Circuitries Involved in the Regulation of Energy Homeostasis: View from the Chair

Abstract

A simple perusal of the wonderful illustrations in the Netter Atlases showing the effects of various hypothalamic lesions on food intake and energy homeostasis makes it very clear that there exists a long history of research directed toward understanding the integrated central nervous system (CNS) circuitries through which the brain is able to achieve such a precise balance of energy intake with energy requirements. The second session of this symposium is four presentations on the “Neurobiology of Obesity,” highlighting some very exciting new technologies and some very important considerations that will clearly need to be a part of the continued effort to understand not only how the brain achieves this balance under normal circumstances, but ultimately to identify the pathological changes that lead to the many clinical abnormalities associated with abnormal regulation of energy homeostasis. Many presentations at this meeting emphasized the potential importance of neurons in the arcuate nucleus to the regulation of feeding and metabolism. Harvey Grill convinced at least this part of the audience that, despite the recognized roles of this hypothalamic region, the “arcuate model” does not take into account the very extensive evidence, suggesting important roles for other hypothalamic, medullary, and midbrain centers in contributing to a “distributed system” for control of energy balance. Interesting reversed parallels exist here in the literature describing neural mechanisms of cardiovascular control. Thus, the medullary dorsal vagal complex was for many years thought to be the primary dominant cardiovascular control center. Our understanding of this system has now evolved to a clearer perspective, which, while still recognizing important roles for this region of the brain, has also identified the additional sophistication of this control system associated with the contributions of midbrain, hypothalamic, and even cortical cardiovascular control centers. A variety of techniques (lesion, stimulation, recording, imaging, and more recently, knockout animals) have been used in attempts to understand the roles of specific neuronal subgroups (anatomical or chemical) in the control of energy homeostasis. These studies, while providing important information, have suffered from many difficulties of interpretation including those associated with fibers of passage, anatomical vs. functional subgroups of neurons; multiplicity of systems directed toward essential “end points,” developmental vs. adult functions in genetically modified animals, and in vivo compared with in vitro effects. Dr. Nina Balthasar’s paper in this supplement describes her recent work using sophisticated modern genetic tools to conditionally compromise the function of very specific neuronal subgroups involved in energy homeostasis and, thus, permit very precise analysis of the contributions of very specific components of the integrated neuronal circuitry. In this work, by specifically targeting leptin receptor knockout on proopiomelanocortin (POMC) neurons, she suggests that the relatively mild obesity that results (only 20% of that observed in full-blown leptin receptor or leptin gene knockouts) argues persuasively that leptins’ role in regulation of this population of neurons cannot be the primary determinant leading to the development of obesity. Similar observations (partial development of obesity) for leptin receptor knockout specific to agouti-related peptide (AgRP) arcuate neurons or steroidogenic factor 1–expressing neurons in the ventromedial hypothalamus similarly argue in favor of multiple sites of action for central leptin in controlling body weight. Similar conclusions emerge from a second equally elegant set of melanocortin-4 receptor (MC4R) manipulations. Knockout mice were developed without the MC4R receptor, which was reinserted specifically into the hypothalamic paraventricular nuclei/amygdala by selective reactivation by Cre-recombinase, whose expression is driven by the Sim-1 promoter. In this case, while these animals showed reversal of the effects of MC4R knockout on food intake (no hyperphagia), effects on energy expenditure remained and could not be normalized by the melanocortin receptor agoDepartment of Physiology, Queen’s University, Kingston, Ontario, Canada. Address correspondence to Alastair V. Ferguson, Department of Physiology, Queen’s University, Kingston, Ontario, Canada K7L 3N6. E-mail: avf@post.queensu.ca Copyright © 2006 NAASO