The failure of pancreatic β cells to adapt to an increasing demand for insulin is the major mechanism by which patients progress from insulin resistance to type 2 diabetes (T2D) and is thought to be related to dysfunctional lipid homeostasis within those cells. In multiple animal models of diabetes, females demonstrate relative protection from β cell failure. We previously found that the hormone 17β-estradiol (E2) in part mediates this benefit. Here, we show that treating male Zucker diabetic fatty (ZDF) rats with E2 suppressed synthesis and accumulation of fatty acids and glycerolipids in islets and protected against β cell failure. The antilipogenic actions of E2 were recapitulated by pharmacological activation of estrogen receptor α (ERα) or ERβ in a rat β cell line and in cultured ZDF rat, mouse, and human islets. Pancreas-specific null deletion of ERα in mice (PERα -/-) prevented reduction of lipid synthesis by E2 via a direct action in islets, and PERα -/-mice were predisposed to islet lipid accumulation and β cell dysfunction in response to feeding with a high-fat diet. ER activation inhibited β cell lipid synthesis by suppressing the expression (and activity) of fatty acid synthase via a nonclassical pathway dependent on activated Stat3. Accordingly, pancreas-specific deletion of Stat3 in mice curtailed ER-mediated suppression of lipid synthesis. These data suggest that extranuclear ERs may be promising therapeutic targets to prevent β cell failure in T2D.

Pairing the selective estrogen receptor modulator bazedoxifene (BZA) with estrogen as a tissue-selective estrogen complex (TSEC) is a novel menopausal therapy. We investigated estrogen, BZA and TSEC effects in preventing diabetisity in ovariectomized mice during high-fat feeding. Estrogen, BZA or TSEC prevented fat accumulation in adipose tissue, liver and skeletal muscle, and improved insulin resistance and glucose intolerance without stimulating uterine growth. Estrogen, BZA and TSEC improved energy homeostasis by increasing lipid oxidation and energy expenditure, and promoted insulin action by enhancing insulin-stimulated glucose disposal and suppressing hepatic glucose production. While estrogen improved metabolic homeostasis, at least partially, by increasing hepatic production of FGF21, BZA increased hepatic expression of Sirtuin1, PPARα and AMPK activity. The metabolic benefits of BZA were lost in estrogen receptor-α deficient mice. Thus, BZA alone or in TSEC produces metabolic signals of fasting and caloric restriction and improves energy and glucose homeostasis in female mice.

Background:The glucocorticoid (GR) and peroxisome proliferator-activated (PPAR␥) receptors are antagonists of lipid metabolism. Results: Protein phosphatase 5 (PP5) dephosphorylates GR and PPAR␥ to reciprocally control their activities. Conclusion: PP5 is a switch point in nuclear receptor control of lipid metabolism. Significance: PP5 is a potential new drug target in the treatment of obesity.

FK506-binding protein-51 (FKBP51) is a molecular cochaperone recently shown to be a positive regulator of peroxisome proliferator-activated receptor (PPAR)γ, the master regulator of adipocyte differentiation and function. In cellular models of adipogenesis, loss of FKBP51 not only reduced PPARγ activity but also reduced lipid accumulation, suggesting that FKBP51 knock-out (KO) mice might have insufficient development of adipose tissue and lipid storage ability. This model was tested by examining wild-type (WT) and FKBP51-KO mice under regular and high-fat diet conditions. Under both diets, FKBP51-KO mice were resistant to weight gain, hepatic steatosis, and had greatly reduced white adipose tissue (WAT) but higher amounts of brown adipose tissue. Under high-fat diet, KO mice were highly resistant to adiposity and exhibited reduced plasma lipids and elevated glucose and insulin tolerance. Profiling of perigonadal and sc WAT revealed elevated expression of brown adipose tissue lineage genes in KO mice that correlated increased energy expenditure and a shift of substrate oxidation to carbohydrates, as measured by indirect calorimetry. To directly test PPARγ involvement, WT and KO mice were fed rosiglitazone agonist. In WT mice, rosiglitazone induced whole-body weight gain, increased WAT mass, a shift of substrate oxidation to lipids, and elevated expression of PPARγ-regulated lipogenic genes in WAT. In contrast, KO mice had reduced rosiglitazone responses for these parameters. Our results identify FKBP51 as an important regulator of PPARγ in WAT and as a potential new target in the treatment of obesity and diabetes.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed at high levels in the hepatocyte, consistent with its role in promoting insulin clearance in liver. CEACAM1 also mediates a negative acute effect of insulin on fatty acid synthase activity. Western blot analysis reveals lower hepatic CEACAM1 expression during fasting. Treating of rat hepatoma FAO cells with Wy14,643, an agonist of peroxisome proliferator-activated receptor ␣ (PPAR␣), rapidly reduces Ceacam1 mRNA and CEACAM1 protein levels within 1 and 2 h, respectively. Luciferase reporter assay shows a decrease in the promoter activity of both rat and mouse genes by Ppar␣ activation, and 5-deletion and block substitution analyses reveal that the Ppar␣ response element between nucleotides ؊557 and ؊543 is required for regulation of the mouse promoter activity. Chromatin immunoprecipitation analysis demonstrates binding of liganded Ppar␣ to Ceacam1 promoter in liver lysates of Ppar␣ ؉/؉ , but not Ppar␣ ؊/؊ mice fed a Wy14,643-supplemented chow diet. Consequently, Wy14,643 feeding reduces hepatic Ceacam1 mRNA and CEACAM1 protein levels, thus decreasing insulin clearance to compensate for compromised insulin secretion and maintain glucose homeostasis and insulin sensitivity in wild-type mice. Together, the data show that the low hepatic CEACAM1 expression at fasting is mediated by Ppar␣-dependent mechanisms. Changes in CEACAM1 expression contribute to the coordination of fatty acid oxidation and insulin action in the fasting-refeeding transition.Plasma insulin levels are determined by several factors, including insulin secretion from pancreatic ␤-cells and insulin clearance (1, 2). Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), 4 a substrate of the insulin receptor tyrosine kinase (3), promotes insulin clearance by up-regulating receptor-mediated insulin endocytosis and degradation in a phosphorylation-dependent manner (4). Its specific inactivation in liver impairs insulin clearance to cause hyperinsulinemia and ensuing insulin resistance with increased hepatic steatosis (5).CEACAM1 is ubiquitously produced with a predominant expression in liver by comparison to kidney and a limited expression in white adipose tissue and skeletal muscle (6). Physiologically, this is consistent with the major role of the liver in insulin clearance by comparison to kidney and the insignificant involvement of the other insulin target tissues in insulin extraction. The mechanistic underpinning of this hierarchal expression profile relates to the up-regulation of Ceacam1 promoter activity by insulin (7), the level of which is 2-3-fold higher in the portal relative to the systemic circulation (8).In addition to CEACAM1, the hepatocyte is home to the highest level of fatty acid synthase, a lipogenic enzyme that catalyzes the conversion of malonyl-CoA to palmitic acid. Similar to CEACAM1, this high level of expression of fatty acid synthase is mediated by transcriptional up-regulation by insulin (9). However, despite the abundance of thi...

