Diet-induced muscle insulin resistance is associated with expansion of extracellular matrix (ECM) components, such as collagens, and the expression of collagenbinding integrin, a2b1. Integrins transduce signals from ECM via their cytoplasmic domains, which bind to intracellular integrin-binding proteins. The integrinlinked kinase (ILK)-PINCH-parvin (IPP) complex interacts with the cytoplasmic domain of b-integrin subunits and is critical for integrin signaling. In this study we defined the role of ILK, a key component of the IPP complex, in diet-induced muscle insulin resistance. Wild-type (ILK lox/lox ) and muscle-specific ILK-deficient (ILK lox/lox HSAcre) mice were fed chow or a high-fat (HF) diet for 16 weeks. Body weight was not different between ILK lox/lox and ILK lox/lox HSAcre mice. However, HF-fed ILK lox/lox HSAcre mice had improved muscle insulin sensitivity relative to HF-fed ILK lox/lox mice, as shown by increased rates of glucose infusion, glucose disappearance, and muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. Improved muscle insulin action in the HF-fed ILK lox/lox HSAcre mice was associated with increased insulin-stimulated phosphorylation of Akt and increased muscle capillarization. These results suggest that ILK expression in muscle is a critical component of diet-induced insulin resistance, which possibly acts by impairing insulin signaling and insulin perfusion through capillaries.Insulin resistance is a commonly associated risk factor for many pathophysiological conditions, including diabetes, cardiovascular diseases, neurological changes, liver diseases, and sleep apnea (1,2). A defect in glucose utilization in the skeletal muscle is a major component of insulin resistance. The pathogenesis of muscle insulin resistance is not fully understood, and pharmacological interventions that reduce insulin resistance are limited and often lose efficacy over time (e.g., biguanides) or have adverse side effects (e.g., thiazolidinediones) (3). Our recent studies have suggested a novel role for extramyocellular factors in regulating muscle insulin action. Expansion of extracellular matrix (ECM) components, such as the collagens and the expression of the collagen-binding integrin a2b1, are associated with muscle insulin resistance induced by a high-fat (HF) diet (4). The ECM is in direct contact with the muscle capillaries. Defects in recruitment of muscle capillaries contribute to the development of muscle insulin resistance (5). Transduction of ECM signals through integrins requires interaction of the integrin cytoplasmic domains with cellular proteins. To investigate the link between ECM-integrin signaling and muscle insulin resistance, we studied a highly conserved central downstream component of the ECM-integrin signaling, integrin-linked kinase (ILK), and its role in muscle insulin resistance.ILK, a pseudokinase with adaptor function, is a central component of the ILK-PINCH-parvin complex (IPP) (6). This complex binds to the cytoplasmic domain of b-integrin subunits. The IPP co...

Background: Although it has been more than a century since endometriosis was initially described in the literature, understanding the etiology and natural history of the disease has been challenging. However, the broad utility of murine and rat models of experimental endometriosis has enabled the elucidation of a number of potentially targetable processes which may otherwise promote this disease.Objective: To review a variety of studies utilizing rodent models of endometriosis to illustrate their utility in examining mechanisms associated with development and progression of this disease.Results: Use of rodent models of endometriosis has provided a much broader understanding of the risk factors for the initial development of endometriosis, the cellular pathology of the disease and the identification of potential therapeutic targets.Conclusion: Although there are limitations with any animal model, the variety of experimental endometriosis models that have been developed has enabled investigation into numerous aspects of this disease. Thanks to these models, our under-standing of the early processes of disease development, the role of steroid responsiveness, inflammatory processes and the peritoneal environment has been advanced. More recent models have begun to shed light on how epigenetic alterations con-tribute to the molecular basis of this disease as well as the multiple comorbidities which plague many patients. Continued de-velopments of animal models which aid in unraveling the mechanisms of endometriosis development provide the best oppor-tunity to identify therapeutic strategies to prevent or regress this enigmatic disease.

Adolescents who enter pregnancy overweight or obese and experience excessive weight gain may be at increased risk for postpartum depressive symptoms. Health care providers should offer preventive interventions during pregnancy and the interconceptional period to support healthy weight gain and safeguard women's mental health.

Preterm birth (PTB), parturition prior to 37 weeks' gestation, is the leading cause of neonatal mortality. The causes of spontaneous PTB are poorly understood; however, recent studies suggest that this condition may arise as a consequence of the parental fetal environment. Specifically, we previously demonstrated that developmental exposure of male mice (F1 animals) to the environmental endocrine disruptor 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was associated with reduced sperm quantity/quality in adulthood and control female partners frequently delivered preterm. Reproductive defects persisted in the F2 and F3 descendants, and spontaneous PTB was common. Reproductive changes in the F3 males, the first generation without direct TCDD exposure, suggest the occurrence of epigenetic alterations in the sperm, which have the potential to impact placental development. Herein, we conducted an epigenetic microarray analysis of control and F1 male-derived placentae, which identified 2171 differentially methylated regions, including the progesterone receptor (Pgr) and insulin-like growth factor (Igf2). To assess if Pgr and Igf2 DNA methylation changes were present in sperm and persist in future generations, we assessed methylation and expression of these genes in F1/F3 sperm and F3-derived placentae. Although alterations in methylation and gene expression were observed, in most tissues, only Pgr reached statistical significance. Despite the modest gene expression changes in Igf2, offspring of F1 and F3 males consistently exhibited IUGR. Taken together, our data indicate that paternal developmental TCDD exposure is associated with transgenerational placental dysfunction, suggesting epigenetic modifications within the sperm have occurred. An evaluation of additional genes and alternative epigenetic mechanisms is warranted.

