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Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin
Kamal Rahmouni, … , Allyn L. Mark, William G. Haynes
Kamal Rahmouni, … , Allyn L. Mark, William G. Haynes
Published September 1, 2004
Citation Information: J Clin Invest. 2004;114(5):652-658. https://doi.org/10.1172/JCI21737.
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Categories: Article Cardiology

Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin

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Abstract

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 p85α 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.

Authors

Kamal Rahmouni, Donald A. Morgan, Gina M. Morgan, Xuebo Liu, Curt D. Sigmund, Allyn L. Mark, William G. Haynes

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