Glucocorticoid receptor-α (GRα) and peroxisome proliferator-activated receptor-γ (PPARγ) are critical regulators of adipogenic responses. We have shown that FK506-binding protein 51 (FKBP51) represses the Akt-p38 kinase pathway to reciprocally inhibit GRα but stimulate PPARγ by targeting serine 112 (PPARγ) and serines 220 and 234 (GRα). Here, this mechanism is shown to be essential for GRα and PPARγ control of cellular adipogenesis. In 3T3-L1 cells, FKBP51 was a prominent marker of the differentiated state and knockdown of FKBP51 showed reduced lipid accumulation and expression of adipogenic genes. Compared with wild-type (WT), FKBP51 knockout (51KO) mouse embryonic fibroblasts (MEFs) showed dramatic resistance to differentiation, with almost no lipid accumulation and greatly reduced adipogenic gene expression. These features were rescued by reexpression of FKBP51 in 51KO cells. 51KO MEFs exhibited reduced fatty acid synthase activity, increased sensitivity to GRα-induced lipolysis, and reduced PPARγ activity at adipogenic genes (adiponectin, CD36, and perilipin) but elevated GRα transrepression at these same genes. A p38 kinase inhibitor increased lipid content in WT cells and also restored lipid levels in 51KO cells, showing that elevated p38 kinase activity is a major contributor to adipogenic resistance in the 51KO cells. In 51KO cells, the S112A mutant of PPARγ and the triple S212A/S220A/S234A mutant of GRα both increased lipid accumulation, identifying these residues as targets of the FKBP51/p38 axis. Our combined investigations have uncovered FKBP51 as a key regulator of adipogenesis via the Akt-p38 pathway and as a potential target in the treatment of obesity and related disorders.

This study examined the prevalence and correlates of smoking initiation among adolescents. We have used data from adolescents (n=5,392) ages 10–18 who participated in the 2003 Tobacco Survey, a representative sample of adolescents in Northwest Ohio. A self-report of cigarette smoking was obtained using a questionnaire administered in classrooms. Data were analyzed using weighted chi-square and multiple logistic regressions in SAS that accounted for the survey design. The prevalence rates for adolescents that ever tried smoking were 7.4% in elementary (grades 4–5); 17.7% in middle (grades 6–8), and 41.4% in high (grades 9–12) schools, respectively. The highest prevalence rate was among Hispanics. Having a close friend that smoked and a smoker at home correlated significantly with both initiation of smoking and smoking at an earlier age. Smoking was correlated with low academic achievement among adolescents in all grades. Students who reported smoking by parents or siblings were significantly more likely to start smoking at an earlier age, compared to other students living in a non-smoking home environment. Smoking prevention program should include components focused on adolescents’ home environment and should start as early as the 4th grade.

Myelination requires a highly organized synthesis of multiple lipid species that regulate myelin curvature and compaction. For reasons that are not understood, central nervous system remyelinated axons often have thin myelin sheaths with a disorganized structure susceptible to secondary demyelination. We found that expression of the sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) during the differentiation of oligodendrocyte progenitor cells (OPCs) to myelinating oligodendrocytes changes their response to inflammatory cytokines. OPCs do not express nSMase2 and exhibit a protective/regenerative response to tumor necrosis factor–α and interleukin-1β. Oligodendrocytes express nSMase2 and exhibit a stress response to cytokine challenge that includes an overproduction of ceramide, a sphingolipid that forms negative curvatures in membranes. Pharmacological inhibition or genetic deletion of nSMase2 in myelinating oligodendrocytes normalized the ceramide content of remyelinated fibers and increased thickness and compaction. These results suggest that inhibition of nSMase2 could improve the quality of myelin and stabilize structure.