PKA functions in metabolism and resistance to obesity: lessons from mouse and human studies

Abstract

Both direct and indirect evidence demonstrate a central role for the cAMP-dependent protein kinase (PKA) signaling pathway in the regulation of energy balance and metabolism across multiple systems. However, the ubiquitous pattern of PKA expression across cell types poses a challenge in pinpointing its tissue-specific regulatory functions and further characterizing its many downstream effects in certain organs or cells. Mouse models of PKA deficiency and over-expression and studies in living cells have helped clarify PKA function in adipose tissue (AT), liver, adrenal, pancreas, and specific brain nuclei, as they pertain to energy balance and metabolic dysregulation. Limited studies in humans suggest differential regulation of PKA in AT of obese compared to lean individuals and an overall dysregulation of PKA signaling in obesity. Despite its complexity, under normal physiologic conditions, the PKA system is tightly regulated by changes in cAMP concentrations upstream via adenylate cyclase and downstream by phosphodiesterase-mediated cAMP degradation to AMP and by changes in PKA holoenzyme stability. Adjustments in the PKA system appear to be important to the development and maintenance of the obese state and its associated metabolic perturbations. In this review we discuss the important role of PKA in obesity and its involvement in resistance to obesity, through studies in humans and in mouse models, with a focus on the regulation of PKA in energy expenditure, intake behavior, and lipid and glucose metabolism.

Loss of habenular Prkar2a reduces hedonic eating and increases exercise motivation

“…Sucrose preference and the behavioral and physiologic responses to chronic HFD exposure were sex-dependent in RIIα-KO mice. Our observations with regards to sex differences in the recorded behaviors and metabolic parameters are consistent with other mouse models of PKA deficiency or overexpression, in which sexual dimorphism is a common characteristic ( 57 ). While the requirement to include females in clinical and basic research protocols is relatively recent, mounting evidence suggests key differences in the regulation of behaviors linked to DA (and other monoamine) signaling.…”

“…Our observations with regards to sex differences in the recorded behaviors and metabolic parameters are consistent with other mouse models of PKA deficiency or overexpression, in which sexual dimorphism is a common characteristic. 58 While the requirement to include females in clinical and basic research protocols is relatively recent, mounting evidence suggests key differences in the regulation of behaviors linked to DA (and other monoamine) signaling. We report a more pronounced decrease in sucrose intake and preference in male compared to female RIIαKO mice, while decreases in intake, weight gain and metabolic efficiency during chronic HFD feeding were significant only in female KO mice.…”

An “Omic” Overview of Fragile X Syndrome

“…Adenylate cyclase is responsible for cAMP synthesis. The majority (9 out of 10) of AC isoforms are membrane-bound enzymes that are regulated by various G protein-coupled receptors (GPCR) [ 165 ]. On the other hand, PDE catalyze cyclic nucleotides (cAMP and cGMP) degradation.…”

Protein Kinase Inhibitor Peptide as a Tool to Specifically Inhibit Protein Kinase A

“…The termination of PKA signaling includes multiple counteracting mechanisms: the degradation of cAMP by phosphodiesterases (PDEs; London et al, 2020), the dephosphorylation of PKA substrates by phosphatases (Burdyga et al, 2018), and the inhibition of PKA by PKI, a soluble peptide in the cell (Meinkoth et al, 1993). While many studies have addressed the degradation of cAMP and the dephosphorylation of PKA substrates, the physiological and pathological roles of PKA inhibition by PKI remain to be elucidated.…”