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Thirugnanam et al. Vessel Plus 2020;4:26 I http://dx.doi.org/10.20517/2574-1209.2020.18 Page 11 of 16

include: (1) SNRK-mediated cell-cell communication in the heart; (2) pharmacological activation of SNRK
selectively in CMs to suppress inflammation and metabolic dysregulation; and (3) SNRK activation in CMs
to promote cardiac output via mitochondrial or other mechanisms. Some of SNRK’s cardiac function are
reminiscent of mitochondrial sirtuin proteins specifically SIRT3, wherein Sirt3 knockout mice are highly
[86]
sensitive to stress, which leads to cardiac hypertrophy, fibrosis, and increased mortality . Compounds
[87]
such as Honokiol that activate mitochondrial Sirt3, block and reverse cardiac hypertrophy in mice and
[88]
show protective cardiac function could be candidates for testing in Snrk cmcKO mice. Collectively, the
therapeutic value of SNRK-CMs-mediated signaling to prevent HF is an emerging area of translational
research in cardiovascular medicine.

SNRK in diabetes
Diabetes mellitus is often referred to as a metabolic condition that results in high blood glucose levels. Type
1 diabetes (T1D) is a severe form of the disease and is often referred to as juvenile diabetes or “insulin-
dependent diabetes” which is the result of loss of insulin-hormone producing islet cells in the pancreas
which normally promotes glucose metabolism. Type 2 diabetes (T2D), the most common form of diabetes,
is also referred to as adult onset diabetes or “non-insulin-dependent diabetes.” In T2D, the insulin receptor
is defective and insulin produced by the pancreatic cells cannot function to facilitate efficient glucose
metabolism. This is often referred to as “insulin-resistance” state. Insulin secreted by pancreas influences
other organs including muscle (glucose uptake and storage), liver (decrease glucose production), and
adipocytes (increased lipogenesis). SNRK’s connection to diabetes was first identified by studying its role
[19]
on adipocytes . SNRK is abundantly expressed in adipose tissue (WAT and BAT), and its expression is
induced by insulin. SNRK knockdown in adipocytes promotes lipolysis, impairs glucose uptake , and
[17]
activates NF-κB inflammatory signaling pathway. Thus, SNRK, like in CMs, seems to function in adipocyte
as a repressor of adipocyte inflammation. The specific mechanism utilized by SNRK to prevent insulin
resistance in adipose tissue is through protein phosphatase 2 regulatory subunit B’ delta (PPP2R5D)
phosphorylation, which impacts PP2A activity and phosphorylation of AKT [Figure 4]. The SNRK-
[17]
AKT connection is intriguing given that this signaling nexus was also observed in heart tissues from Snrk
cmcKO mice . Thus, further investigations is needed into the direct versus indirect regulation of SNRK-
[14]
AKT pathway in CMs and adipocytes.

[89]
Obesity is a key risk factor for insulin resistance T2D . Interestingly, in humans and mouse models
of obesity, adipose SNRK expression levels are diminished. Further, adipocyte-specific deletion of Snrk
[18]
causes inflammation in WAT along with ectopic lipid deposition in liver and muscle . Homozygous loss
of Snrk in adipocytes decreases the expression of uncoupling protein 1 (UCP1), PR domain containing
16 (PRDM16), and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)
in BAT. One of the primary functions of adipocytes is to insulate the body, a process also referred to
as “thermogenesis”. All three molecules UCP1, PRDM16, and PGC-1α play an important role in BAT
thermogenesis . To increase heat production, lipids in adipocytes are catabolized, a process that
[18]
gets dysregulated in obese conditions, which results in increased inflammation and insulin resistance.
Adipocyte-specific deletion of Snrk cause impairment in adaptive thermogenesis in BAT leading to
decreased energy expenditure, elevated body weight, and insulin resistance. Importantly, a significant
[18]
association in SNRK genetic variants and obesity risk was identified in humans . These studies collectively
make a case for SNRK as a novel target for treating obesity and insulin resistance-related metabolic
disorders including diabetes.

SNRK in cancer
[90]
Reprogramming of cellular energy metabolism is one of the principal hallmarks of cancer . We think
that tumor cells can exploit SNRK’s role in controlling metabolic pathways in various tissues. For example,
LKB1, an upstream regulator of SNRK function, has been identified as a critical cancer suppressor protein