ABSTRACT
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.
Subject(s)
Diabetes Mellitus, Type 2 , Ghrelin , Mice , Animals , Male , Ghrelin/metabolism , Agouti-Related Protein/genetics , Agouti-Related Protein/metabolism , Diabetes Mellitus, Type 2/metabolism , Neuropeptide Y/genetics , Neuropeptide Y/metabolism , Neurons/metabolism , Obesity/metabolism , Mice, Knockout , Eating , Calcium-Calmodulin-Dependent Protein Kinase Type 1/metabolismABSTRACT
The olfactory system is at the crossroad between sensory processing and metabolic sensing. In addition to being the center of detection and identification of food odors, it is a sensor for most of the hormones and nutrients responsible for feeding behavior regulation. The consequences of modifications in body homeostasis, nutrient overload and alteration of this brain network in the pathological condition of food-induced obesity and type 2 diabetes are still not elucidated. The aim of this review was first to use both humans and animal studies to report on the current knowledge of the consequences of obesity and type 2 diabetes on odorant threshold and olfactory perception including identification discrimination and memory. We then discuss how olfactory processing can be modified by an alteration of the metabolic homeostasis of the organism and available elements on pharmacological treatments that regulate olfaction. We focus on data within the olfactory system but also on the interactions between the olfactory system and other brain networks impacted by metabolic diseases.
