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Inactivation of SPAK kinase reduces body weight gain in mice fed a high-fat diet by improving energy expenditure and insulin sensitivity
- Source :
- American journal of physiology. Endocrinology and metabolism. 314(1)
- Publication Year :
- 2017
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
Physiology
Endocrinology, Diabetes and Metabolism
030209 endocrinology & metabolism
Mice, Transgenic
Biology
Protein Serine-Threonine Kinases
Body weight
Diet, High-Fat
Weight Gain
03 medical and health sciences
Mice
0302 clinical medicine
Physiology (medical)
Internal medicine
medicine
Animals
Gene Knock-In Techniques
Gene Silencing
Protein kinase A
Cells, Cultured
Kinase
Insulin sensitivity
medicine.disease
Obesity
Dietary Fats
Thermogenin
Mice, Inbred C57BL
030104 developmental biology
Endocrinology
Metabolic syndrome
Insulin Resistance
Cotransporter
Energy Metabolism
Subjects
Details
- ISSN :
- 15221555
- Volume :
- 314
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- American journal of physiology. Endocrinology and metabolism
- Accession number :
- edsair.doi.dedup.....ee37a4bb87e0fe364878f492becf1b06