The article discusses the role of the cyclic AMP-responsive element-binding protein (CREB) and its co-activators, the cAMP-regulated transcriptional co-activators (CRTCs), in sensing hormonal and metabolic signals. CREB is phosphorylated in response to various signals, but only a subset of its target genes are activated. CRTCs, which are activated through dephosphorylation, work in concert with CREB to mediate the effects of fasting and feeding on metabolic programs in insulin-sensitive tissues. Phosphorylation of CREB at Ser133 is crucial for its activity, and this is regulated by the protein kinase A (PKA) pathway. CRTCs are sequestered in the cytoplasm through phosphorylation-dependent interactions with 14-3-3 proteins and are activated by cAMP and calcium signals. Once activated, CRTCs bind to CREB and enhance its activity, leading to the expression of target genes. The study also highlights the role of CRTCs in glucose and lipid metabolism, particularly in the liver, pancreatic islets, adipose tissue, skeletal muscle, and the central nervous system. CREB and CRTCs are involved in the regulation of gluconeogenesis, insulin sensitivity, and energy homeostasis. The article also discusses the role of CREB in adipose tissue, where it modulates lipid metabolism and insulin resistance. Additionally, the study explores the role of CREB in skeletal muscle, where it influences myogenic gene expression and mitochondrial function. The hypothalamic CREB pathway is also discussed, highlighting its role in coordinating glucose and lipid metabolism in peripheral tissues. The article concludes with a discussion on the broader role of CREB and CRTCs in regulating energy balance and lifespan, as well as their potential as therapeutic targets for metabolic disorders.The article discusses the role of the cyclic AMP-responsive element-binding protein (CREB) and its co-activators, the cAMP-regulated transcriptional co-activators (CRTCs), in sensing hormonal and metabolic signals. CREB is phosphorylated in response to various signals, but only a subset of its target genes are activated. CRTCs, which are activated through dephosphorylation, work in concert with CREB to mediate the effects of fasting and feeding on metabolic programs in insulin-sensitive tissues. Phosphorylation of CREB at Ser133 is crucial for its activity, and this is regulated by the protein kinase A (PKA) pathway. CRTCs are sequestered in the cytoplasm through phosphorylation-dependent interactions with 14-3-3 proteins and are activated by cAMP and calcium signals. Once activated, CRTCs bind to CREB and enhance its activity, leading to the expression of target genes. The study also highlights the role of CRTCs in glucose and lipid metabolism, particularly in the liver, pancreatic islets, adipose tissue, skeletal muscle, and the central nervous system. CREB and CRTCs are involved in the regulation of gluconeogenesis, insulin sensitivity, and energy homeostasis. The article also discusses the role of CREB in adipose tissue, where it modulates lipid metabolism and insulin resistance. Additionally, the study explores the role of CREB in skeletal muscle, where it influences myogenic gene expression and mitochondrial function. The hypothalamic CREB pathway is also discussed, highlighting its role in coordinating glucose and lipid metabolism in peripheral tissues. The article concludes with a discussion on the broader role of CREB and CRTCs in regulating energy balance and lifespan, as well as their potential as therapeutic targets for metabolic disorders.