CNS Regulation of Glucose Homeostasis: Role of the Leptin-Melanocortin System
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OBESITY (KM GADDE AND P SINGH, SECTION EDITORS)
CNS Regulation of Glucose Homeostasis: Role of the Leptin-Melanocortin System Alexandre A. da Silva 1
&
Jussara M. do Carmo 1 & John E. Hall 1
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose of Review In this brief review, we highlight studies that have contributed to our current understanding of glucose homeostasis by the central nervous system (CNS) leptin-melanocortin system, particularly proopiomelanocortin neurons and melanocortin-4 receptors (MC4R). Recent Findings Leptin deficiency is associated with insulin resistance and impaired glucose metabolism whereas leptin administration improves tissue glucose uptake/oxidation and reduces hepatic glucose output. These antidiabetic effects of leptin have been demonstrated in experimental animals and humans, even when circulating insulin levels are barely detectable. Recent evidence suggests that these antidiabetic actions of leptin are mediated, in large part, by stimulation of leptin receptors (LRs) in the CNS and require activation of proopiomelanocortin (POMC) neurons and MC4R. These chronic antidiabetic effects of the CNS leptin-melanocortin system appear to be independent of autonomic nervous system and pituitary-thyroid-adrenal (PTA) axis mechanisms. Summary The powerful antidiabetic actions of the CNS leptin-melanocortin system are capable of normalizing plasma glucose even in the absence of insulin and involve interactions of multiple neuronal populations and intracellular signaling pathways. Although the links between the CNS leptin-melanocortin system and its chronic effects on peripheral tissue glucose metabolism are still uncertain, they are independent of insulin action, activation of the autonomic nervous system, or the PTA axis. Unraveling the pathways that contribute to the powerful antidiabetic effects of the CNS leptin-melanocortin system may provide novel therapeutic approaches for diabetes mellitus. Keywords Insulin . Brain . Autonomic nervous system . POMC . Diabetes . Streptozotocin . Glucagon
Introduction In recent years, the number of adults with diabetes mellitus in the USA has significantly increased [https://www.cdc.gov/ diabetes/pdfs/data/statistics/national-diabetes-statistics-report. pdf.]. Although much research has focused on peripheral mechanisms that lead to impaired insulin sensitivity and
This article is part of the Topical Collection on Obesity * Alexandre A. da Silva [email protected] 1
Department of Physiology and Biophysics, Mississippi Center for Obesity Research, and Cardiovascular-Renal Research Center, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA
pancreatic β cell dysfunction, the central nervous system (CNS) also plays an important role in regulating insulin sensitivity and whole-body glucose homeostasis [1, 2]. Among the many factors proposed to modulate CNS control of glucose homeostasis, leptin has been shown to exert perhaps the most powerful actions. Soon after its discovery in
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