A Caenorhabditis elegans nutrient response system partially dependent on nuclear receptor NHR-49

Abstract

Appropriate response to nutritional stress is critical for animal survival and metabolic health. To better understand regulatory networks that sense and respond to nutritional availability, we developed a quantitative RT-PCR strategy to monitor changes in metabolic gene expression resulting from short-term food deprivation (fasting) in Caenorhabditis elegans. Examining 97 fat and glucose metabolism genes in fed and fasted animals, we identified 18 genes significantly influenced by food withdrawal in all developmental stages. Fasting response genes fell into multiple kinetic classes, with some genes showing significant activation or repression just 1 h after food was removed. As expected, fasting stimulated the expression of genes involved in mobilizing fats for energy production, including mitochondrial ␤-oxidation genes. Surprisingly, however, we found that other mitochondrial ␤-oxidation genes were repressed by food deprivation. Fasting also affected genes involved in mono-and polyunsaturated fatty acid synthesis: four desaturases were induced, and one stearoylCoA desaturase (SCD) was strongly repressed. Accordingly, fasted animals displayed considerable changes in fatty acid composition. Finally, nuclear receptor nhr-49 played a key role in nutritional response, enabling induction of ␤-oxidation genes upon food deprivation and facilitating activation of SCD in fed animals. Our characterization of a fasting response system and our finding that nhr-49 regulates a sector within this system provide insight into the mechanisms by which animals respond to nutritional signals.fasting ͉ fat metabolism ͉ HNF4 ͉ stearoyl-CoA desaturase P recise control of energy storage and consumption is essential for surviving periods of food deprivation. Regulatory networks that govern fat and glucose metabolism are optimized to expend carbohydrates and accumulate fat when food intake is abundant, and switch to the consumption of stored fat when food is scarce (1, 2). In mammals, an overnight fast stimulates fat breakdown for the production of energy, enabling maintenance of glucose supply for CNS function and yielding acetyl-CoA for ketone body synthesis (3, 4). Orchestration of the fasting response is critical, and mutations that disrupt it can cause potentially lethal hypoglycemia and hypoketonemia (4, 5). Indeed, even subtle misregulation of these pathways can bring about diabetes and obesity (1, 6).A complex network of hormonal signals and regulatory mechanisms governs adaptation to food availability. In mammals, much of the fasting response is transcriptionally regulated (7-9). Increased fat consumption is facilitated by the induction of genes involved in fatty acid ␤-oxidation, whereas repression of glycolysis genes and activation of gluconeogenic genes maintains glucose supply. Additionally, activation of ketogenic genes enhances conversion of fatty acid ␤-oxidation products into ketone bodies (3). Despite these general observations, studies of the fasting response have been limited to a select group of genes in only a subse...

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

“…NHR‐49 and MDT‐15 regulate lipid metabolism and are needed to induce several lipid metabolism genes in fasted worms (Taubert et al., 2006; Van Gilst et al., 2005; Van Gilst, Hadjivassiliou & Yamamoto, 2005). As fmo‐2 is also induced by fasting (Leiser et al., 2015), we tested whether nhr‐49 is required for fmo‐2 induction in fasted worms.…”

“…NHR‐49 regulates transcription in response to fasting, to drive changes in lipid metabolism (Van Gilst, Hadjivassiliou & Yamamoto, 2005). Here, we report nhr‐49 ‐dependent expression of several fasting‐induced genes with pro‐survival/longevity functions that are not involved in lipid metabolism, including the glyoxylate cycle enzyme icl‐1 , the oxidoreductase sodh‐1 , and the flavin‐containing monooxygenase fmo‐2 .…”

“…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.…”

Nuclear hormone receptors as mediators of metabolic adaptability following reproductive perturbations

“…22 NHR-49 is sequentially similar to HNF4a but performs functions undertaken by peroxisome proliferator activated receptor a (PPARa) in vertebrates. 29,30 The degree of equivalence between NHR-49 and PPARa is currently unclear, but in view of their similar activities, and for clarity and convenience, NHR-49 is referred to as the functional homolog of PPARa, here and in other studies. 27,[31][32][33] PPARa is a key regulator of fatty-acid b-oxidation and a member of the PPAR family that also includes other modulators of energy metabolism.…”

“…34 nhr-49 was first identified as a regulator of mitochondrial b-oxidation genes during development and for inducing the expression of some b-oxidation while repressing others during short-term fasting. 29,30 In subsequent studies, it was found to be essential for adult reproductive diapause (ARD), an adaptive mechanism by which sexually mature adults delay reproduction and retain a small group of GSCs that are used to repopulate the gonad and continue reproduction when feeding is resumed. 35 Our study disclosed that NHR-49/ PPARa was critical for any lifespan increment following GSC removal.…”