Sphk2-/- mice are protected from obesity and insulin resistance.

Sphingosine kinases phosphorylate sphingosine to sphingosine 1­phosphate (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 old 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.

Adaptation of Intestinal and Bile Acid Physiology Accompany the Metabolic Benefits Following Ileal Interposition in the Rat.

PURPOSE: Ileal interposition recapitulates many of the metabolic improvements similar to Roux-en-Y gastric bypass. We aimed to determine whether the metabolic improvements seen following ileal interposition were conferred solely by the interposed segment by examining changes in neighboring intestinal segments as well as the composition of the bile acid pool. MATERIALS AND METHODS: Adult male rats were treated with either sham or ileal interposition surgeries. Glucose tolerance tests, body composition analysis, polymer chain reaction, enzyme-linked immunosorbent assay, and mass spectrometry were done after the surgeries. RESULTS: This study showed that ileal interposition improved glucose tolerance and enhanced both fasting and glucose-stimulated GLP-1 secretion in diabetic rats. Total bile acid pool was similar between groups but the composition favored glycine-conjugation in rats with ileal interposition. Insulin secretion was highly correlated with the 12-alpha-hydroxylase index of activity. The interposed ileum exhibited an increase in mRNA for preproglucagon and peptide YY; however, the bile acid transporter, apical sodium bile acid transporter, was dramatically reduced compared to sham rats. The interposed segment becomes jejunized in its new location as indicated by an increase in Glut2 and Pepck mRNA, genes predominantly synthesized within the jejunum. CONCLUSION: Ileal relocation alone can significantly alter the bile acid pool to favor a more insulin-sensitive metabolism in association with intestinal wide alterations in mRNA for a variety of genes. Ileal interposition may confer metabolic improvement via both the interposed segment and the associated intestinal changes in all segments of the intestine, including the colon.