Neuronal Calcium Signaling in Metabolic Regulation and Adaptation to Nutrient Stress

Abstract

All organisms can respond physiologically and behaviorally to environmental fluxes in nutrient levels. Different nutrient sensing pathways exist for specific metabolites, and their inputs ultimately define appropriate nutrient uptake and metabolic homeostasis. Nutrient sensing mechanisms at the cellular level require pathways such as insulin and target of rapamycin (TOR) signaling that integrates information from different organ systems like the fat body and the gut. Such integration is essential for coordinating growth with development. Here we review the role of a newly identified set of integrative interneurons and the role of intracellular calcium signaling within these neurons, in regulating nutrient sensing under conditions of nutrient stress. A comparison of the identified Drosophila circuit and cellular mechanisms employed in this circuit, with vertebrate systems, suggests that the identified cell signaling mechanisms may be conserved for neural circuit function related to nutrient sensing by central neurons. The ideas proposed are potentially relevant for understanding the molecular basis of metabolic disorders, because these are frequently linked to nutritional stress.

Keywords: AgRP neurons; Drosophila melanogaster; glutamatergic neurons; hypothalamus; mNSC; neuronal control of metabolism.

Figure 1

Neuronal circuit motifs regulating feeding and satiety are conserved between mammals and Drosophila. Comparison of circuits regulating feeding and satiety in mammals (A) and Drosophila larvae (B) equates the hypothalamus with the medial neurosecretory cells (mNSC; green), the pituitary region to the ring gland (orange), the brain stem to the sub-oesophageal ganglion (SOG or the sub-oesophageal zone, SEZ; pink) and the spinal cord to the ventral ganglion (blue). Studies have shown that the agouti-related peptide (AgRP) neurons and pro-opiomelanocortin (POMC) neurons housed in the arcuate nucleus (ARC) are critical for driving feeding behavior. However, in the absence of these two key cell types, feeding and satiety are also influenced by the paraventricular nucleus (PVH of the hypothalamus), which activates the cells in the ARC as well as drives activity in the para-brachial nucleus (PBN) for attaining satiety (Wu et al., , ; Sternson and Eiselt, 2017). Glutamatergic interneurons in the mid-ventral ganglion (mVG) similarly activate the mNSC to regulate response to starvation (Jayakumar et al., 2016). In (A) the arrowheads show activation, and the arrow with the flatline indicates inhibition. The various regions are important for achieving satiety. In (B) we also highlight that intracellular calcium signaling mechanisms through various G-protein coupled receptors (GPCRs) involving both the inositol-1,4,5-trisphosphate receptor (IP₃R) mediated calcium release as well as store-operated calcium entry (SOCE) in the mVG neurons possibly allow integration of environmental dietary quality with internal metabolic state. Hence the with internal metabolic state. Hence the mVG-mNSC connection in Drosophila larvae may be a precursor of an evolved and complex spinal.