Acute effects of zinc and insulin on arcuate anorexigenic proopiomelanocortin neurons

Abstract

Background and Purpose Acute insulin administration hyperpolarized, with concomitant decrease of firing rate, a subpopulation of arcuate proopiomelanocortin (POMC) and neuropeptide Y/agouti‐related peptide cells. This rapid effect on cellular activity has been proposed as a cellular correlate of insulin effects on energy balance and glucose homoeostasis. 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 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 inhibited the zinc‐induced hyperpolarization of POMC neurons, whereas effects of insulin on POMC cellular activity were unchanged after chelation. Zinc‐free insulin also hyperpolarized arcuate POMC neurons. Insulin failed to hyperpolarize POMC neurons deficient for insulin receptors, suggesting that insulin receptors are required for these effects. Activation of POMC neurons by guinea pig insulin was independent of insulin receptors but was inhibited by PDGF receptor antagonism or loss of TRPC5 channel subunits. Conclusions and Implications Together, these findings suggest that insulin inhibited arcuate POMC neurons independent of zinc and highlights a possible role of putative PDGF receptors in the acute effects of guinea pig insulin.

Beneficial metabolic role of β-arrestin-1 expressed by AgRP neurons

“…4, A to D). Consistent with previous reports (18,44,45), insulin (50 nM) hyperpolarized arcuate AgRP neurons from control mice (change of resting potential, −9.1 ± 0.8 mV; Fig. 4, E and M) and greatly reduced action potential (AP) firing frequency [artificial cerebrospinal fluid (ACSF): 1.7 ± 0.4 Hz; insulin + ACSF: 0.17 ± 0.10 Hz; *P < 0.05)] (Fig.…”

Direct and indirect effects of liraglutide on hypothalamic POMC and NPY/AgRP neurons – Implications for energy balance and glucose control

“…To identify POMC and NPY neurons with or without LepR, we generated POMC-hrGFP::LepR-cre::tdTomato (PLT) and NPY-hrGFP::LepR-cre::tdTomato (NLT) mice as previously described [41], [42], [43], [44]. Briefly, LepR reporter mice were made by mating LepR-cre mice [45] with the tdTomato reporter mouse (#007908; The Jackson Laboratory).…”

Effects of metabolic state on the regulation of melanocortin circuits

“…Our lab and others, have demonstrated that the activity of various metabolic signals either synergize or segregate into subpopulations of POMC and NPY/AgRP neurons( Fig. 3 ) [ 51 , 52 , 82 , 99 , 101 , 108 , 109 , 111 , 127 , 160 , 163 , 173 , 174 , 180 , 195 , 197 , 198 ]. For example, acute leptin receptor activity in ARH POMC neurons colocalizes with adiponectin and GLP-1 receptor (GLP-1r) activity [ 98 , 180 ].…”

“…In particular, leptin, serotonin (via serotonin 2c receptors – 5-HT 2c R), adiponectin, and glucagon-like peptide 1 (GLP-1) serve to activate, while insulin inhibits POMC neurons via their cognate receptors [ 5 , 48 , 52 , 82 , 98 , 99 , 102 , 103 , 108 , 109 , 161 , 163 , 174 , 180 , 181 ]. Conversely, leptin, serotonin (via serotonin 1b receptors - 5-HT 1b R), adiponectin, insulin, and GLP-1 inhibit NPY/AgRP cells [ 5 , 13 , 48 , 98 , 99 , 103 , 111 , 127 , 163 , 190 ]. While leptin, serotonin, adiponectin, and insulin directly inhibit NPY/AgRP neurons, GLP-1 indirectly inhibits NPY/AgRP neurons via GABAergic synaptic connectivity [ 98 , 163 ].…”

“…Thus, it is also possible that, similar to the overlap in the acute effects of various metabolic receptors in the ARH, exercise-induced plasticity in POMC and NPY/AgRP neurons may be influenced by several factors. [ 82 , 99 , 108 , 109 , 111 , 116 , 160 , 173 , 174 , 180 , 195 , 197 , 198 ]. Ultimately, identification of these signals and understanding how they influence the neural activity of discrete ARH neuron subpopulations will be important for understanding the neural basis for the beneficial effects of exercise.…”