Germline Signals Deploy NHR-49 to Modulate Fatty-Acid β-Oxidation and Desaturation in Somatic Tissues of C. elegans

Abstract

In C. elegans, removal of the germline extends lifespan significantly. We demonstrate that the nuclear hormone receptor, NHR-49, enables the response to this physiological change by increasing the expression of genes involved in mitochondrial β-oxidation and fatty-acid desaturation. The coordinated augmentation of these processes is critical for germline-less animals to maintain their lipid stores and to sustain de novo fat synthesis during adulthood. Following germline ablation, NHR-49 is up-regulated in somatic cells by the conserved longevity determinants DAF-16/FOXO and TCER-1/TCERG1. Accordingly, NHR-49 overexpression in fertile animals extends their lifespan modestly. In fertile adults, nhr-49 expression is DAF-16/FOXO and TCER-1/TCERG1 independent although its depletion causes age-related lipid abnormalities. Our data provide molecular insights into how reproductive stimuli are integrated into global metabolic changes to alter the lifespan of the animal. They suggest that NHR-49 may facilitate the adaptation to loss of reproductive potential through synchronized enhancement of fatty-acid oxidation and desaturation, thus breaking down some fats ordained for reproduction and orchestrating a lipid profile conducive for somatic maintenance and longevity.

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

“…Notably, the tBOOH‐ and fasting‐induced expression of seven of these genes was impaired in nhr‐49 ( nr2041 ) worms, indicating that NHR‐49 is important for the shared transcriptional response to these stresses (Figure 1c,d). nhr‐49 is also required for metabolic remodeling and increased lifespan due to loss of glp‐1/notch receptor activity in a glp‐1 ( e2141 ) mutant (Ratnappan et al., 2014). Notably, meta‐analysis of transcriptome data revealed significant overlaps between genes induced in glp‐1 ( bn18 ) mutants (Steinbaugh et al., 2015) and induced by either tBOOH or fasting (Figure 2a).…”

“…NHR‐49 levels are increased in glp‐1 mutants due to DAF‐16‐ and TCER‐1‐driven increases in nhr‐49 mRNA levels (Ratnappan et al., 2014). Hence, we used an Pnhr‐49::nhr‐49::GFP transgene that encodes all known nhr‐49 isoforms (Figure S4a; Ratnappan et al., 2014) to test whether levels or localization of NHR‐49::GFP fusion proteins also change in response to tBOOH or fasting. The high basal levels of nuclear NHR‐49::GFP made stress‐induced changes difficult to detect by microscopy (Figure 4a).…”

“…NHR‐49 is a critical regulator of lipid metabolism and longevity (Burkewitz et al., 2015; Chamoli, Singh, Malik & Mukhopadhyay, 2014; Folick et al., 2015; Khan et al., 2013; Ratnappan et al., 2014; Seah et al., 2016), while related nuclear receptors, HNF4 and PPARα, are therapeutic targets that share at least some of these functions in mammals. Here, we show that NHR‐49 is also vital for an adaptive transcriptional response to the organic peroxide tBOOH.…”

“…Collectively, our data suggest that, in addition to its role in regulating lipid metabolism, NHR‐49 participates in a cytoprotective acute stress response program that functions parallel to and independently of SKN‐1/Nrf2 and HLH‐30/TFEB signaling (Blackwell et al., 2015; Lapierre et al., 2013). This raises the possibility that NHR‐49's pro‐longevity function, for example in glp‐1 mutants (Ratnappan et al., 2014), may involve modulating both lipid metabolism and stress defenses (Figure 6). …”

“…We found that the nuclear hormone receptor (NHR)‐49, an HNF4/PPARα ortholog and established regulator of C. elegans lipid metabolism and longevity (Pathare, Lin, Bornfeldt, Taubert & Van Gilst, 2012; Ratnappan et al., 2014; Van Gilst, Hadjivassiliou, Jolly & Yamamoto, 2005; Van Gilst, Hadjivassiliou & Yamamoto, 2005), is also activated by and required for oxidative stress resistance. We show that NHR‐49 and MDT‐15 are both required for the increased expression of fmo‐2 as part of a stress response program activated by organic peroxide, fasting, and in long‐lived, germline‐less glp‐1 mutants.…”