Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPARα

Abstract

Adaptation to fasting involves both Glucocorticoid Receptor (GRα) and Peroxisome Proliferator-Activated Receptor α (PPARα) activation. Given both receptors can physically interact we investigated the possibility of a genome-wide cross-talk between activated GR and PPARα, using ChIP- and RNA-seq in primary hepatocytes. Our data reveal extensive chromatin co-localization of both factors with cooperative induction of genes controlling lipid/glucose metabolism. Key GR/PPAR co-controlled genes switched from transcriptional antagonism to cooperativity when moving from short to prolonged hepatocyte fasting, a phenomenon coinciding with gene promoter recruitment of phosphorylated AMP-activated protein kinase (AMPK) and blocked by its pharmacological inhibition. In vitro interaction studies support trimeric complex formation between GR, PPARα and phospho-AMPK. Long-term fasting in mice showed enhanced phosphorylation of liver AMPK and GRα Ser211. Phospho-AMPK chromatin recruitment at liver target genes, observed upon prolonged fasting in mice, is dampened by refeeding. Taken together, our results identify phospho-AMPK as a molecular switch able to cooperate with nuclear receptors at the chromatin level and reveal a novel adaptation mechanism to prolonged fasting.

Distinct but complementary contributions of PPAR isotypes to energy homeostasis

“…In the fed state, PPARα activity is enhanced through insulin-activated MAPK and glucose-activated PKC, while glucagon-activated PKA and AMPK increase PPARα signaling in fasting (49). Moreover, the fasting response is co-controlled by PPARα and GRα, which show extensive chromatin colocalization and interact to induce lipid metabolism genes upon prolonged fasting through genomic AMPK recruitment (110). Conversely, GRβ antagonizes glucocorticoid signaling during fasting via inhibition of GRα and PPARα, thus increasing inflammation and hepatic lipid accumulation (111).…”

AMPKα1 is essential for Glucocorticoid Receptor triggered anti-inflammatory macrophage activation

“…In addition, dexamethasone was shown to increase AMPK activity in hepatocytes while decreasing it in adipocytes (Christ-Crain et al, 2008). Finally, a physical link between phospho-AMPK and phospho-GR was shown in complex with PPARa to increase the transcriptional activity of the latter upon starvation (Ratman et al, 2016). These studies show that AMPK-GR interaction impacts on GR transcriptional activity.…”

“…Only scant studies have reported a link between AMPK signaling and GR signaling, and all in metabolic organs and cells (Liu et al, 2016;Nader et al, 2010;Ratman et al, 2016). Indirect AMPK activation is observed in muscle cells where dexamethasone treatment induces mitochondrial dysfunction leading to decreased ATP, thus activating AMPK (Liu et al, 2016).…”

“…However, the mechanisms by which AMPK signaling contributes to other antiinflammatory signals is not understood. GR and AMPK were previously shown to communicate in their role as regulators of metabolism in non-immune cells (Christ-Crain et al, 2008;Nader et al, 2010;Ratman et al, 2016;Seelig et al, 2017). We therefore sought to determine whether AMPK regulates GR anti-inflammatory actions and controls the tissue regenerative actions of macrophages.…”

Glucocorticoid resistance as a major drive in sepsis pathology

“…Interestingly, GR binds the PDK4 enhancer in concert with PPARα, but GR represses PDK4 induction [201]. So, in GC resistant conditions, more PDK4 induction is expected to lead to more pyruvate accumulation and L-lactate formation (Figure 2).…”