A growing body of evidence from research in rodents and humans has identified insulin as an important neuoregulatory peptide in the brain, where it coordinates diverse aspects of energy balance and peripheral glucose homeostasis. This review discusses where and how insulin interacts within the brain and evaluates the physiological and pathophysiological consequences of central insulin signalling in metabolism, obesity and type 2 diabetes.
K E Y W O R D SAgRP, energy homeostasis, glucose homeostasis, hypothalamus, insulin, POMC
| INTRODUCTIONInsulin targets peripheral tissues, including skeletal muscle, adipose tissue, where it promotes glucose uptake from the blood, and the liver, where it inhibits gluconeogenesis and glycogenolysis and promotes glycogen synthesis to coordinately repress hepatic glucose production.In this way, insulin prevents postprandial hyperglycaemia and maintains euglycaemia. In addition to these peripheral targets, insulin also signals in the brain, although the physiological significance of this interaction has only recently started to emerge. Research over the past two decades has provided compelling evidence that central insulin signalling plays pivotal roles in many aspects of energy and glucose homeostasis (Figure 1). Given the epidemics of obesity and type 2 diabetes (T2D) in developed and increasingly developing countries, there is a pressing need to fully understand the mechanisms by which the body coordinates energy and glucose homeostasis. A key hallmark of obesity and T2D is insulin resistance, where defective insulin signalling downstream of the insulin receptor (IR) renders the peripheral target tissues of insulin insensitive to the action of insulin. What is becoming increasingly apparent is that neurones in the brain also become resistant to insulin; however the relative contributions of central insulin resistance to the development of obesity and T2D remain poorly understood.This review discusses the role of insulin in the brain with respect to coordinating glucose metabolism with energy expenditure. In particular, we discuss our understanding of the locations and mechanisms by which insulin elicits its effects in the brain, its influence on glucose metabolism and energy expenditure, and the potential contributions of central insulin resistancein the development of obesity and the metabolic syndrome.