Methylglyoxal-derived hydroimidazolone, MG-H1, increases food intake by altering tyramine signaling via the GATA transcription factor ELT-3 in Caenorhabditis elegans
- The Buck Institute for Research on Aging, United States
- Department of Chemistry, University of California, Berkeley, United States
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, United States
- Department of Urology, University of California, San Francisco, United States
Figures
Figure 1
Graphical representation for the formation of α-dicarbonyls and advanced glycation end-products (AGEs).
Dicarbonyls are highly reactive byproducts from metabolic pathways such as lipid peroxidation and glycolysis. In the above example, methylglyoxal (MGO) spontaneously forms from dihydroxyacetone …
Figure 2 with 1 supplement
The glyoxalase mutant, glod-4, and methylglyoxal (MGO)-derived advanced glycation end-product (AGE), MG-H1, increases pharyngeal pumping and feeding in C. elegans.
(A) Quantification of pharyngeal pumping (#/30 s) in N2 (wt) and glod-4 (gk189) mutant at different stages of adulthood. (B) Food clearance assay in N2 (wt) and glod-4 (gk189) mutant after 72 hr of …
Figure 2—figure supplement 1
The glyoxalase mutant, glod-4, and methylglyoxal (MGO)-derived advanced glycation end-product (AGE), MG-H1, increases pharyngeal pumping and feeding in C. elegans.
(A) Food clearance assay demonstrating increased food intake with an increasing number of worms. (B, C) Food clearance assay of wildtype N2 (wt) and glod-4 (gk189) mutant with 5 mM treatment of …
Figure 3 with 2 supplements
Role of tdc-1 and tyramine receptors in mediating the MG-H1-induced feeding behavior.
(A) Differential expression of 66 neurotransmitters and feeding genes in glod-4 RNAi background. (B) The flowchart shows the pathway of biogenic amine synthesis, which functions as a …
Figure 3—figure supplement 1
Gene ontology analysis for upregulated genes in glod-4 mutant worms.
Figure 3—figure supplement 2
Role of tdc-1 and tyramine receptors in mediating the MG-H1-induced feeding behavior.
(A) Quantification of pharyngeal pumping (quick screening by visual counting) on mutants of enzymes involved in the biosynthesis of biogenic amines after MG-H1 treatment (suppressor screen). (B) …
Figure 4 with 1 supplement
Role of elt-3 transcription factor in regulating MG-H1-induced feeding in C. elegans.
(A) List of transcription factors identified by motif analysis. (B) Flowchart demonstrating the method of identification of transcription factors. (C) Quantification of pharyngeal pumping after …
Figure 4—figure supplement 1
Role of elt-3 transcription factor in regulating MG-H1-induced feeding in C. elegans.
(A) Quantification of pharyngeal pumping (Quick visual counting), suppressor screen for top 5 transcription factors listed in Figure 4A. (B) Quantification of pharyngeal pumping in glod-4 mutant …
Figure 5
Exogenous tyramine rescues the suppressed pumping in double mutants.
(A) Quantification of pharyngeal pumping in N2 wildtype worms treated with tyramine at various concentrations. (B) Quantification of pharyngeal pumping in elt-3, glod-4, elt-3;glod-4 untreated and el…
Figure 6 with 1 supplement
Suppression of glod-4 phenotypes in tdc-1;glod-4 double mutant.
(A) Survival assay with N2 (wt), tdc-1, glod-4, and tdc-1;glod-4 double mutants. (B) Survival assay with N2 (wt), tyra-2, glod-4, and tyra-2;glod-4 double mutants. (C) Survival assay with N2 (wt), se…
Figure 6—figure supplement 1
Survival analysis of N2 and glod-4 mutant worms after MG-H1 treatment at 150 µM.
Log-rant (Mantel–Cox) test for statistical analysis. **p < 0.01, ***p < 0.001, and ****p < 0.0001.
Scheme 1
Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) (3).
Scheme 2
Nε-carboxymethyl-lysine (CML) (7a) and Nε-(1-carboxyethyl)-lysine (CEL) (7b).
Scheme 3
Synthesis of F-ly (12).
Author response image 1
Quantification of pharyngeal pumping.
One way ANOVA with Fisher’s LSD test. **** p<0.0001. Error bar ± SD.
Author response image 2
Quantification of pharyngeal pumping in N2 wildtype, glod-4 (gk189), tdc-1 (n3420) as well as in double mutants (A) and with elt-3 knockdown (B).
One way ANOVA with Fisher’s LSD test. **** p<0.0001. Error bar ± SD.
Additional files
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Supplementary file 1
A list of genes identified in RNAseq between N2 wildtype and glod-4 knockdown along with the data of fold change and significance.
- https://cdn.elifesciences.org/articles/82446/elife-82446-supp1-v3.xlsx
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MDAR checklist
- https://cdn.elifesciences.org/articles/82446/elife-82446-mdarchecklist1-v3.pdf
