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Am J Physiol Endocrinol Metab. 2018 Jan 1;314(1):E53-E65. doi: 10.1152/ajpendo.00108.2017. Epub 2017 Oct 24.

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

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Department of Nutrition Physiology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán , Mexico City, Mexico.
Department of Pharmacology, Instituto Nacional de Cardiología Ignacio Chávez , México City, Mexico.
Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán , Mexico City, Mexico.
Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán , México City, Mexico.
Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México , Mexico City, Mexico.
Tecnologico de Monterrey, Escuela de Medicina y de Ciencias de la Salud, Monterrey, Mexico.


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-]i, 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.


STE20/SPS1-related proline-alanine-rich protein kinase; glucose tolerance; hepatic steatosis; kinase; metabolic syndrome; obesity; uncoupling protein 1

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