The serum- and glucocorticoid-induced kinase 1 (SGK1) is a transcriptional target of steroid hormones including glucocorticoids or aldosterone in addition to other stimuli such as glucose. SGK1 is activated via phosphoinositide 3-kinase, placing it downstream of insulin signaling. SGK1 participates in the upregulation of kidney Na+ reabsorption by aldosterone and has been linked to obesity-related hypertension in humans. We hypothesized that a systemic increase in SGK1 activity may trigger a multiplicity of mechanisms leading to simultaneous development of the main conditions that characterize the metabolic syndrome (MetS), including hypertension. We used a transgenic mouse model made with a bacterial artificial chromosome containing the whole mouse Sgk1 gene modified to introduce an activating point mutation. Wild type or transgenic 14-week-old male mice were fed with standard chow diet or high-fat diet for up to 18 weeks. Development of the main features of MetS and hepatic steatosis were monitored, and in vitro adipocyte differentiation was studied. Our results show that transgenic animals under high-fat diet rapidly and markedly develop MetS characterized by obesity, glucose intolerance, insulin resistance, dyslipidemia and hypertension. In addition, SGK1 gain-of-function accelerates the development of hepatic steatosis. Our study suggests that inappropriate SGK1 activity represents a risk factor in developing MetS with hypertension and related end-organ damage. Our data support SGK1 as a possible therapeutic target in MetS and related complications and provides a useful gain-of-function model for pre-clinical drug testing.
Keywords: blood pressure; fatty liver; insulin resistance; mouse model; serum and glucocorticoid-induced kinase.