Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin

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 insulinmediated 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.

Hypothalamic-autonomic control of energy homeostasis

“…Under starvation or fasting, on the other hand, insulin levels are lowered and BAT shows reduced glucose uptake [26,28,200]. In keeping with this, in rodents insulin can trigger sympathetic activation to BAT and lead to increased NST through its action within the brain [201]. Besides its effect on BAT, insulin also acts as one of the principal regulators of WAT metabolism.…”

“…Thus, genetic inactivation of IRs in either of these organs abrogates the effect of insulin [206][207][208]. IRs have been found in several hypothalamic sites involved in sympathetic regulation of glucose homeostasis [209,210].…”

The central melanocortin system directly controls peripheral lipid metabolism

“…Male Sprague-Dawley rats equipped with i.c.v. cannula 1 week before the study (62) were anesthetized using ketamine (91 mg/kg) and xylazine (9.1 mg/kg, i.p. ), and a catheter was inserted into the jugular vein for maintenance of anesthesia with α-chloralose (50 mg/kg/h).…”

“…A bipolar platinum-iridium electrode (Cooner Wire) was suspended under the nerve and secured with silicone gel (Kwik-Cast; WPI). The nerve signal was amplified and filtered as described previously (62).…”

Insulin Transport into the Brain and Cerebrospinal Fluid

“…The widespread distribution of insulin receptors within the brain is evidence of the diverse central actions of insulin. Indeed, insulin effects within the CNS include roles in energy homeostasis Bruning et al, 2000;Woods et al, 1979), systemic glucose production (Fisher, Bruning, Lannon, & Kahn, 2005), reproductive development (Bruning et al, 2000), cognitive functioning (Stockhorst, de Fries, Steingrueber, & Scherbaum, 2004;Stockhorst, Huenig, Ziegler, & Scherbaum, 2011;van der Heide, Ramakers, & Smidt, 2006), and sympathetic nervous system activity (Rahmouni et al, 2004;Ward et al, 2011).…”