Insulin action in the brain: Roles in energy and glucose homeostasis

Abstract

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.

Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment

“…Abnormalities in the IR‐mediated processes can be due to an impairment in the initial IR activation, reduced insulin availability, and compromised IR‐triggered downstream signaling . A large body of evidence has established their link to a broad range of CNS disorders, including, as mentioned above, neurodevelopmental syndromes, neurotoxicity, cancer, and neurodegenerative and neuropsychiatric disorders .…”

“…At the same time, as the implication of IR in the regulation of energy and glucose homeostasis in the brain has been revisited, these processes are now not considered to be entirely insulin‐independent, and compromised glucose metabolism in the brain resulting from deficient IR function is regarded as another critical factor in the risk for neuropsychiatric disorders. In particular, glucose uptake in the hippocampus was shown to be dependent on IR‐stimulated translocation of the glucose transporter GLUT4 to the plasma membrane .…”

Zuogui Jiangtang Jieyu Decoction Ameliorates Depression-Like Behavior in Diabetic Rats via Activation of Neuronal and Astrocytic IR/IRS-1 Signaling Pathway

“…Brain IR/IRS-1 signaling in the hippocampus may contribute to neuronal activity by effecting the glucose utilization and energy metabolism [18]. In this study, an insulin-sensitive glucose transporter, GLUT4 was obviously reduced in the hippocampus of diabetic rat, and the ATP release was decreased as well ( Fig.…”

Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes

“…In the brain, particularly the hypothalamus, insulin plays important roles in energy homeostasis, decreasing food intake and increasing energy expenditure. It increases energy expenditure by elevating body temperature and sympathetic nervous system activity [63]. As an anorexigenic hormone, insulin binds to its receptors within the arcuate nucleus of the hypothalamus, causing reduced expression of orexigenic neuropeptides such as neuropeptide Y (NPY) and Agouti-related peptide (AgRP) to cause cessation of hunger and reduce food intake [64].…”