Regulation of skeletal muscle sucrose, non-fermenting 1/AMP-activated protein kinase-related kinase (SNARK) by metabolic stress and diabetes

Abstract

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-α (25-fold, p<0.05), but not to oleate, glucose or IL-6, whereas expression of the AMP-activated protein kinase α2 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-α- 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-α- or palmitate-induced insulin resistance in primary human myotubes.