The role of CaMK1D in energy homeostasis – HypoCaMK

Tight regulation of energy homeostasis at multiple levels is instrumental for organisms to cope with changes in food availability. The Central Nervous System (CNS) orchestrates a complex array of processes mediating energy intake and expenditure. Hormonal, neuronal and nutritional signals according to changes in food absorption, energy storage and energy consumption in different organs reach the CNS which in turn triggers corresponding changes in feeding behavior and peripheral cellular metabolism. Orexigenic neuropeptide Y (NPY) and agouti-related peptide (AgRP)-expressing AgRP/NPY neurons and anorexigenic proopiomelancortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus are primarily involved in the regulation of energy homeostasis. To control appetite and peripheral metabolism, these neurons are regulated by several hormones. Among others, leptin, ghrelin and insulin emerged as key players in this context. Both leptin and insulin receptors are expressed in these neurons and both insulin and leptin have been found to activate POMC and to inhibit AgRP/NPY neurons. Ghrelin enhances the activity of AgRP/NPY neurons via its receptor, while it decreases the action of POMC neurons through a ghrelin receptor independent mechanism.
Dysfunction of these neuronal circuits is known to contribute to overnutrition and obesity that eventually culminates in life-threatening type 2 diabetes (T2D) and/or cardiovascular diseases. Recent genome-wide association studies (GWAS) and GWAS meta-analyses revealed that they represent complex polygenic diseases. In fact more than ~250 genetic loci have been identified for monogenic, syndromic, or common forms of T2D and/or obesity-related traits. Despite this remarkable success, the contribution of most obesity- and T2D-associated single nucleotide polymorphism (SNPs) to the pathogenesis of these diseases remains largely elusive.
CDC123 (cell division cycle protein 123)/CaMK1D (calcium/calmodulin-dependent protein kinase ID) represents one such locus on chromosome 10 strongly associated with T2D. Fine mapping identified a predominant SNP within this locus enhancing CaMK1D gene transcription. Thus, CaMK1D expression might be enhanced in and contribute to T2D.
Substantial work in the past including our own efforts established a concept in which canonical stress kinase signaling interferes with physiologic metabolic pathways contributing to obesity-related insulin resistance and beta cell dysfunction, two main hallmarks of T2D. Keeping the focus and expertise on kinase-mediated signaling, we recently started to center our efforts on CaMK1D and its role in this disease context. In the last years, we have generated results directing us to hypothesize that CaMK1D primarily acts in AgRP neurons in the hypothalamus to control appetite and energy expenditure in response to ghrelin. The objective will be to explore more fundamentally the role of CaMK1D in AgRP neurons, opening a new avenue going beyond our previous research activity and expertise. To this end, we initiated a national collaborative project with the laboratory of Dr. Serge Luquet at the Functional and Adaptive Biology Unit at University of Paris specialized in central control of feeding behaviour and energy expenditure. Our partner laboratory will provide state-of-the-art neurometabolic tools and the necessary complementary expertise to pinpoint a role of CaMK1D in AgRP neurons. Our comprehensive experimental approach covering basic aspects of cellular signaling, physiology and neuroscience will thus set the stage for a new concept explaining as to how CaMK1D controls body weight and how its deregulation may contribute to obesity and T2D.