Inactivation of SPAK kinase reduces body weight gain in mice fed a high-fat diet by improving energy expenditure and insulin sensitivity

• Published in: American journal of physiology: endocrinology and metabolism 2018-01, Vol.314 (1), p.E53-E65
• Main Authors: Torre-Villalvazo, Ivan, Cervantes-Pérez, Luz Graciela, Noriega, Lilia G, Jiménez, Jose V, Uribe, Norma, Chávez-Canales, María, Tovar-Palacio, Claudia, Marfil-Garza, Braulio A, Torres, Nimbe, Bobadilla, Norma A, Tovar, Armando R, Gamba, Gerardo
• Format: Article
• Language: English
• Subjects: Adipose tissue; Adipose tissue (brown); Alanine; Animals; Blood pressure; Body weight; Body weight gain; Cell size; Cells, Cultured; Chlorides; Deactivation; Diet; Diet, High-Fat - adverse effects; Dietary Fats - pharmacology; Energy balance; Energy expenditure; Energy Metabolism - drug effects; Energy Metabolism - genetics; Fatty liver; Gene Knock-In Techniques; Gene Silencing; Glucose; Glucose tolerance; High fat diet; Hormones; Hypertension; Hypertrophy; Inactivation; Insulin; Insulin Resistance - genetics; Kinases; Male; Metabolic syndrome; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Modulation; Muscles; Obesity; Oils & fats; Proline; Protein kinase; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - physiology; Rodents; Salts; Sensitivity; Skeletal muscle; Steatosis; Substrates; Thermogenesis; Weight Gain - drug effects; Weight Gain - genetics; Weight reduction
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00108.2017

The STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) controls the activity of the electroneutral cation-chloride cotransporters (SLC12 family) and thus physiological processes such as modulation of cell volume, intracellular chloride concentration [Cl ] , and transepithelial salt transport. Modulation of SPAK kinase activity may have an impact on hypertension and obesity, as STK39, the gene encoding SPAK, has been suggested as a hypertension and obesity susceptibility gene. In fact, the absence of SPAK activity in mice in which the activating threonine in the T loop was substituted by alanine (SPAK-KI mice) is associated with decreased blood pressure; however its consequences in metabolism have not been explored. Here, we fed wild-type and homozygous SPAK-KI mice a high-fat diet for 17 wk to evaluate weight gain, circulating substrates and hormones, energy expenditure, glucose tolerance, and insulin sensitivity. SPAK-KI mice exhibit resistance to HFD-induced obesity and hepatic steatosis associated with increased energy expenditure, higher thermogenic activity in brown adipose tissue, increased mitochondrial activity in skeletal muscle, and reduced white adipose tissue hypertrophy mediated by augmented whole body insulin sensitivity and glucose tolerance. Our data reveal a previously unrecognized role for the SPAK kinase in the regulation of energy balance, thermogenesis, and insulin sensitivity, suggesting that this kinase could be a new drug target for the treatment of obesity and the metabolic syndrome.