Hepatic expression of gluco-regulatory enzymes after acutely normalizing blood glucose in glucose transporter 4 over-expressing mice (G4Tg) and wild-type (WT) littermates.

<p>Hepatic expression of glucokinase (GK; A), glucose-6-phosphatase (G6Pase; B), and cytosolic phospho<i>enol</i>pyruvate kinase (PEPCK; C) are shown before and after normalizing blood glucose in 5h-fasted mice that over-express glucose transporter 4 (Glut4) in skeletal muscle, heart, and adipose tissue (G4Tg) and wild-type (WT) littermates during a 90 min phloridzin (80 μg·kg⁻¹·min⁻¹)-glucose (115 mg·dL⁻¹) clamp. Separate cohorts of mice were used to obtain basal and clamp data. Data are presented as means ± SEM and normalized to cyclophilin expression and basal levels in WT mice. * and ϕ indicate p<0.05 compared to WT littermates or to basal values within a genotype, respectively. n = 7–8 mice in each group.</p

Hormonal and glucose flux responses to acutely normalizing blood glucose in glucose transporter 4 over-expressing mice (G4Tg) and wild-type (WT) littermates.

<p>A 90 min phloridzin (80 μg·kg⁻¹·min⁻¹)-glucose (115 mg·dL⁻¹) clamp was performed in conscious, chronically-catheterized, 5 h-fasted mice that over-express glucose transporter 4 (Glut4) in skeletal muscle, heart, and adipose tissue and wild-type (WT) littermates to normalize basal differences in arterial blood glucose (A) using an exogenous glucose infusion rate (B). Basal and clamp endogenous appearance (endoR_a; C) and disappearance (R_d; D) of glucose were measured using a primed, constant infusion of [3-³H] glucose (50 μCi bolus +0.05 μCi·min⁻¹). Basal and clamp arterial insulin, non-esterified fatty acids (NEFA), and glucagon are shown in panels E-G, respectively. Data are presented as means ± SEM and * and ϕ indicate p<0.05 compared to WT littermates or to basal values within a genotype, respectively. n = 7–8 mice in each group.</p

Hepatic glycogen and related enzyme activities in response to acutely normalizing blood glucose in glucose transporter 4 over-expressing mice (G4Tg) and wild-type (WT) littermates.

<p>Hepatic glycogen content (A), hepatic glycogen breakdown (B), and activities or activity ratios of glucokinase (GK; C), glucose-6-phosphatase (G6Pase; D), glycogen phosphorylase (GP; E), and glycogen synthase (GS; F)] are shown before and after normalizing blood glucose in 5 h-fasted mice that over-express glucose transporter 4 (Glut4) in skeletal muscle, heart, and adipose tissue and wild-type (WT) littermates using a 90 min phloridzin (80 μg·kg⁻¹·min⁻¹)-glucose (115 mg·dL⁻¹) clamp. Separate cohorts of mice were used to obtain basal and clamp data. Dashed lines in panel B denote changes in endogenous appearance of glucose (endoR_a; shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052355#pone-0052355-g001" target="_blank">Figure 1C</a>). Data are presented as means ± SEM and * and ϕ indicate p<0.05 compared to WT littermates or to basal values within a genotype, respectively. n = 7–8 mice in each group.</p

Basal characteristics of wild-type (WT) and littermate mice with over-expression of glucose transporter 4 (G4Tg).

<p>Measurements were taken in 5h fasted mice prior to phloridzin-glucose clamps and represent combined data from control and experimental animals. * indicates p<0.05 compared to WT littermates.</p

Striatal Dopamine Homeostasis is Altered in Mice Following Roux-en‑Y Gastric Bypass Surgery

Roux-en-Y gastric bypass (RYGB) is an effective treatment for obesity. Importantly, weight loss following RYGB is thought to result in part from changes in brain-mediated regulation of appetite and food intake. Dopamine (DA) within the dorsal striatum plays an important role in feeding behavior; we therefore hypothesized that RYGB alters DA homeostasis in this subcortical region. In the current study, obese RYGB-operated mice consumed significantly less of a high-fat diet, weighed less by the end of the study, and exhibited lower adiposity than obese sham-operated mice. Interestingly, both RYGB and caloric restriction (pair feeding) resulted in elevated DA and reduced norepinephrine (NE) tissue levels compared with ad libitum fed sham animals. Consequently, the ratio of NE to DA, a measure of DA turnover, was significantly reduced in both of these groups. The RYGB mice additionally exhibited a significant increase in phosphorylation of tyrosine hydroxylase at position Ser31, a key regulatory site of DA synthesis. This increase was associated with augmented expression of extracellular-signal-regulated kinases ERK1/2, the kinase targeting Ser31. Additionally, RYGB has been shown in animal models and humans to improve insulin sensitivity and glycemic control. Curiously, we noted a significant increase in the expression of insulin receptor-β in RYGB animals in striatum (a glucosensing brain region) compared to sham ad libitum fed mice. These data demonstrate that RYGB surgery is associated with altered monoamine homeostasis at the level of the dorsal striatum, thus providing a critical foundation for future studies exploring central mechanisms of weight loss in RYGB