Overview
Our research interests include the pathophysiology diabetes, obesity and metabolic syndrome and novel mechanisms by which diabetes and obesity contribute to morbidity and mortality. We are also quite interested in hormone action, including insulin, leptin, and glucagon-like peptide-1. Our research focuses on integrated in vivo metabolism, including glucose and lipid homeostasis. We have studied rodent models of obesity and diabetes and have identified pathogenic mechanisms by which tissues become resistant to the effects of hormonal action. Our therapeutic interests lie in developing novel small molecule approaches to modulate GLP-1 receptor signaling.
Insulin Regulation of Monoamine Signaling: Pathway to Obesity
Modern dietary practices are out of control: despite knowing better, we consume too many calories, too much fat, and too much sugar. In our modern, energy-dense food environment, reward drives poor dietary decisions. Reward-driven over-consumption of obesogenic foods quickly leads to neuronal insulin resistance and impaired dopamine signaling in striatum. In this stage the "hypodopaminergic reward deficiency syndrome" is established, in which decreased dopamine tone results in increased intake of obesogenic foods to achieve a normal level of reward in the setting of decreased dopamine tone. Our overarching hypothesis is that reward for food triggers midbrain insulin resistance, which sustains increased food intake, maladaptive feeding and behaviors, and as a consequence, obesity. Identification of the molecular mechanisms by which insulin fine-tunes control of feeding in the hypothalamus and reward centers in midbrain and identification of the mechanisms by which dysregulation of this system develops in obesity will yield tremendous insight. To achieve this goal, we will use a rodent model of diet-induced obesity in which dramatic changes in feeding behaviors occur. We will initiate the studies in vivo, and will then model in vivo findings in ex vivo preparations, thereby distilling individual aspects of feeding regulation, a complex process involving cognition and reward. Finally, genetic tools in mouse models will illuminate the roles of insulin and dopamine signaling in the development of obesity in specific neuronal populations (e.g. dopamine neurons). Investigating this link between insulin and dopaminergic behavior will lay the foundation for understanding possible shared mechanisms of obesity and dopamine-related co- morbidities; cognitive dysfunction, bipolar disorder, schizophrenia, and attention-deficit disorder.
Allosteric Modulators of the Glucagon-Like Peptide-1 Receptor
Recent innovations in type 2 diabetes therapeutics have focused on gut-derived incretin hormones that have distinct effects on insulin secretion, satiety, and body weight. One such hormone, glucagon-like peptide-1 (GLP-1), is released post-prandially from the intestine and potentiates glucose-dependent insulin secretion from pancreatic beta cells (among many other activities) via its family B G protein-coupled receptor (GPCR). GPCRs in general been highly successfully "drugged" with small molecules. The GLP-1 receptor (GLP1R), however, has eluded successful small molecule targeting likely because its large, complex orthosteric binding sites. Allosteric modulation (potentiation or suppression of activity generated by ligand in the orthosteric site by a small molecule that binds elsewhere or induces activity on its own), was therefore, an attractive mode of targeting the GLP1R. We have completed a high-throughput screen and initial structure-activity work in which ~200 compounds with unique modes of pharmacological activity, including positive allosteric modulation (PAM) and allosteric agonists of the GLP1R have been identified. While GLP-1 based therapeutics have clear efficacy in diabetes and weight control, significant liabilities exist. We hypothesize that "fine-tuning" GLP1R signaling via PAM offers the potential to optimize therapeutic outcomes in diabetes, obesity, and other disorders. This approach may capitalize on native GLP-1 secretion, or may be coupled to combination therapy with other GLP-1 targeted therapeutics.
Imaging in Obesity
Signals from the brain and from other organs throughout the body drive healthy eating behavior. Changes in the balance of these systems contribute to the obesity epidemic. However, little is known about imbalances in functional brain networks in obesity. While homeostatic control of feeding behavior is largely regulated by the hypothalamus, distributed brain networks are increasingly recognized as potent non-homeostatic modulators of eating habits. Non-homeostatic modulators include palatability/reward, stress, motivation, and the balance between emotional drive and cognitive control.
In our environment in which high-calorie, highly-palatable food is readily available and ubiquitous exposure to visual images of food are known to strongly influence feeding behaviors, overeating (increased emotional drive) coupled with a reduced ability to control one’s eating behaviors (decreased cognitive control) promotes unhealthy eating habits.
Because lifestyle intervention in adults does not lead to long-lasting weight loss, and co-morbidities such as diabetes and cardiovascular disease develop over many years, the Niswender Lab seeks a thorough understanding of the interaction of metabolic metabolic signals from the brain with behavior, the neurobiology of metabolism, and imaging in obesity.
Although the association of obesity, altered metabolism, and diabetes is well established in adults, we have little information about these associations during childhood and their relationships to future diabetes as these children become adults. Specifically, we do not understand the interaction of brain function, eating behavior, and obesity during childhood. Our research examines brain network function in children who are healthy weight or obese to discover differences in brain networks. These differences can then be targeted for the treatment, early intervention, and, ultimately, prevention of obesity.