Abstract
Through their well described actions in the hypothalamus, appetitive peptides such as insulin, orexin and leptin are recognized as important regulators of food intake, body weight and body composition. Beyond these metabolic activities, these peptides also are critically involved in a wide variety of activities ranging from modulation of immune and neuroendocrine function to addictive behaviors and reproduction. The neurological activities of insulin, orexin and leptin also include facilitation of hippocampal synaptic plasticity and enhancement of cognitive performance. While patients with metabolic disorders such as obesity and diabetes have greater risk of developing cognitive deficits, dementia and Alzheimer's disease (AD), the underlying mechanisms that are responsible for, or contribute to, age-related cognitive decline are poorly understood. In view of the importance of these peptides in metabolic disorders, it is not surprising that there is a greater focus on their potential role in cognitive deficits associated with aging. The goal of this review is to describe the evidence from clinical and pre-clinical studies implicating insulin, orexin and leptin in the etiology and progression of age-related cognitive decline. Collectively, these studies support the hypothesis that leptin and insulin resistance, concepts normally associated with the hypothalamus, are also applicable to the hippocampus.