Salt-inducible kinase 2 (SIK2) is an AMPK-related kinase abundantly expressed in adipose tissue. Our aim was to identify molecular targets and functions of SIK2 in adipocytes, and to address the role of PKA-phosphorylation of SIK2 on Ser358. Modulation of SIK2 in adipocytes resulted in altered phosphorylation of CREB-regulated transcription co-activator 2 (CRTC2) and -3, and class IIa histone deacetylase 4 (HDAC4). Furthermore, CRTC2, CRTC3, HDAC4 and protein phosphatase 2A (PP2A) interacted with SIK2, and the binding of CRTCs and PP2A to wild-type, but not Ser358Ala SIK2, was reduced by cAMP-elevation. Silencing of SIK2 resulted in reduced GLUT4 protein levels, whereas cells treated with CRTC2 or HDAC4 siRNA displayed increased GLUT4. Over-expression or pharmacological inhibition of SIK2 resulted in increased and decreased glucose uptake, respectively. We also describe a SIK2/CRTC2/HDAC4 pathway and its regulation in human adipocytes, strengthening the physiological relevance of our findings. Collectively, we demonstrate that SIK2 acts directly on CRTC2, CRTC3 and HDAC4, and that cAMP/PKA reduces the interaction of SIK2 with CRTCs and PP2A. Downstream, SIK2 promotes GLUT4 levels and glucose uptake in adipocytes.