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Thirugnanam et al. Vessel Plus 2020;4:26 I http://dx.doi.org/10.20517/2574-1209.2020.18 Page 7 of 16
[13]
[13]
cardiac functional deficits in Snrk cmcKO hearts . ROCK signaling pathway activation is also implicated
in major cardiovascular disorders such as atherosclerosis, restenosis, hypertension, pulmonary hypertension,
[48]
and cardiac hypertrophy . Tribbles homologue 3 (Trib3) is another substrate of SNRK in the heart [Figure 2],
[16]
and SNRK overexpression in the heart decreases oxygen consumption and improves cardiac function .
[49]
Trib3 is also a known inhibitor of AKT signaling and metabolic flux is maintained by PPARα-dependent
[16]
UCP3 (uncoupling protein 3) downregulation . Thus, SNRK improves cardiac mitochondrial efficiency
[16]
and decreases mitochondrial uncoupling . Collectively, SNRK acts as a cardiomyocyte-centric metabolic
sensor in cardiac tissues to maintain cardiac function and homeostasis, and is a novel candidate to target in
order to improve cardiac health.

SNRK in adipocyte metabolism
Adipose tissue is a loose connective tissue composed of adipocytes, cells which contain either a single large
lipid droplet (white adipose tissue) or multiple lipid droplets (brown adipose tissue). Adipocytes release
fatty acids into the bloodstream via lipolysis of lipids. Adipose is a highly dynamic tissue and contains
adipocytes of various size referred to as small and large adipocytes. The properties of adipocytes cells have
been extensively explored for the relationship between cell size and various disease conditions such as
inflammation [50,51] , insulin resistance [52,53] , and diabetes [54,55] . The correlation between its size and cellular
function as well as in metabolic disease concluded that the size of the adipocyte is an important factor in
[56]
predicting pathophysiological conditions .
The most known and recognized function of adipose is its role in the storage and release of lipid species,
[57]
particularly free fatty acids . SNRK is ubiquitously and abundantly expressed in both white adipose
[19]
tissue (WAT) and brown adipose tissue (BAT) . Phosphoproteomic analysis revealed SNRK knockdown
in adipocytes significantly decreased phosphorylation of 49 proteins by 25% or more and increased
phosphorylation of 43 proteins by onefold or higher. Among these proteins, several were involved in
the inflammatory pathways. Pathways such as mTOR signaling were implicated in addition to those that
[19]
reduce adipocyte function . In adipocytes, acute inhibition of mTOR signaling by rapamycin increases
insulin-stimulated glucose uptake, but chronic inhibition of mTOR signaling (rapamycin) impairs insulin-
[58]
stimulated glucose uptake . Thus, SNRK’s role in regulating insulin-mediated glucose uptake is context-
[17]
dependent. In support of this hypothesis, a recent study, from Li et al. , reported that SNRK controls
insulin signaling through Protein Phosphatase 2 Regulatory Subunit B’Delta (PPP2R5D) phosphorylation
[Figure 2], which subsequently influences protein phosphatase 2A (PP2A) activity and phosphorylates
AKT in both WAT and BAT. PPP2R5D is one of the four major Ser/Thr phosphatases implicated in the
negative control of cell growth and division. This implies that SNRK activates insulin-stimulated AKT
phosphorylation and glucose uptake in adipocytes. Further, SNRK, specifically in adipocytes, maintains
body weight but it does not change the size of the WAT depot . SNRK keeps circulatory triglycerides and
[18]
free fatty acids in check in order to regulate the body weight. These data imply that SNRK is a potential
target for interference in adipocytes to check body weight.

SNRK and inflammation
Tissue inflammation is a key protective mechanism to promote repair caused by ischemia and to
prevent further damage. SNRK appears to control tissue inflammation especially by suppressing the
inflammatory pathways mediated through nuclear factor kappa-light-chain-enhancer of activated B cells
(NF-κB) signaling [14,22] [Figure 2]. To restore normal tissue architecture, post-injury inflammation occurs
in three distinct phases. In the early proinflammatory first phase, components of the innate immune
response initiate the repair by mobilizing the recruitment of key inflammatory cells. In the second
phase, the proinflammatory response begins to diminish and inflammatory cells such as macrophages
switch phenotype to a reparative mode. In the final phase, tissue homeostasis is reestablished when the
inflammatory cells either withdraw from the site of injury or are abolished through apoptosis. However, the