.  Role of the AMP-activated protein kinase (AMPK) in hormonal and nutrient regulation of energy balance.
AMPK is a “metabolic master switch” and a fuel sensor pathway. Dr. Kahn’s lab discovered that key metabolic effects of leptin in peripheral tissues such as stimulation of fatty acid oxidation, as well as leptin effects in the hypothalamus on food intake and energy balance are mediated by AMP kinase.  Leptin and other anorexigenic hormones and nutrients inhibit AMPK activity in specific hypothalamic nuclei and orexigenic peptides activate it.  Furthermore, activation of AMPK in hypothalamic nuclei is sufficient to stimulate appetite and increase body weight and inhibition of AMPK is necessary for leptin’s anorexigenic effects. In obese, leptin-resistant states, AMPK regulation in the hypothalamus and peripheral tissues is impaired. Studies now aim to identify the specific neuronal pathways involved in the effects of AMPK on food intake and adiposity, and the molecular mechanisms for these effects.  These studies will provide critical insights into the signaling circuits that mediate hormonal and nutrient regulation of energy balance.