CaMK1D signalling in AgRP neurons promotes ghrelin-mediated food intake

• Published in: Nature metabolism Vol. 5; no. 6; p. 1045
• Main Authors: Vivot, Karl, Meszaros, Gergö, Pangou, Evanthia, Zhang, Zhirong, Qu, Mengdi, Erbs, Eric, Yeghiazaryan, Gagik, Quiñones, Mar, Grandgirard, Erwan, Schneider, Anna, Clauss-Creusot, Etienne, Charlet, Alexandre, Faour, Maya, Martin, Claire, Berditchevski, Fedor, Sumara, Izabela, Luquet, Serge, Kloppenburg, Peter, Nogueiras, Ruben, Ricci, Romeo
• Format: Journal Article
• Language: English
• Published: Germany 01.06.2023
• Subjects: Agouti-Related Protein - genetics; Agouti-Related Protein - metabolism; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 1 - metabolism; Diabetes Mellitus, Type 2 - metabolism; Eating; Ghrelin - metabolism; Male; Mice; Mice, Knockout; Neurons - metabolism; Neuropeptide Y - genetics; Neuropeptide Y - metabolism; Obesity - metabolism
• DOI: 10.1038/s42255-023-00814-x

Hypothalamic AgRP/NPY neurons are key players in the control of feeding behaviour. Ghrelin, a major orexigenic hormone, activates AgRP/NPY neurons to stimulate food intake and adiposity. However, cell-autonomous ghrelin-dependent signalling mechanisms in AgRP/NPY neurons remain poorly defined. Here we show that calcium/calmodulin-dependent protein kinase ID (CaMK1D), a genetic hot spot in type 2 diabetes, is activated upon ghrelin stimulation and acts in AgRP/NPY neurons to mediate ghrelin-dependent food intake. Global Camk1d-knockout male mice are resistant to ghrelin, gain less body weight and are protected against high-fat-diet-induced obesity. Deletion of Camk1d in AgRP/NPY, but not in POMC, neurons is sufficient to recapitulate above phenotypes. In response to ghrelin, lack of CaMK1D attenuates phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP/NPY in fibre projections to the paraventricular nucleus (PVN). Hence, CaMK1D links ghrelin action to transcriptional control of orexigenic neuropeptide availability in AgRP neurons.