Hunting for the SNARK in metabolic disease.

DYSREGULATION OF ENERGY BALANCE is a primary constituent in the etiology of obesity and type 2 diabetes mellitus, which is manifested by altered metabolic homeostasis and insulin resistance in a variety of tissues, including brain, liver, and skeletal muscle. The discovery of the AMP-activated protein kinase (AMPK), an evolutionarily conserved serine/ threonine kinase that acts a master sensor and regulator of energy balance at the cellular level (8, 31), has been critical to our understanding of whole body energy homeostasis. Modulation of AMPK activity in various metabolic tissues is a feature of therapeutic strategies, such as exercise (1) and metformin (27), known to improve metabolic homeostasis in type 2 diabetes and insulin resistance. Metabolic regulation by AMPK has been extensively studied, but little is known of the role of AMPK-related kinases in metabolic regulation. Twelve protein kinases (BRSK1, BRSK2, NUAK1, NUAK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) in the human kinome are closely related to AMPK 1 and AMPK 2 (18), thus forming a 14 kinase phylogenetic tree known as “AMPK-related kinases” (Fig. 1A). In this issue of the Journal, Ichinoseki-Sekine et al. (9) have explored the role of NUAK2, also known as SNARK [SNF (sucrose, nonfermenting) 1/AMPK-related kinase)], in whole body energy homeostasis in sedentary and physically active animals. They provide evidence for a robust effect on whole body metabolism by hemiallelic Snark deficiency (Fig. 1B), suggesting that this AMPKrelated kinase is a previously unrecognized regulator of whole-body metabolism. Thorough reviews of the structure, regulation, and metabolic effects of AMPK have been published elsewhere (8, 17, 31); some aspects are briefly discussed here. AMPK was originally identified as a kinase responsible for inhibitory effects of 5 -AMP on both HMG-CoA reductase and acetyl-CoA carboxylase activity (3), although earlier workers had implicated AMP sensing in cellular metabolism (5, 33). A wide range of cellular stresses that deplete ATP (such as metabolic poisons) or increase the cellular AMP/ATP ratio (such as glucose deprivation or muscle contraction) activate AMPK (8). Consequently, AMPK acts as a master regulator of cellular metabolism in response to alterations in energy charge in the cell (8). The generalized effects of AMPK activation occur in such a manner as to conserve ATP by inhibiting biosynthetic pathways and anabolic pathways while stimulating catabolic pathways that generate ATP in a control mechanism that acts to restore cellular energy (ATP) stores (8). In the context of skeletal muscle, this is observed acutely as a suppressive effect of AMPK on glycogen synthesis (11) and protein synthesis (2) and a permissive effect on glucose transport (19) and fatty acid oxidation (28). The effects of chronic or constitutive AMPK activation lead to alterations in metabolic gene expression and mitochondrial biogenesis (6, 34), which enhance the ability of the cell to rapidly replenish ATP or resist metabolic perturbation. However, several experiments now demonstrate that AMPK is dispensable in modulating the effects of contraction or pharmacological activation on fuel metabolism and gene expression, raising the possibility that AMPK-independent pathways may regulate glucose and lipid metabolism. Contraction-mediated glucose uptake is unaltered or slightly impaired in AMPK 2 knockout (KO) and AMPK 2 kinase-dead mice (11, 22), whereas AMPK is dispensable for fat oxidation during contraction or AICAR stimulation (4, 21). Similarly, the mitochondrial adaptation to exercise training is preserved in these mice (10, 24). Despite the apparent capacity of AMPK to increase mitochondrial biogenesis, it is not required for classical exercise-induced training responses. The tumor suppressor LKB1 kinase is a master kinase regulating activity of 13 of the 14 kinases of the AMPK-related kinase subfamily (16). In muscle-specific LKB1-KO mice, AMPK activation during contraction is prevented and glucose uptake is blunted (26). Similarly, the contraction-induced increase in acetyl-CoA carboxylase (ACC) phosphorylation and decline in malonyl-CoA levels were attenuated in these animals, although fat oxidation was not measured directly (26, 29). However, these observations do not necessarily mean that AMPK is solely responsible for LKB1 effects on metabolism, but rather suggest a role in cellular metabolism for other AMPK-related pathways (25) or alternative signaling pathways such as calciumdependent protein kinases (23, 32). A pertinent point here is that results obtained in transgenic animals may be affected by compensatory alterations in AMPK isoform activity or alternative signaling pathways. However, the possibility that AMPK-related kinases play a permissive role in contraction or pharmacological effects on fuel metabolism represents an attractive and worthy hypothesis. Ichinoseki-Sekine et al. have investigated the in vivo effects of altering expression of SNARK by using hemiallelic loss of SNARK (Snark / ) on whole body metabolic homeostasis and physical activity behavior. Prior to this publication, little was known about the metabolic role of SNARK, but earlier reports from in vitro studies have identified remarkably similar aspects of regulation and activity to AMPK (13, 14, 16) . Homozygous Snark-deficient mice have a high incidence of embryonic lethality, whereas the heterozygous Snark-deficient mice have an obvious metabolic phenotype with mature-onset obesity and increased white adipose tissue mass evident after 4 mo of age (9, 30). These changes are accompanied by liver fat accumulation and increased serum triglyceride concentration, as well as hyperinsulinemia, hyperglycemia, glucose intolerance, and enhanced tumorgenesis (30). Further published characterization of this phenotype is eagerly awaited, but fat synthesis and deposition are reported to be enhanced, along with a reduction in total body temperature and daily energy expenditure, as assessed by oxygen uptake (30). Habitual Address for reprint requests and other correspondence: J. R. Zierath, Dept. of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet, S-171 77, Stockholm, Sweden (E-mail: [email protected]). Am J Physiol Endocrinol Metab 296: E969–E972, 2009; doi:10.1152/ajpendo.00178.2009.