Thinking Above and Below the Hypothalamus: The Role of Higher Cognitive Centers in Obesity & Diabetes
Wednesday, April 11, 2007
Presented by the Diabetes and Obesity Discussion Group
Organizer: Bruce McEwen, The Rockefeller University
The Brain as a Site of Early Complications in Type 2 Diabetes
Antonio Convit, MD
NYU School of Medicine
Obesity and type 2 diabetes mellitus (T2DM) are rising dramatically. I will present data demonstrating that the brain is impacted early in the course of T2DM and that the hippocampus is one of the first areas to be affected. Although cortisol is elevated in T2DM, HPA dysregulation does not appear to add to the negative effects of abnormal glucose regulation. Brain abnormalities are also present among obese adolescents with T2DM or pre-diabetes, years before there is any evidence of overt vascular disease. I will present a model that attempts to integrate how the hippocampal damage may arise in T2DM.
Insulin receptor signaling, hippocampal plasticity and cognitive deficits in diabetes phenotypes.
Lawrence P. Reagan, PhD
University of South Carolina School of Medicine
In the central nervous system, insulin plays critical functional roles ranging from metabolism, cognition and reproductive behavior. Conversely, impairments in insulin receptor (IR) signaling are proposed to contribute to the deleterious consequences of diabetes. In this regard, our previous studies have revealed that deficits in IR signaling are associated with impaired performance of hippocampal-dependent tasks in diabetic rats. Our ongoing studies provide evidence that impairments in hypothalamic IR expression and signaling may adversely affect hippocampal plasticity. These findings will be discussed in the context of how deficits in brain IR activity may contribute to the growing obesity epidemic.
Metabolic sensing neurons and the regulation of energy intake, expenditure and storage: from need to desire
Barry E. Levin, MD
University of Medicine and Dentistry of New Jersey
The balance among energy intake, expenditure and storage ("energy homeostasis") is regulated by a constant dialogue among the brain, periphery and external environment. This dialogue is heavily influenced by the interaction with an individual's genetic background and factors such as perinatal environment, psychosocial milieu and availability and characteristics of food. A specialized group of "metabolic sensing" neurons use metabolites such as glucose, lactate, fatty acids and hormones such as leptin, insulin, ghrelin as signaling molecules to control their firing rate, transmitter release and gene transcription. These neurons are located in a distributed network of interconnected nodes scattered throughout the brain. Such nodes include brain areas which moderate both energy homeostasis (hypothalamic nuclei) and the rewarding properties of food (ventral tegmental area, lateral hypothalamus, amygdala, prefrontal cortex). Both the metabolic and reward pathways are modulated by insulin and leptin. However, in contrast to the relatively tight control of the output of metabolic pathways by these hormones, intake of highly rewarding foods can easily override their inhibitory input leading to hyperphagia and obesity. In fact, obesity has many causes. In some individuals an inborn reduction in the sensitivity to the inhibitory effects of leptin, insulin and metabolites such as glucose appears to predispose them to become obese when the caloric density and fat content of their diets increases. Thus, the integrated output of metabolic sensing neurons, acted upon by inputs from the periphery, form the cornerstone of both normal and abnormal regulation of energy homeostasis.
The Role of Striatal Dopamine in Obesity
Peter K. Thanos, PhD
Brookhaven National Laboratory
Dopamine (DA) regulates food intake by modulating food reward and motivation but its involvement in obesity is much less understood. Excessive food intake b