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BackgroundInsulin resistance is manifested in muscle, adipose tissue, and liver and is associated with adipose tissue inflammation. The cellular components and mechanisms that regulate the onset of diet-induced insulin resistance are not clearly defined.Methodology and Principal FindingsWe initially observed osteopontin (OPN) mRNA over-expression in adipose tissue of obese, insulin resistant humans and rats which was normalized by thiazolidinedione (TZD) treatment in both species. OPN regulates inflammation and is implicated in pathogenic maladies resulting from chronic obesity. Thus, we tested the hypothesis that OPN is involved in the early development of insulin resistance using a 2–4 week high fat diet (HFD) model. OPN KO mice fed HFD for 2 weeks were completely protected from the severe skeletal muscle, liver and adipose tissue insulin resistance that developed in wild type (WT) controls, as determined by hyperinsulinemic euglycemic clamp and acute insulin-stimulation studies. Although two-week HFD did not alter body weight or plasma free fatty acids and cytokines in either strain, HFD-induced hyperleptinemia, increased adipose tissue inflammation (macrophages and cytokines), and adipocyte hypertrophy were significant in WT mice and blunted or absent in OPN KO mice. Adipose tissue OPN protein isoform expression was significantly altered in 2- and 4-week HFD-fed WT mice but total OPN protein was unchanged. OPN KO bone marrow stromal cells were more osteogenic and less adipogenic than WT cells in vitro. Interestingly, the two differentiation pathways were inversely affected by HFD in WT cells in vitro.ConclusionsThe OPN KO phenotypes we report reflect protection from insulin resistance that is associated with changes in adipocyte biology and adipose tissue inflammatory status. OPN is a key component in the development of HFD-induced insulin resistance.

Subramaniam S, Sears DD. Multi-tissue, selective PPAR␥ modulation of insulin sensitivity and metabolic pathways in obese rats. Am

␤-Arrestin1 is an adapter/scaffold for many G proteincoupled receptors during mitogen-activated protein kinase signaling. Phosphorylation of ␤-arrestin1 at position Ser-412 is a regulator of ␤-arrestin1 function, and in the present study, we showed that insulin led to a timeand dose-dependent increase in ␤-arrestin1 Ser-412 phosphorylation, which blocked isoproterenol-and lysophosphatidic acid-induced Ser-412 dephosphorylation and impaired ERK signaling by these G proteincoupled receptor ligands. Insulin treatment also led to accumulation of Ser-412-phosphorylated ␤-arrestin1 at the insulin-like growth factor 1 receptor and prevented insulin-like growth factor 1/Src association. Insulin-induced Ser-412 phosphorylation was partially dependent on ERK as treatment with the MEK inhibitor PD98059 inhibited the insulin effect (62% reduction, p ‫؍‬ 0.03). Inhibition of phosphatidylinositol 3-kinase by wortmannin did not have a significant effect (9% reduction, p ‫؍‬ 0.41). We also found that the protein phosphatase 2A (PP2A) was in a molecular complex with ␤-arrestin1 and that the PP2A inhibitor okadaic acid increased Ser-412 phosphorylation. Concomitant addition of insulin and okadaic acid did not produce an additive effect on Ser-412 phosphorylation, suggesting a common mechanism. Small t antigen specifically inhibited PP2A, and in HIRcB cells expressing small t antigen, ␤-arrestin1 Ser-412 phosphorylation was increased, and insulin had no further effect. Insulin treatment caused increased ␤-arrestin1 Ser-412 phosphorylation, which blocked mitogen-activated protein kinase signaling and internalization by ␤-arrestin1-dependent receptors with no effect on ␤-adrenergic receptor G s -mediated cAMP production. These findings provide a new mechanism for insulin-induced desensitization of ERK activation by G␣ icoupled receptors.Many hormone signaling systems are mediated by G proteincoupled receptors (GPCRs), 1 and several have been found to utilize ␤-arrestin as a key regulatory protein (1-8). In addition, the insulin-like growth factor-1 (IGF-1) receptor, a receptor tyrosine kinase, has recently been found to activate MAP kinase signaling in a G␣ i -and ␤-arrestin1-dependent manner (9). Thus, changes in ␤-arrestin function can have widespread implications for hormone signaling. We have recently found that insulin treatment is associated with down-regulation of ␤-arrestin1 protein (10) as well as phosphorylation of ␤-arrestin1 Ser-412 (11), representing possible new mechanisms of insulininduced impairment of ␤-arrestin1-dependent GPCR signaling. Activation of adenylate cyclase and generation of cAMP following ligand binding to some GPCRs coupled to G␣ s is attenuated once ␤-arrestin1 binds to the activated GPCR and sterically uncouples the receptor from further interaction with G␣ s (5). Other GPCRs, however, utilize ␤-arrestin as a scaffold for assembly of a multiprotein signaling complex that leads to activation of ERK1/2 (12-14). In addition, ␤-arrestin interacts with clathrin, targeting activated receptors to clathrin-...

Approximately 0.5% of all births occur before the third trimester of pregnancy, and these very early deliveries result in the majority of neonatal deaths and more than 40% of infant deaths. A recent executive summary of proceedings from a joint workshop defined periviable birth as delivery occurring from 20 0/7 weeks to 25 6/7 weeks of gestation. When delivery is anticipated near the limit of viability, families and health care teams are faced with complex and ethically challenging decisions. Multiple factors have been found to be associated with short-term and long-term outcomes of periviable births in addition to gestational age at birth. These include, but are not limited to, nonmodifiable factors (eg, fetal sex, weight, plurality), potentially modifiable antepartum and intrapartum factors (eg, location of delivery, intent to intervene by cesarean delivery or induction for delivery, administration of antenatal corticosteroids and magnesium sulfate), and postnatal management (eg, starting or withholding and continuing or withdrawing intensive care after birth). Antepartum and intrapartum management options vary depending upon the specific circumstances but may include short-term tocolytic therapy for preterm labor to allow time for administration of antenatal steroids, antibiotics to prolong latency after preterm premature rupture of membranes or for intrapartum group B streptococci prophylaxis, and delivery, including cesarean delivery, for concern regarding fetal well-being or fetal malpresentation. Whenever possible, periviable births for which maternal or neonatal intervention is planned should occur in centers that offer expertise in maternal and neonatal care and the needed infrastructure, including intensive care units, to support such services. This document describes newborn outcomes after periviable birth, provides current evidence and recommendations regarding interventions in this setting, and provides an outline for family counseling with the goal of incorporating informed patient preferences. Its intent is to provide support and guidance regarding decisions, including declining and accepting interventions and therapies, based on individual circumstances and patient values.