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Insulin Signaling in the Central Nervous System

A Critical Role in Metabolic Homeostasis and Disease From C. elegans to Humans

¹ Division of Metabolism, Diabetes, and Endocrinology, University of California San Diego, San Diego, California
² Veterans Affairs San Diego Health Care System, San Diego, California
³ Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, Washington
⁴ Veterans Affairs Puget Sound Health Care System, Seattle, Washington
⁵ Harborview Medical Center, Seattle, Washington

Insulin and its signaling systems are implicated in both central and peripheral mechanisms governing the ingestion, distribution, metabolism, and storage of nutrients in organisms ranging from worms to humans. Input from the environment regarding the availability and type of nutrients is sensed and integrated with humoral information (provided in part by insulin) regarding the sufficiency of body fat stores. In response to these afferent inputs, neuronal pathways are activated that influence energy flux and nutrient metabolism in the body and ensure reproductive competency. Growing evidence supports the hypothesis that reduced central nervous system insulin signaling from either defective secretion or action contributes to the pathogenesis of common metabolic disorders, including diabetes and obesity, and may therefore help to explain the close association between these two disorders. These considerations implicate insulin action in the brain, an organ previously considered to be insulin independent, as a key determinant of both glucose and energy homeostasis.

Abbreviations: AGE, advanced glycation end product; AgRP, Agouti-related peptide; BAT, brown adipose tissue; CART, cocaine and amphetamine-regulated transcript; CNS, central nervous system; ICV, intracerebroventricular; IRS, insulin receptor substrate; JAK-STAT, Janus kinase-signal transducers and activators of transcription; K_ATP channel, ATP-sensitive K⁺ channel; NPY, neuropeptide Y; PI3K, phosphatidylinositol 3-OH kinase; POMC, precursor proopiomelanocortin; PPY_3–36, peptide YY_3–36; SNS, sympathetic nervous system; SOCS3, suppressor of cytokine signaling 3

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