Sphk2−/− mice are protected from obesity and insulin resistance

Abstract

Sphingosine kinases phosphorylate sphingosine to sphingosine 1-phosphate (S1P), which functions as a signaling molecule. We have previously shown that sphingosine kinase 2 (Sphk2) is important for insulin secretion. To obtain a better understanding of the role of Sphk2 in glucose and lipid metabolism, we have characterized 20-and 52-week old Sphk2 −/− mice using glucose and insulin tolerance tests and by analyzing metabolic gene expression in adipose tissue. A detailed metabolic characterization of these mice revealed that aging Sphk2 −/− mice are protected from metabolic decline and obesity compared to WT mice. Specifically, we found that 52-week male Sphk2 −/− mice had decreased weight and fat mass, and increased glucose tolerance and insulin sensitivity compared to control mice. Indirect calorimetry studies demonstrated an increased energy expenditure and food intake in 52-week old male Sphk2 −/− versus control mice. Furthermore, expression of adiponectin gene in adipose tissue was increased and the plasma levels of adiponectin elevated in aged Sphk2 −/− mice compared to WT. Analysis of lipid metabolic gene expression in adipose tissue showed increased expression of the Atgl gene, which was associated with increased Atgl protein levels. Atgl encodes for the adipocyte triglyceride lipase, which catalyzes the rate-limiting step of lipolysis. In summary, these data suggest that mice lacking the Sphk2 gene are protected from obesity and insulin resistance during aging. The beneficial metabolic effects observed in aged Sphk2 −/− mice may be in part due to enhanced lipolysis by Atgl and increased levels of adiponectin, which has lipid-and glucose-lowering effects.

Sphingolipid Metabolism and Signaling in Skeletal Muscle: From Physiology to Physiopathology

“…In opposite to SphK1, muscle SphK2 overexpression had no effect on muscle lipid content, suggesting that SphK2 did no regulate muscle ceramide levels (155). More recently, Ravichandran et al (161) aimed to better understand the role of SphK2 in glucose and lipid metabolism. They characterized metabolic parameters of SphK2 KO old mice compared to control old mice, as aging is associated with weight gain and obesity (161).…”

“…More recently, Ravichandran et al (161) aimed to better understand the role of SphK2 in glucose and lipid metabolism. They characterized metabolic parameters of SphK2 KO old mice compared to control old mice, as aging is associated with weight gain and obesity (161). SphK2 KO mice seemed to be protected against age-related changes of adipose tissue as they displayed decreased weight and fat mass and increased lean mass (161).…”

“…They characterized metabolic parameters of SphK2 KO old mice compared to control old mice, as aging is associated with weight gain and obesity (161). SphK2 KO mice seemed to be protected against age-related changes of adipose tissue as they displayed decreased weight and fat mass and increased lean mass (161). Moreover, old SphK2 KO mice saw their glucose tolerance and insulin sensitivity improved with aging compared with WT mice (161).…”

“…SphK2 KO mice seemed to be protected against age-related changes of adipose tissue as they displayed decreased weight and fat mass and increased lean mass (161). Moreover, old SphK2 KO mice saw their glucose tolerance and insulin sensitivity improved with aging compared with WT mice (161). These enhanced metabolic e?ects could be the result of increased adiponectin plasma levels and enhanced lipolysis (161).…”

Apolipoprotein M and Sphingosine-1-Phosphate: A Potentially Antidiabetic Tandem Carried by HDL

“…Compared with wild-type mice, Apom knockout mice are characterized by larger brown adipose tissue mass, accelerated normalization of postprandial hypertriglyceridemia, and protection from HFD-induced obesity (18). The treatment of mice with fingolimod, which inhibits all five S1P receptors and is in clinical use for the treatment of multiple sclerosis, improved both secretion and peripheral action of insulin as well as HFD-induced hepatosteatosis (19)(20)(21). Likewise, genetic interference with S1p2 and Sphk2 in mice resulted in improved b-cell function and insulin resistance (22,23).…”