Hormonal signals help to maintain glucose and lipid homeostasis in the liver during the periods of fasting. Glucagon, a pancreas-derived hormone induced by fasting, promotes gluconeogenesis through induction of intracellular cAMP production. Glucagon also stimulates hepatic fatty acid oxidation but the underlying mechanism is poorly characterized. Here we report that following the acute induction of gluconeogenic genes () and () expression through cAMP-response element-binding protein (CREB), glucagon triggers a second delayed phase of fatty acid oxidation genes () and () expression via extracellular cAMP. Increase in extracellular cAMP promotes PPARα activity through direct phosphorylation by AMP-activated protein kinase (AMPK), while inhibition of cAMP efflux greatly attenuates and expression. Importantly, cAMP injection improves lipid homeostasis in fasted mice and obese mice, while inhibition of cAMP efflux deteriorates hepatic steatosis in fasted mice. Collectively, our results demonstrate the vital role of glucagon-stimulated extracellular cAMP in the regulation of hepatic lipid metabolism through AMPK-mediated PPARα activation. Therefore, strategies to improve cAMP efflux could serve as potential new tools to prevent obesity-associated hepatic steatosis.

The NF-κB pathway has important roles in innate immune responses and its regulation is critical to maintain immune homeostasis. Here, we report a newly discovered feedback mechanism for the regulation of this pathway by TLR ligands in macrophages. Lipopolysaccharide (LPS) induced the expression of ICER via p38-mediated activation of CREB in macrophages. ICER, in turn, inhibited the transcriptional activity of NF-κB by direct interaction with the p65 subunit of NF-κB. Deficiency in ICER elevated binding of NF-κB to promoters of pro-inflammatory genes and their subsequent gene expression. Mice deficient in ICER were hypersensitive to LPS-induced endotoxic shock and showed propagated inflammation. Whereas ICER expression in ICER KO bone marrow transplanted mice rescued the ultra-inflammation phenotype, expression of a p65 binding-deficient ICER mutant failed to do so. Our results thus establish p38-CREB-ICER as key components of a negative feedback mechanism necessary to regulate TLR-driven inflammation. Cell Death and Differentiation (2017) 24, 492-499; doi:10.1038/cdd.2016; published online 23 December 2016Activation of TLR4, a pattern recognition receptor used in the innate immune system, by lipopolysaccharide (LPS) leads to the transcription of pro-inflammatory mediators that promote innate immune responses.1 One critical pathway triggered by TLR4 is the NF-κB pathway.2 TLR4 initiates a signaling cascade through adapter molecules MyD88 and TRIF, resulting in TRAF6 activation. TRAF6 in turn triggers the phosphorylation of IκB by IKK and proteosomal degradation of IκB. Subsequently, NF-κB disassociates from IκB and translocates to the nucleus where it promotes the transcription of genes involved in pro-inflammatory responses.3,4 Activation of TRAF6 also leads to downstream activation of the MAPK cascade, including JNKs and p38 isoforms. 5 The p38 pathway has attracted considerable interest as a possible target for antiinflammatory drugs. Activation of p38 results in the activation of CREB, a transcription factor that regulates diverse cellular responses including proliferation, survival and immune responses. CREB is phosphorylated and activated by MSK1/2, a downstream kinase of p38, and subsequently mediates the transcription of genes containing a cAMP-responsive element. Several anti-inflammatory genes possess this cAMPresponsive element, including Dusp1 and IL-10. 6 In addition, phosphorylated CREB has been proposed to directly inhibit NF-κB activation by blocking the binding of CREB binding protein to the NF-κB complex, thereby limiting proinflammatory responses. 7Inducible cAMP early repressors (ICERs) are members of the cAMP-response element (CRE) modulator family and are induced by CREB.8 ICER is transcribed via an alternative internal promoter in the CREM gene and consists of four different isoforms generated by alternative splicing of its transcript (ICERI, ICERIγ, ICERII, ICERIIγ). 9 The isoforms encode either CREB-like (ICERI) or CREM-like (ICERII) DNA-binding domains (DBDs) with or without the alternat...