Heritable transmission of stress resistance by high dietary glucose in Caenorhabditis elegans

Abstract

Glucose is a major energy source and is a key regulator of metabolism but excessive dietary glucose is linked to several disorders including type 2 diabetes, obesity and cardiac dysfunction. Dietary intake greatly influences organismal survival but whether the effects of nutritional status are transmitted to the offspring is an unresolved question. Here we show that exposing Caenorhabditis elegans to high glucose concentrations in the parental generation leads to opposing negative effects on fecundity, while having protective effects against cellular stress in the descendent progeny. The transgenerational inheritance of glucose-mediated phenotypes is dependent on the insulin/IGF-like signalling pathway and components of the histone H3 lysine 4 trimethylase complex are essential for transmission of inherited phenotypes. Thus dietary over-consumption phenotypes are heritable with profound effects on the health and survival of descendants.

Figure 1. Heritable diminution of progeny from glucose exposure in the parental generation.

(A) In parental P0 generation animals, glucose enrichment (GE) decreased the average number of progeny of wild type N2 and hif-1 mutant worms compared to untreated controls. GE had no effect on daf-16, aak-2 or sir-2.1 mutants. **P<0.01 versus untreated hif-1 controls, ****P<0.0001 versus untreated N2 controls (B) F1 generation N2 and hif-1 descendants had reduced progeny numbers compared to F1 descendants from untreated P0 controls. *P<0.05, ***P<0.001 (C) N2 worms in the F2 generation from P0 parents exposed to GE also had reduced progeny numbers. *P<0.05 (D) F3 generation descendants from GE treated P0 parents had comparable progeny numbers compared to animals descendent from untreated P0 parents.

Figure 2. Transgenerational inheritance of resistance to oxidative stress.

(A) N2 animals exposed to GE are highly resistant to juglone-induced lethality and this resistance was transmitted to descendent progeny in the F1 and generation, P<0.0001 versus untreated animals. (B–E) Resistance to oxidative stress by GE was lost in the P0 and F1 generations in animals mutant for (B) daf-16, (C) aak-2, or (D) sir-2.1. (E) GE continued to provide resistance to P0 and F1 animals mutant for hif-1, P<0.0001 versus untreated animals. (F) GE increased oxidative stress resistance in P0 N2 animals but this effect was lost in F1 animals treated with daf-16, aak-2 or sir-2.1 RNAi clones.

Figure 3. Parental exposure to glucose provides transgenerational protection against neurodegeneration.

(A–B) GE reduces TDP-43 mediated age-dependent (A) paralysis, P<0.0001 versus untreated animals and (B) neurodegeneration in P0 animals and their F1 descendants, *P<0.0001 versus untreated animals.

Figure 4. Transgenerational inheritance of glucose phenotypes requires H3K4me3 components.

(A) N2 animals treated with 2% GE had an increased H3K4me3 mark and this effect was lost in subsequent generations. (B–C) GE delayed late onset paralysis in P0 but not in F1 generation of mTDP-43; set-2(ok952) (B) and mTDP-43; wdr-5.1(ok1417) (C) animals compared to untreated control and this protection was lost in F1 generation. (D–E) Stress resistance was increased in P0 but not in F1 generation of COMPASS (Complex Proteins Associated with Set1) mutants (D) set-2(ok952) and (E) wdr-5.1(ok1417). (F–G) Total progeny numbers were reduced in P0 but not in F1 generations of (F) set-2 and (G) wdr-5.1 mutants.

Figure 5. The germline is required for transmission of glucose protection.

(A–B) Glucose increased stress resistance in P0 and F1 generation of fem-3(e2006) mutants at 15°C, but failed in the F1 generation at 25°C. (C–D) Glucose increased resistance to juglone in P0 and F1 generation of pgl-1(bn102) mutants at 15°C but failed in the F1 generation at 25°C.