Acute effects of zinc and insulin on arcuate anorexigenic Proopiomelanocortin (POMC) neurons.

BACKGROUND AND PURPOSE: Acute insulin administration results in a hyperpolarization and concomitant decrease of firing rate in a subpopulation of arcuate Proopiomelanocortin (POMC) and Neuropeptide Y/Agouti-related peptide (NPY/AgRP) cells. This rapid effect on cellular activity has been implicated as a cellular correlate of insulin effects on energy balance and glucose homeostasis. Recent evidence suggests that zinc in mammalian insulin formulations is required for the insulin-induced inhibition of arcuate POMC neurons, while guinea-pig insulin, which fails to bind zinc, activates POMC neurons in mice. Here, we tested the effects of zinc and insulin formations on arcuate POMC neurons.

EXPERIMENTAL APPROACH: The effects of zinc and insulin formulations were assessed through whole-cell patch clamp recordings on transgenic mice in vitro.

KEY RESULTS: Insulin formulations containing zinc hyperpolarized POMC neurons. Zinc also hyperpolarized arcuate POMC neurons, albeit at much higher concentration than found in various insulin formulations. Chelation of zinc caused a rightward shift in the dose response of the zinc-induced hyperpolarization of POMC neurons, while the insulin effects on POMC cellular activity remained intact after chelation. Zinc-free insulin also hyperpolarized arcuate POMC neurons. Moreover, insulin failed to hyperpolarize POMC neurons deficient for insulin receptors, suggesting that insulin receptors are required for these effects. Notably, the activation of POMC neurons by guinea pig insulin was independent of insulin receptors while abrogated with PDGF receptor antagonism or loss of TRPC5 subunits.

CONCLUSIONS & IMPLICATIONS: Together, these findings suggest insulin inhibits arcuate POMC neurons independent of zinc, and highlights a possible role of putative PDGF receptors in the acute effects of guinea pig insulin.