Interrelationships between ghrelin, insulin and glucose homeostasis: Physiological relevance

Figure 1 Crosstalks between ghrelin and insulin signaling. A: In the CNS, the interaction between GHS-R1a and ghrelin leads to the activation of PKC and PKA and ultimately to the opening of calcium channels. In the ARC, AG’s orexigenic effects are solely mediated through PKA activation and the intracellular entry of Ca²⁺; which in turn, generate a depolarization/activation of NPY neurons. GHS-R1a activation also triggers AMPK phosphorylation. Also, the activation insulin signaling pathway leads to a phosphorylation cascade that involves PI3K, Akt/PKB and mTORC1. mTORC1 has been shown to reduce food intake by inhibiting NPY expression in ARC neurons. This suggests the existence of a crosstalk between these two signaling pathways, considering that AMPK inhibits mTORC1 activation while ghrelin also reduces the anorexigenic effects of insulin-mTORC1. GHS-R1a could also mediate mTORC1 activation through an AMPK-independent mechanism. Moreover, GHS-R1a has been shown to dimerize with some GPCRs such as Gpr83, DRD1/2 and MC3R; B: In the periphery, the adipogenic effects of ghrelin have been shown to synergize with insulin signaling. In contrast to its central effects, the interaction between GHS-R1a and AG leads to decreases in AMPK activity in the periphery. GHS-R1a also activates Akt, PKB, mTORC1 and ultimately PPAR-γ to stimulate insulin-induced adipogenesis. CNS: Central nervous system; PKC: Protein kinase C; PKA: Protein kinase A; ARC: Arcuate nucleus; GHS-R1a: Growth hormone secretagogue receptor 1a; NPY: Neuropeptide Y; AG: Acylated ghrelin; AMPK: AMP-activated protein kinase; mTORC1: Mechanistic target of rapamycin complex 1; MC3R: Melanocortin receptor 3; DRD1/2: Dopamine receptor subtypes 1 and 2; Gpr83: G protein-coupled receptor 83; GPCR: G protein-coupled receptors; PPAR-γ: Peroxisome proliferator-activated receptor γ; IR: Insulin receptor.