Abstract: TH-PO696

Inactivation of the SPAK Kinase Generates an Obesity-Resistant Phenotype in Mice

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Marfil, Braulio Alejandro, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
  • Tovar, Armando R., Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
  • Gamba, Gerardo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
  • Torre-Villalvazo, Ivan, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
  • Cervantes-perez, Luz Graciela, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
  • Noriega, Lilia G., Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
  • Chavez-Canales, Maria, Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico
  • Jimenez, Jose Víctor, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
  • Uribe-uribe, Norma O., Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
  • Torres, Nimbe, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
  • Bobadilla, Norma, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
Background

The WNK (with-no-lysine)/SPAK (Ste20-related proline/alanine rich kinase) pathway has a well-known role in hypertension through its predominant effect on renal salt reabsorption. Recent evidence suggests this pathway could also be involved in the pathophysiology of obesity, which could link both diseases intrinsically. In humans the STK39 gene, which encodes SPAK, has been suggested as a susceptibility gene for arterial hypertension and for obesity. In this regard, the lack of SPAK activity in a knockin mice model (SPAK-T243A/T243A) leads to a reduction in blood pressure, but the effect of SPAK inactivation on body weight balance has not been evaluated.

Methods

To characterize the role of SPAK in energy balance, we fed wild-type and SPAK-knockin mice (SPAK-T243A/T243A) a high-fat diet (HFD) for 17 weeks and evaluated body composition, energy expenditure, thermogenesis, lipid metabolism, leptin levels, glucose metabolism and end-organ damage such as hepatic lipid content and pancreatic islet hypertrophy.

Results

Our results reveal that in contrast to wild type mice fed with HFD, the SPAK-T243A/T243A mice fed a HFD exhibit a significantly lower weight gain (15.1 ± 0.8 vs 10.2 ± 2.0 g; p<0.001) and decreased adiposity along the study, exhibiting at the end a better glucose tolerance, lower cholesterol, triglyceride and leptin levels, less hepatic steatosis and less pancreatic islet hypertrophy. The HFD intake was similar in both groups along the study. Calorimetric studies showed in the SPAK-T243A/T243A mice an increased thermogenic activity in brown adipose tissue, increased UCP1 expression, and white adipose tissue browning.

Conclusion

Our data suggest that SPAK-T243A/T243A mice are partially resistant to obesity induced with a HFD due to an increase in energy expenditure and thermogenesis, suggesting that the WNK/SPAK pathway could play a role in the pathophysiology of obesity and energy balance. Our results also suggest that inhibition of SPAK activity could have a therapeutic value in obesity.
Supported by “Fronteras de la Ciencia” grant No. 23 from Conacyt, Mexico to GG.

Funding

  • Government Support - Non-U.S.