Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin. J Clin Invest 2004 Sep;114(5):652-8
Date
09/03/2004Pubmed ID
15343383Pubmed Central ID
PMC514588DOI
10.1172/JCI21737Scopus ID
2-s2.0-85047693533 (requires institutional sign-in at Scopus site) 172 CitationsAbstract
The action of insulin in the central nervous system produces sympathetic nervous system activation (also called sympathoactivation), although the neuronal intracellular mechanisms that mediate this are unclear. We hypothesized that PI3K and MAPK, the major pathways involved in insulin receptor signaling, mediate sympathetic nerve responses to insulin. Intracerebroventricular administration of insulin in rat increased multifiber sympathetic nerve activity to the hindlimb, brown adipose tissue (BAT), adrenal gland, and kidney. Ex vivo biochemical studies of mediobasal hypothalamic tissue revealed that insulin stimulated the association of insulin receptor substrate-1 with the p85alpha subunit of PI3K and also tyrosine phosphorylation of p42 and p44 subunits of MAPK in the hypothalamus. In order to determine whether PI3K and/or MAPK were involved in insulin-mediated sympathoactivation, we tested the effect of specific inhibitors of PI3K (LY294002 and wortmannin) and MAPK (PD98059 and U0126) on regional sympathetic responses to insulin. Interestingly, regional sympathoactivation to insulin was differentially affected by blockade of PI3K and MAPK. Inhibition of PI3K specifically blocked insulin-induced sympathoactivation to the hindlimb, while inhibition of MAPK specifically blocked insulin-induced sympathoactivation to BAT. Sympathoactivation to corticotrophin-releasing factor, however, was not affected by inhibition of PI3K and MAPK. These data demonstrate that PI3K and MAPK are specific and regionally selective mediators of the action of insulin on the sympathetic nervous system.
Author List
Rahmouni K, Morgan DA, Morgan GM, Liu X, Sigmund CD, Mark AL, Haynes WGAuthor
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adipose Tissue, BrownAdrenal Glands
Animals
Hindlimb
Hypothalamus
Insulin
Kidney
Male
Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinases
Rats
Rats, Sprague-Dawley
Sympathetic Nervous System
Time Factors
