Postnatal triglyceride accumulation is regulated by mineralocorticoid receptor activation under basal and stress conditions

Abstract

Key points Glucocorticoids (GCs) either enhance or reduce obesity in mammals, but limited information exists on the role of corticosteroid receptors in mediating the effect of GCs on lipid metabolism during postnatal development. Mineralocorticoid receptor (MR) activation leads to triglyceride (TG) accumulation post‐feeding, whereas glucocorticoid receptor (GR) activation reduces TG levels. The TG profile was inversely related to the lipoprotein lipase (lpl) transcript abundance, and this gene was downregulated by MR activation. Cortisol plays an important role in adipogenesis during postnatal development in zebrafish, and this includes gene/pathway‐specific signalling by GR, MR and GR/MR interactions. Ubiquitous MR and GR knockout in zebrafish provides an excellent model to study the mode of action of GCs in regulating lipid metabolism. Abstract Glucocorticoids (GCs) act through two receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), which differ in both their affinity to bind GCs and their function. As MR has 10‐fold higher affinity for GCs compared to GR, it has been postulated that MR activation occurs at basal levels, while stress levels of these steroid hormones activate GR signalling. There is a growing body of evidence that both these receptors are involved in GC‐mediated lipid metabolism. However, the role of GCs in lipogenesis and lipolysis is controversial, as these steroids appear to both enhance and reduce obesity. As lipid synthesis is a critical part of early development, we hypothesized that both MR and GR contribute to lipid regulation by GCs during postnatal growth. Using MR and GR knockout zebrafish, we demonstrate that MR activation, but not GR activation, is involved in triglyceride (TG) accumulation during the larval development post feeding. Lack of MRs did not affect the gene expression of fatty acid synthase (fas), or acyl‐CoA:diacylglycerol acyltransferase 2 (dgat2), but increased lipoprotein lipase (lpl) transcript abundance. Activation of GR with exogenous cortisol decreased TG levels and increased lpl mRNA levels, but these responses require the presence of MR. Larval transcriptome revealed that MR was the primary regulator of genes involved in lipid synthesis, while GR activation favoured lipid catabolism. Our results underscore a key role for MR activation in mediating postnatal lipid accumulation, as well as cooperatively regulating GR‐mediated lipolysis during postnatal stress.

Loss of the glucocorticoid receptor causes accelerated ovarian ageing in zebrafish

“…At 15 days post-fertilization (dpf ), cortisol-treated WT larvae had twofold less tert mRNA compared to both WT control and GRKO larvae (figure 1a). Cortisol levels for 15 dpf larvae treated with 5 µg ml −1 of cortisol have been previously reported [25], and the GRKO larvae are hypercortisolemic compared to WT larvae, precluding the need for additional cortisol treatment [25]. These results further confirm that the cortisol-mediated reduction in tert transcript abundance in the WT larvae is under transcriptional control of GR.…”

Glucocorticoid and mineralocorticoid receptor activation modulates postnatal growth

“…Although MRs are present in the mammalian skeletal muscle and responsive to aldosterone (Chadwick et al 2015), a physiological role for GC-MR activation in skeletal muscle growth is yet to be characterized. A recent study suggested that MR bind to GREs to mediate GR function in mammals (Mifsud & Reul 2016), and we also recently showed that lipid accumulation in zebrafish larvae requires the activation of both GR and MR, supporting a conserved role for corticosteroid receptors (CRs) interactions in energy metabolism (Faught & Vijayan 2019b).…”

“…It is generally accepted that cortisol signaling, especially in terms of metabolic regulation, occurs through GR in fish (Mommsen et al 1999, Mommsen 2001. There is evidence that MR is involved in lipid accumulation and adipogenesis in mammals (Marzolla et al 2012), and this was also recently shown in zebrafish (Faught & Vijayan 2019b). Furthermore, activation of MR in human skeletal muscles with the GR agonist prednisolone regulated a suite of genes similar to that seen in response to GR activation by the same agonist (Chadwick et al 2015).…”

“…Using MRKO and GRKO zebrafish larvae, combined with exogenous cortisol treatment, we established a CR activation paradigm based on the readout of GR-and MR-responsive gene expression (Faught & Vijayan 2019b). Briefly, CR activation (Fig.…”

Glucocorticoid receptor activities in the zebrafish model: a review

“…A similar comparative experimental setting was conceived by Faught & Vijayan (2019b) to study the roles of Gr and Mr, as well as their specific interaction, on lipid metabolism, under basal and stressful conditions (cortisol treatment). In their work, the authors showed that Mr, the only receptor present in Gr mutants, plays a fundamental role in the biosynthesis of triglycerides and in lipid accumulation by downregulating the transcription of the enzyme lipoprotein lipase, thus explaining the increase of adipose tissue previously reported in Gr mutant lines (Facchinello et al 2017, Faught & Vijayan 2019a.…”