Functional Neurocircuitry of Body Weight Control

Early studies in the area of the control of food intake and body weight were limited to destructive anatomic lesions in the brain. These studies identified regions of the hypothalamus as playing important roles. A major advancement was the discovery of ligands (leptin, a-melanocyte stimulating hormone – aMSH, ghrelin, etc.) and receptors (leptin receptors - LEPRs, melanocortin receptors – MC3Rs and MC4Rs, serotonin receptors, ghrelin receptors – GHSRs, etc.) important in controlling body weight. Through the use of neuroanatomical methods, we and many other laboratories have offered models predicting the specific neurons and neurocircuits controlling energy homeostasis.

Going forward, interventional studies aimed at directly testing the validity of these models are required. With this in mind, my laboratory has formed a large collaborative effort with Dr. Bradford Lowell. This combined research program focuses primarily, but not exclusively, on using Cre/lox technology to perturb specific genes in narrow subsets of neurons. A comprehensive program in this area requires the generation of numerous transgenic mice in which expression of cre is directed to different sub-populations of neurons and, as companions for these cre mice, mutant mice bearing “loxed” alleles of relevant genes (i.e. lox-LEPRs, lox-MC4Rs, lox-5-HT2C-Rs, lox-GHSRs, etc.). The Elmquist / Lowell collaborative effort is using state-of-the-art BAC genomic clone methodologies to transgenically drive expression of Cre to subsets of neurons (i.e. POMC-Cre, AGRP-Cre, NPY-Cre, SF1-Cre, SIM1-Cre, etc.). Mouse embryonic stem (ES) cell / gene targeting methodologies are being used to create the various loxed alleles.

The generated animals, plus those obtained from collaborators, are already being used to determine the importance of a given molecule within a narrow subset of neurons. To date, the combined efforts of the Elmquist / Lowell Research Groups have generated a number of “reagents” which are useful for determining the relative roles of various neurons, and molecules within those neurons, in regulating energy homeostasis. This collaborative, ambitious effort, which is large in scope, has the ultimate goal of establishing the functional neurocircuitry underlying coordinated regulation of body weight and glucose homeostasis. We already have a large number of mouse models to use as tools to comprehensively test these modes. Also, as evidenced by the papers listed below, this approach has already resulted in several published studies, all of which led to unexpected findings. Indeed, all demonstrate the power of this line of investigation and underscore the need to use these types of approaches in the future to understand the mechanisms by which the nervous system regulates food intake, body weight and glucose homeostasis in both health and disease.