Insulin resistance in KLHL1 KO hypothalamic neurons

MARTÍNEZ-HERNÁNDEZ E; PERISSINOTTI, PP; HE Y; KOOB MD; PIEDRAS-RENTERÍA ES

Chicago

Congreso; Society for Neuroscience Annual Meeting; 2015

Insulin (Ins) is a negative feedback signal regulator of energy homeostasis in the CNS. Ins acts on proopiomelanocortin (POMC+) and neuropeptide Y (NPY+) neurons in the hypothalamus. Ins activates PIP2 production and subsequent TRPC1 channel activation, resulting in enhanced excitability in the former; whereas it activates KATP channels in the latter, inducing hyperpolarization and significant reduction in neuronal excitability. Our laboratory has shown that Kelch-like 1 protein (KLHL1) modulates T-type channel function and that these channels medidate POMC neuronal excitability and leptin responses. We investigated their role mediating Ins effects in POMC+ and NPY+ neurons using the KLHL1 KO model.As expected from the literature, Ins treatment (100 nM) increased the excitability in POMC+ KLHL1 WT neurons (Rheobase (Rh) +/- Ins = 19.4 ± 1.8 and 24.1 ± 1.1 pA, n= 7)) and caused a significant reduction in NPY+ neuron excitability (Rh +/- Ins = 34.1 ± 3.8 and 21.8 ± 2.5 pA, n= 7). Insulin responses in the KLHL1 KO were normal in NPY+ neurons (indistinguishable from WT: (Rh +/-Ins= 18.0 ± 0.9 and 26.4 ± 2.8 pA, n = 8). Interestingly KLHL1 KO were insulin-resistant (Rh +/-Ins=19.1 ± 0.3 and 19.33 ± 2.9 pA, n= 10). Ins resistance results from increased LVA current density, whihc in turn caused increased basal excitability. These data corroborate T-type channel activity is necessary for excitability in POMC neurons activated by leptin or insulin; T-type channel activity is downstream of TRPC1 activation and is responsible for triggering Na-mdiated APs in hypothalamic neurons.