The cAMP-dependent protein kinase (PKA) system represents a primary cell-signaling pathway throughout systems and across species. PKA facilitates the actions of hormones, neurotransmitters and other signaling molecules that bind G-protein coupled receptors (GPCR) to modulate cAMP levels. Through its control of synaptic events, exocytosis, transcriptional regulation, and more, PKA signaling regulates cellular metabolism and emotional and stress responses making it integral in the maintenance and dysregulation of energy homeostasis. Neural PKA signaling is regulated by afferent and peripheral efferent signals that link specific neural cell populations to the regulation of metabolic processes in adipose tissue, liver, pancreas, adrenal, skeletal muscle, and gut. Mouse models have provided invaluable information on the roles for PKA subunits in brain and key metabolic organs. While limited, human studies infer differential regulation of the PKA system in obese compared to lean individuals. Variants identified in PKA subunit genes cause Cushing syndrome that is characterized by metabolic dysregulation associated with endogenous glucocorticoid excess. Under healthy physiologic conditions, the PKA system is exquisitely regulated by stimuli that activate GPCRs to alter intracellular cAMP concentrations, and by PKA cellular localization and holoenzyme stability. Adenylate cyclase activity generates cAMP while phosphodiesterase-mediated cAMP degradation to AMP decreases cAMP levels downstream of GPCRs. Chronic perturbations in PKA signaling appear to be capable of resetting PKA regulation at several levels; in addition, sex differences in PKA signaling regulation, while not well understood, impact the physiologic consequences of metabolic dysregulation and obesity. This review explores the roles for PKA signaling in the pathogenesis of metabolic diseases including obesity, type 2 diabetes mellitus and associated co-morbidities through neural-peripheral crosstalk and cAMP/PKA signaling pathway targets that hold therapeutic potential.