Insulin Excites Anorexigenic Proopiomelanocortin Neurons via Activation of Canonical Transient Receptor Potential Channels

Abstract

SUMMARY Proopiomelanocortin (POMC) neurons within the hypothalamic arcuate nucleus are vital anorexigenic neurons. Although both the leptin receptor and insulin receptor are coupled to activation of phosphatidylinositide3-kinase (PI3K) in POMC neurons, they are thought to have disparate actions on POMC excitability. Using whole-cell recording and selective pharmacological tools, we have found that similar to leptin, purified insulin depolarized POMC, and adjacent kisspeptin neurons via activation of TRPC5 channels, which are highly expressed in these neurons. In contrast, insulin hyperpolarized and inhibited NPY/AgRP neurons via activation of KATP channels. Moreover, Zn2+, which is found in insulin formulations at nanomolar concentrations, inhibited POMC neurons via activation of KATP channels. Finally as predicted, insulin given intracerebroventrically robustly inhibited food intake and activated c-fos expression in arcuate POMC neurons. Our results show that purified insulin excites POMC neurons in the arcuate nucleus, which we propose is a major mechanism by which insulin regulates energy homeostasis.

Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling

“…In the ARC, insulin binding results in IR activation and phosphorylation of insulin receptor substrate 2 (IRS-2) to recruit PI3K and activate the serine/threonine protein kinase AKT, which phosphorylates FoxO1 to increase POMC and decrease AgRP/NPY expression (Figures 2 and 3). Besides altering neuropeptide expression, insulin-induced PI3K signaling stimulates ATP sensitive K+ channels (KATP) to 6 alter the electrical activity of POMC and AgRP neurons [43][44][45] (Figure 3). CNS insulin signaling lowers hepatic glucose production [33] and this can be blocked by the infusion of a KATP blocker into the mediobasal hypothalamus, or by hepatic vagotomy [42].…”

Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood

“…In particular, a set of neurons located in the arcuate nucleus of the hypothalamus expresses proopiomelanocortin (Pomc), a gene that encodes the anorexigenic melanocortins α-, β-and γ-melanocyte-stimulating hormone (MSH). POMC neurons sense leptin, insulin and glucose levels, and receive multiple synaptic contacts which, together, orchestrate neuronal activity and determine the pattern of melanocortins release (2,3). The physiological relevance of the central melanocortin system can be readily appreciated in hypothalamic Pomc-deficient mice, which are hyperphagic and display early onset severe obesity (4).…”

Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation

“…Subsets of ARC POMC neurons have been reported to express mRNA for the vesicular glutamate transporter-2 (Dicken et al 2012;Hentges et al 2009;Meister 2007;Ziegler et al 2002). Although insulin has been reported to hyperpolarize POMC neurons (Williams et al 2010), recent evidence suggests that purified insulin (without Zn in the formulation) depolarizes and excites POMC neurons (Qiu et al 2014). Therefore, insulin may activate ARC neurons to corelease ␣-melanocyte-stimulating hormone (␣-MSH) and glutamate in the PVH.…”

“…Insulin receptors are highly expressed within the ARC (Grillo et al 2007;Marks et al 1990;Obici et al 2002;Werther et al 1987), and in vitro bath application of insulin alters the activity of proopiomelanocortin (POMC) and neuropeptide Y/agouti-related peptide (NPY/ AgRP) neurons in the ARC (Qiu et al 2014;Williams et al 2010). Direct microinjection of insulin into the ARC increases lumbar SNA and alters baroreflex function (Cassaglia et al 2011;Luckett et al 2013;Steiner et al 2014).…”