Over the past decade, two startling health statistics have captured widespread public attention: first, that all children born in the year 2000 face a one in three chance of developing diabetes during their lifetime and second, that nearly one third of the US population is overweight or obese. Although sedentary habits, high fat diet, and altered sleep-wake patterns have been implicated, how environmental and genetic factors interact in the development of diabetes and obesity is still uncertain. Recent evidence suggests that pathways within the brain also play a critical role in the regulation of organismal energy balance and in peripheral fuel utilization. Our group studies the molecular links between neural circuits coordinating feeding behavior, sleep and wakefulness with systems important in peripheral fuel utilization, including the insulin-signaling pathway. There are two overarching themes in our research:
<strong>1: Transcriptional and posttranslational interactions between circadian and metabolic gene networks in the development of diabetes and obesity: </strong>
Recently we discovered that mutation of the gene encoding the transcription factor CLOCK, present within both brain and in peripheral metabolic tissues, leads to altered sleep, feeding activity, obesity and diabetes (Science 2005). These studies prompted us to search for targets of the Clock gene network within appetite centers of the brain and within peripheral tissues involved in lipid and carbohydrate utilization. We exploit both genetic and biochemical methods to elucidate mechanisms linking circadian and metabolic systems to processes ranging from beta-cell insulin secretion to neural regulation of appetite. Understanding the pathways that link circadian activity, sleep, feeding and metabolic homeostasis, and delineating the impact of changes in each parameter on the whole organism will hopefully bring us one step closer to a unified "systems" map of metabolic disease.
<strong>2: Genetic and genomic analysis of glucose metabolism and insulin resistance:</strong>
We have developed genetic and genomic tools to evaluate targets involved in the regulation of body weight, glucose and lipid metabolism in vertebrates. One approach has been to use "reverse" gene targeting to create new diabetes "knock-in" mice in which human mutations have been introduced into the mouse genome. The new humanized diabetic mice that we have generated reconstitute the human disease but also lead to new surprises that we are now pursuing at multiple levels, ranging from whole animal studies to interrogation of tissue, cell and molecular pathways important in both beta-cell function and insulin action. These studies are conducted in parallel with analyses of factors regulating insulin receptor signaling and trafficking. Gene knock-in and cell-based platforms provide new approaches to correlating genotype with phenotype in human insulin resistance syndromes.
We have also developed two unbiased experimental systems to search for new genetic susceptibility factors for diabetes and obesity. The first project involves analysis of over 30 of the major inbred genetically-identical mouse strains to identify regions of the genome in these animals that give rise to differences in glucose, lipid, insulin, leptin and body weight and involves interactions with the Genomics Institute of the Novartis Foundation (La Jolla). The second unbiased genetic approach involves the generation and cloning of novel diabetes genes in the mouse using deliberate chemical mutagenesis. This latter approach has led to our development of multiple novel diabetic models that we are currently analyzing using meiotic mapping and metabolic analyses. Together, our genomics and genetic strategies establish powerful new screens for diabetes target and pathway discovery that will provide many opportunities for the development of small molecule and protein-based treatments.