Elevated reactive oxygen species (ROS) are linked to insulin resistance and islet dysfunction. Manganese superoxide dismutase (SOD2) is a primary defense against mitochondrial oxidative stress. To test the hypothesis that heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion (GSIS) and insulin action, wild-type (sod2+/+) and heterozygous knockout mice (sod2+/−) were fed a chow or high-fat (HF) diet, which accelerates ROS production. Hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI) clamps were performed to assess GSIS and insulin action in vivo. GSIS during HG clamps was equal in chow-fed sod2+/− and sod2+/+ but was markedly decreased in HF-fed sod2+/−. Remarkably, this impairment was not paralleled by reduced HG glucose infusion rate (GIR). Decreased GSIS in HF-fed sod2+/− was associated with increased ROS, such as superoxide ion. Surprisingly, insulin action determined by HI clamps did not differ between sod2+/− and sod2+/+ of either diet. Since insulin action was unaffected, we hypothesized that the unchanged HG GIR in HF-fed sod2+/− was due to increased glucose effectiveness. Increased GLUT-1, hexokinase II, and phospho-AMPK protein in muscle of HF-fed sod2+/− support this hypothesis. We conclude that heterozygous SOD2 deletion in mice, a model that mimics SOD2 changes observed in diabetic humans, impairs GSIS in HF-fed mice without affecting insulin action.

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Background: Necrotizing enterocolitis (NEC) is a rare, but potentially fatal intestinal inflammatory condition most often arising in premature infants. Infants provided formula are also at greater risk of developing this disease. Although the majority of formula-fed, preterm infants do not develop NEC, up to 30% of infants with the disease do not survive. Thus, identifying additional, currently unrecognized factors, which may predispose a specific infant to NEC development would be a significant clinical advancement. In this regard, we have previously reported that offspring of female or male mice with a history of developmental exposure to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exhibit altered sensitivity to inflammatory challenges and are frequently born premature. Herein, we examined the possibility that, compared to unexposed mice (F1 NONE), developmental TCDD exposure of either parent (maternal, F1M TCDD , or paternal, F1P TCDD) would enhance the risk of NEC in offspring (F2 TCDD mice) in association with supplemental formula feeding. Methods: Beginning on postnatal day 7, all neonates were randomized to maternal milk only or maternal milk with up to 20 supplemental formula feedings. All pups remained with the Dams and were additionally allowed to nurse ad libitum. Results: Formula-fed F2 NONE pups rarely developed NEC while this disease was common in formula-fed F2M TCDD and F2P TCDD mice. Unexpectedly, 50% of F2M TCDD pups that were not provided supplemental formula also developed NEC. Conclusions: Our studies provide evidence that a history of parental TCDD exposure enhances the risk of NEC in offspring and suggest exposure to environmental immunotoxicants such as TCDD may also contribute to this inflammatory disease in humans.

Development of adhesions commonly occurs in association with surgery for endometriosis. Even in the absence of surgery, women with endometriosis appear to be at an enhanced risk of developing adhesions. In the current study, we utilized a chimeric mouse model of experimental endometriosis in order to examine the role of inflammasome activation in the development of postsurgical adhesions. Mice were randomized to receive peritoneal injections of human endometrial tissue fragments or endometrial tissue conditioned media (CM) from women with or without endometriosis 16 hours after ovariectomy and placement of an estradiol-releasing silastic capsule. A subset of mice receiving CM was also treated with interleukin (IL) 1 receptor antagonist (IL-1ra). Our studies demonstrate that peritoneal injection of endometrial tissue fragments near the time of surgery resulted in extensive adhesive disease regardless of tissue origin. However, adhesion scores were significantly higher in mice receiving CM from tissues acquired from patients with endometriosis compared to control tissue CM ( P = .0001). Cytokine bead array analysis of endometrial CM revealed enhanced expression of IL-1β from patients with endometriosis compared to controls ( P < .01). Finally, the ability of human tissue CM to promote adhesive disease was dramatically reduced in mice cotreated with IL-1ra ( P < .0001). Our data implicate enhanced expression of IL-1β in women with endometriosis as a potential causal factor in their increased susceptibility of developing postsurgical adhesions. Thus, targeting inflammasome activation may be an effective strategy for the prevention of surgical adhesions in patients with endometriosis.