AMP-activated protein kinase (AMPK) is a fundamental enzyme that controls energy homeostasis, through orchestrating the cellular response to a reduction in energy availability. Under conditions of cellular energy stress AMPK senses the decrease in ATP levels and responds by activating catabolic pathways, which will generate ATP, and switching off ATP-consuming ones, in order to restore the energy balance. AMPK regulates several signaling cascades linked to metabolism, overall favoring cellular consumption of glucose and lipid, allowing the cell to adapt to sustained energetic challenges through modulation of gene transcription. The aim of this thesis is to investigate the role that AMPK plays in the adaptive reprogramming of metabolism through transcriptional control. To identify genes and pathways regulated in an AMPK-dependent mechanism, we performed a whole-genome transcriptome profiling using microarray technology and compared the effects of two small molecule AMPK activators acting via distinct mechanisms, namely 991, which binds at the allosteric drug and metabolite site, and the AMP mimetic, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). The impact on gene expression of 991 and AICAR was investigated using two cellular and genetic models, mouse embryonic fibroblasts (MEFs) and mouse primary hepatocytes, either wild-type or AMPK-deficient. Statistical analysis of differential gene expression, followed by pathway analysis, revealed compound- and model-specific gene expression signatures. Notably we found that in contrast to AICAR, 991 affected gene expression almost exclusively in an AMPK-dependent manner. Interestingly, we identified that 991 modulated genes involved in the metabolic and lysosomal pathways, and that a number of these genes are under the control of the sterol regulatory element-binding protein (SREBP) and transcription factor EB (TFEB). We identified the tumor suppressor folliculin (Flcn) and its binding partners, folliculin interacting protein (Fnip), as novel transcriptional targets of AMPK. We confirmed the upregulated expression of Flcn in response to pharmacological activation of AMPK in MEFs and primary hepatocytes. Furthermore, by taking advantage of a novel zebrafish whole-body knockout model of AMPK, we confirmed that physiological activation of AMPK partly mediates the increase in expression of Flcn and Fnip. We further identified TFEB as a mediator of the AMPK transcriptional response, accounting for the increase in Flcn expression through modulating its promoter activity. Moreover, we revealed the existence of a novel mechanism by which AMPK regulates TFEB through promoting dephosphorylation and nuclear translocation, independently of mammalian target of rapamycin complex 1 (mTORC1). Taken together, we identified several new AMPK-dependent/-regulated genes and pathways that are differentially modulated in a cell type- and compound-specific manner. Most importantly, we discovered a novel and conserved AMPK-TFEB-FLCN axis in cellular and in vivo models. This work contributes to advance our understanding of AMPK-mediated regulation of transcriptional programs, nevertheless future studies will be required to elucidate the physiological relevance of the AMPK-TFEB-FLCN cascade.