AIMS/HYPOTHESIS:
Sucrose, non-fermenting 1/AMP-activated protein kinase-related
kinase (SNARK) is involved in cellular
stress responses linked to
obesity and
type 2 diabetes. We determined the role of SNARK in response to
metabolic stress and
insulin action on
glucose and
lipid metabolism in
skeletal muscle. METHODS:
Vastus lateralis skeletal muscle biopsies were obtained from normal
glucose tolerant (n = 35) and type 2
diabetic (n = 31) men and women for SNARK expression studies. Primary
myotube cultures were
derived from
biopsies obtained from normal
glucose tolerant individuals for
metabolic studies. RESULTS: SNARK (also known as
NUAK2)
mRNA expression was unaltered between normal
glucose tolerant individuals and type 2
diabetic patients. SNARK expression was increased in
skeletal muscle from
obese (BMI >31 kg/m(2)) normal
glucose tolerant individuals and type 2
diabetic patients (1.4- and 1.4-fold, respectively, p < 0.05) vs
overweight (BMI <28 kg/m(2)) normal
glucose tolerant individuals and type 2
diabetic patients. SNARK
mRNA was increased in
myotubes exposed to
palmitate (12-fold; p < 0.01), or
TNF-alpha (25-fold, p < 0.05), but not to
oleate,
glucose or IL-6, whereas expression of the
AMP-activated protein kinase alpha2
subunit was unaltered. Small interfering (si)
RNA against SNARK reduced
mRNA and protein in
myotubes by 61% and 60%, respectively (p < 0.05). SNARK siRNA was without effect on basal or insulin-stimulated
glucose uptake or
lipid oxidation, and insufficient to rescue TNF-alpha- or palmitate-induced
insulin resistance. CONCLUSIONS/INTERPRETATION:
Skeletal muscle SNARK expression is increased in human
obesity, and in response to
metabolic stressors, but not
type 2 diabetes. Partial SNARK depletion failed to modify either
glucose or
lipid metabolism, or protect against TNF-alpha- or palmitate-induced
insulin resistance in primary human
myotubes.
