Elmquist, Joel Keith
Identification of central serotonergic pathways that regulate energy and glucose homeostasis
General Research Subject: Obesity
Focus: Genetics\Type 2 Diabetes, Integrated Physiology\Regulation of Food Intake, Obesity\Pathogenesis
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2011
Project End Date: June 30, 2015
Serotonin acts as a neurotransmitter in the brain and signals through fourteen serotonin receptors. Drugs that globally elevate serotonin signaling in the brain suppress food intake and ameliorate diabetic symptoms; however, the underlying mechanisms through which serotonin exerts anti-obesity and anti-diabetes effects remain to be defined. The studies proposed in this application will use unique mouse models in which we can specifically manipulate serotonin receptors and explore the neural pathways that mediate serotonin's actions on energy and glucose balance. These studies will not only help better understand the mechanisms through which serotonin regulates food intake and glucose balance, but also may provide more refined pharmacological targets for the treatment of diabetes and obesity.
Mentor: Elmquist, Joel, DVM, PhD Postdoctoral Fellow: Sohn, Jong-Woo
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Obesity is a primary cause of many disease entities collectively referred to as the metabolic syndrome, which includes type 2 diabetes. The neurotransmitter serotonin has been shown to decrease body weight and lower blood glucose, but the underlying mechanisms are still unclear. We recently described an important role of serotonin receptors in a specific subpopulation of hypothalamic neurons (POMC neurons) in regulating energy and glucose balance, and clarified the cellular mechanisms by which serotonin receptors affect those neurons. We now intend to focus on the role of serotonin receptors on different types of central neurons in forebrain and hindbrain. We will delete or reactivate serotonin receptors specifically in these neurons and evaluate the metabolic changes by these genetic manipulations. In addition, involvement of ion channels, which are important in determining neuronal excitability, in mediating serotonin effects in these neurons will be evaluated using electrophysiology. By illustrating the cellular mechanisms for serotonin-induced antiobesity and anti-diabetic effects, this project will further facilitate applications of serotonin and analogs in the treatment of obesity and diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Since type 2 diabetes is frequently associated with obesity, the control
of body weight is essential for preventing and treating diabetes.
Unfortunately, the availability of effective anti-obesity drugs is very
limited. For example, d-fenfluramine (d-FEN) was widely prescribed and
was clinically effective to combat diabetes in the 1990s. However, the
drug was withdrawn from clinical use due to adverse cardiopulmonary
events. Since it is known that serotonin receptors contribute to the
anorexigenic effects of d-FEN, identification of serotonin-regulated
brain sites and elucidation of cellular mechanisms through which
serotonin mediates its anti-obesity and anti-diabetic effects may lead
development of new drugs with fewer side effects for the treatment of obesity and diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
We have long been investigating on the role of brain in regulating food intake, body weight, energy expenditure and glucose metabolism. Our research has focused on the identification of specific types of central neurons responsible for energy homeostasis and glucose metabolism regulation by specific hormones or neurotransmitters. Importantly, central serotonergic pathways regulate both energy homeostasis and glucose metabolism. Therefore, identification of brain sites and the cellular mechanisms responsible for central serotonin action will provide novel insights in comprehensive understanding of energy homeostasis and glucose metabolism. This award will certainly facilitate our research by supporting these efforts.
In what direction do you see the future of diabetes research going?
Accumulating evidence suggests that type 2 diabetes may be caused by altered responsiveness of key hypothalamic neurons to metabolic cues such as serotonin, leptin, ghrelin, insulin, glucose, fatty acids and other neurotransmitters. However, direct experimental evidence linking the onset of type 2 diabetes and hypothalamic resistance to key neurotransmitters and metabolic cues is still missing. We strongly believe an understanding of the central serotonergic pathways maintaining metabolic and glucose homeostasis will be required for the clinical management of type 2 diabetes.
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