CaMK1D signaling in AgRP neurons promotes ghrelin-mediated food intake

Vivot, K.; Meszaros, G.; Zhang, Z.; Erbs, E.; Yeghiazaryan, G.; Quinones, M.; Grandgirard, E.; Schneider, A.; Clauss--Creusot, E.; Charlet, A.; Faour, M.; Martin, C.; Luquet, S.; Kloppenburg, P.; Nogueiras, R.; Ricci, R.

doi:10.1101/2021.12.07.471546

bioRxiv · 10.1101/2021.12.07.471546

CaMK1D signaling in AgRP neurons promotes ghrelin-mediated food intake

Vivot, K.·Meszaros, G.·Zhang, Z.·Erbs, E.·Yeghiazaryan, G.·Quinones, M.·Grandgirard, E.·Schneider, A.·Clauss--Creusot, E.·Charlet, A.·Faour, M.·Martin, C.·Luquet, S.·Kloppenburg, P.·Nogueiras, R.·Ricci, R.

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Abstract

Hypothalamic AgRP/NPY neurons are key players in the control of feeding behavior. Ghrelin, a major hormone released under fasting conditions, activates orexigenic AgRP/NPY neurons to stimulate food intake and adiposity. However, cell-autonomous ghrelin-dependent signaling mechanisms in AgRP/NPY neurons remain poorly defined. Here we demonstrate that calcium/calmodulin-dependent protein kinase ID (CaMK1D), a genetic hot spot in type 2 diabetes, is activated in hypothalamus upon ghrelin stimulation and acts in AgRP neurons to promote ghrelin-dependent food intake. Global CaMK1D knockout mice are resistant to the orexigenic action of ghrelin, gain less body weight and are protected against high-fat diet-induced obesity. Deletion of CaMK1D in AgRP but not in POMC neurons is sufficient to recapitulate above phenotypes. Lack of CaMK1D attenuates phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP/NPY as well as the amount of AgRP fiber projections to the Paraventricular nucleus (PVN), while electrical activity of AgRP neurons and 5 AMP-activated protein kinase (AMPK) signaling are unaffected. Hence, CaMK1D links ghrelin action to transcriptional control of orexigenic neuropeptide availability in AgRP neurons. HighlightsO_LIWhole-body deletion of CaMK1D in mice reduces food intake, ghrelin sensitivity and protects against obesity. C_LIO_LIAgRP/NPY neuron-specific deletion of CaMK1D reduces food intake, ghrelin sensitivity, energy expenditure and protects against obesity. C_LIO_LICaMK1D is dispensable for ghrelin-stimulated electrical activity of AgRP neurons and hypothalamic AMPK signaling. C_LIO_LICaMK1D controls phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP and NPY. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=174 HEIGHT=200 SRC="FIGDIR/small/471546v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@40d7d7org.highwire.dtl.DTLVardef@11a8c64org.highwire.dtl.DTLVardef@1f6fad3org.highwire.dtl.DTLVardef@1cd5581_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Vivot, K., Meszaros, G., Zhang, Z., Erbs, E., Yeghiazaryan, G., Quinones, M., Grandgirard, E., Schneider, A., Clauss--Creusot, E., Charlet, A., Faour, M., Martin, C., Luquet, S., Kloppenburg, P., Nogueiras, R., Ricci, R.. 2021-12-07. CaMK1D signaling in AgRP neurons promotes ghrelin-mediated food intake. https://doi.org/10.1101/2021.12.07.471546

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