Loss of a Neural AMP-Activated Kinase Mimics the Effects of Elevated Serotonin on Fat, Movement, and Hormonal Secretions

Abstract

AMP-activated protein kinase (AMPK) is an evolutionarily conserved master regulator of metabolism and a therapeutic target in type 2 diabetes. As an energy sensor, AMPK activity is responsive to both metabolic inputs, for instance the ratio of AMP to ATP, and numerous hormonal cues. As in mammals, each of two genes, aak-1 and aak-2, encode for the catalytic subunit of AMPK in C. elegans. Here we show that in C. elegans loss of aak-2 mimics the effects of elevated serotonin signaling on fat reduction, slowed movement, and promoting exit from dauer arrest. Reconstitution of aak-2 in only the nervous system restored wild type fat levels and movement rate to aak-2 mutants and reconstitution in only the ASI neurons was sufficient to significantly restore dauer maintenance to the mutant animals. As in elevated serotonin signaling, inactivation of AAK-2 in the ASI neurons caused enhanced secretion of dense core vesicles from these neurons. The ASI neurons are the site of production of the DAF-7 TGF-β ligand and the DAF-28 insulin, both of which are secreted by dense core vesicles and play critical roles in whether animals stay in dauer or undergo reproductive development. These findings show that elevated levels of serotonin promote enhanced secretions of systemic regulators of pro-growth and differentiation pathways through inactivation of AAK-2. As such, AMPK is not only a recipient of hormonal signals but can also be an upstream regulator. Our data suggest that some of the physiological phenotypes previously attributed to peripheral AAK-2 activity on metabolic targets may instead be due to the role of this kinase in neural serotonin signaling.

Developmental and Cell Cycle Quiescence Is Mediated by the Nuclear Hormone Receptor Coregulator DIN-1S in the Caenorhabditis elegans Dauer Larva

“…Although the premature dauer recovery of aak-2 mutants has been previously described (Apfeld et al 2004;Cunningham et al 2014), in our hands only very few if any of the daf-2; aak-2 or daf-2 control dauer larvae recover after three days, while over 14% of din-1S; daf-2; aak-2 dauer larvae had recovered (Table 5). The observation that din-1S and aak-2 undergo premature dauer recovery is suggestive of their activity being required downstream of, or in parallel to, ILS to maintain the dauer state, much like that observed in mutants that lack serotonin signaling (Cunningham et al 2014).In addition, although aak-2 has no effect alone on somatic gonadal cell quiescence during the dauer stage, it enhanced the din-1S supernumerary proximal somatic gonadal cell defect almost twofold (Table 5, rows E and G, and F and H). Therefore, the loss of din-1S sensitizes the somatic gonadal cells to a reduction in AMPK signaling, despite the fact that loss of AMPK alone has no effect on the somatic gonadal cell numbers.…”

“…Although the premature dauer recovery of aak-2 mutants has been previously described (Apfeld et al 2004;Cunningham et al 2014), in our hands only very few if any of the daf-2; aak-2 or daf-2 control dauer larvae recover after three days, while over 14% of din-1S; daf-2; aak-2 dauer larvae had recovered (Table 5). The observation that din-1S and aak-2 undergo premature dauer recovery is suggestive of their activity being required downstream of, or in parallel to, ILS to maintain the dauer state, much like that observed in mutants that lack serotonin signaling (Cunningham et al 2014).…”

Kynurenic Acid Is a Nutritional Cue that Enables Behavioral Plasticity

“…Another possibility raised by our studies is that the effects of KynA may be due to modulation of neural circuits whose normal, physiological functions may have beneficial impacts on proteostasis and neurodegeneration. In C. elegans , serotonin signaling, which we show is attenuated by KynA, regulates release of systemic neuroendocrine molecules including insulin (Cunningham et al, 2014; Liang et al, 2006), a well-known modulator of proteostasis (Taylor et al, 2014). …”

RNAi Interrogation of Dietary Modulation of Development, Metabolism, Behavior, and Aging in C. elegans

“…This phenotype can be recapitulated by RNAi of pept-1 using OP50(xu363) and HT115 (Figure 3E and 3F). Furthermore, neuroendocrine signaling has been suggested to play a role in C. elegans fat metabolism (Cunningham et al, 2014). unc-31 encodes the worm ortholog of CAPS that functions in neurons and neuroendocrine cells and is required for DCV (dense core vesicle) exocytosis and hence neuroendocrine signaling (Livingstone, 1991; Speese et al, 2007).…”