May 7, 2009 - The selective estrogen receptor modulator raloxifene was administered ... The combination of raloxifene and pentobarbital led to significantly ...
T R A N S L A T I O N A L
H I G H L I G H T S
F R O M
E N D O C R I N O L O G Y
A b s t r a c t s
The following abstracts from Endocrinology have been selected by the editors of JCEM as being particularly relevant to readers interested in translational science.
Adipose Tissue Inflammation: Developmental Ontogeny and Consequences of Gestational Nutrient Restriction in Offspring Don Sharkey, Michael E. Symonds, and Helen Budge (Endocrinology, published May 7, 2009, 10.1210/en.2008-1784) ABSTRACT Increasing adiposity predisposes to the development of the metabolic syndrome, in part, through adipose tissue dysregulation and inflammation. In addition, offspring nutrient restricted (NR) in utero can exhibit an increased risk of early-onset insulin resistance and obesity, although the mechanisms remain unclear. We aimed to: 1) define adipose tissue ontogeny of key proinflammatory and endoplasmic reticulum stress gene expression from late fetal to early adult life and 2) examine the impact on these genes in gestational nutrient restriction. Pregnant sheep were fed 100% (control) or 50% (NR) of their nutritional requirements between early to mid (28 – 80 d, term ⬃147 d) or late (110 –147 d) gestation. In control offspring, toll-like receptor 4 (TLR4), and the macrophage marker CD68, peaked at 30 d of life before declining. IL-18 peaked at 6 months of age, whereas the endoplasmic reticulum chaperone glucose-regulated protein 78 peaked at birth and subsequently declined through postnatal life. TLR4 and CD68 positively correlated with relative adipose tissue mass and with each other. Early to midgestational NR offspring had decreased abundance of IL-18 at 6 months of age. In late gestational NR offspring, CD68 was significantly lower at birth, a pattern that reversed in juvenile offspring, coupled with increased TLR4 abundance. In conclusion, the in utero nutritional environment can alter the adipose tissue inflammatory profile in offspring. This may contribute to the increased risk of insulin resistance or obesity, dependent on the timing of nutrient restriction. Establishing the optimal maternal diet during pregnancy could reduce the burden of later adult disease in the offspring.
Endotoxin-Induced Growth Hormone Resistance in Skeletal Muscle Yu Chen, Sumita Sood, Vidya M. R. Krishnamurthy, Peter Rotwein, and Ralph Rabkin (Endocrinology, published May 14, 2009, 10.1210/en.2008-1703) ABSTRACT Inflammation-induced skeletal muscle wasting is a serious clinical problem and arises in part because of resistance to GH-stimulated IGF-I expression. Although it is established that in the liver, resistance develops because of impaired signaling through the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) transduction pathway, together with a more distal defect in STAT5 DNA-binding activity, the situation in skeletal muscle is unclear. Accordingly, we set out to characterize the mechanisms behind the skeletal muscle resistance to GH in rats with acute inflammation induced by endotoxin. Endotoxin caused significant declines in GH-stimulated STAT5a/b phosphorylation and IGF-I gene expression, and this occurred despite a lack of change in signaling protein levels or phosphorylation of JAK2. In whole muscle, GH-stimulated phospho-STAT5a/b levels were reduced by half, and in the nucleus, phospho-STAT5b levels were similarly reduced. Furthermore, the binding of phosphorylated STAT5b to DNA was reduced and to a similar extent to the reduction in nuclear phosphorylated STAT5b. Interestingly, GH-induced androgen receptor gene expression was also suppressed. Thus, it appears that skeletal muscle resistance to GH-stimulated IGF-I expression in acute endotoxemia arises from a defect in STAT5b signaling, with a proportionate reduction in STAT5b DNA binding. Finally, it appears that resistance to GH-induced androgen receptor expression also develops and, together with the attenuated GH-induced IGF-I expression, likely plays an important role in the muscle wasting that arises in endotoxin-induced inflammation.
2670
jcem.endojournals.org
J Clin Endocrinol Metab, July 2009, 94(7):2670 –2671
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 07 November 2016. at 04:20 For personal use only. No other uses without permission. . All rights reserved.
J Clin Endocrinol Metab, July 2009, 94(7):2670 –2671
jcem.endojournals.org
2671
A Rat Model of Epilepsy in Women: A Tool to Study Physiological Interactions Between Endocrine Systems and Seizures Helen E. Scharfman, Gauri H. Malthankar-Phatak, Daniel Friedman, Patrice Pearce, Daniel P. McCloskey, Cynthia L. Harden, and Neil J. MacLusky (Endocrinology, published May 14, 2009, 10.1210/en.2009-0135) ABSTRACT Epilepsy in women is influenced by endocrine status and antiepileptic drugs (AEDs), but without an animal model, the effects of endocrine variables and AEDs cannot be easily dissociated from the influence of epilepsy itself. Animal models have had limited utility because experimentally-induced seizures typically result in reproductive failure. This study was conducted to develop an improved animal model. The muscarinic convulsant pilocarpine was used to elicit status epilepticus (SE) in adult female SpragueDawley rats. The selective estrogen receptor modulator raloxifene was administered 30 min before pilocarpine. An anticonvulsant barbiturate, pentobarbital, was injected 5–10 min after the onset of SE, and at least once thereafter to minimize acute convulsions. Mortality, morbidity, estrous cyclicity, and the ultimate success of the procedure (i.e. induction of recurrent, spontaneous seizures) were monitored. The combination of raloxifene and pentobarbital led to significantly improved estrous cyclicity compared to previous methods. Animals treated with raloxifene and pentobarbital became epileptic, as defined by the recurrence of spontaneous convulsions in the weeks after SE. The results of this study provide an improved animal model to examine the interactions between seizures and ovarian hormone secretion. The results also suggest that treatment of SE with raloxifene may benefit women with SE.
A Unique Rodent Model of Cardiometabolic Risk Associated with the Metabolic Syndrome and Polycystic Ovary Syndrome Danni Shi, Michael K. Dyck, Richard R. E. Uwiera, Jim C. Russell, Spencer D. Proctor, and Donna F. Vine (Endocrinology, published May 21, 2009, 10.1210/en.2008-1612) ABSTRACT Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-/anovulation and polycystic ovarian morphology, and is a complex endocrine disorder that also presents with features of the metabolic syndrome, including obesity, insulin resistance and dyslipidemia. These latter symptoms form cardiometabolic risk factors predisposing individuals to the development of type-2 diabetes and cardiovascular disease (CVD). To date, animal models to study PCOS in the context of the metabolic syndrome and CVD risk have been lacking. The aim of this study was to investigate the JCR:LA-cp rodent as an animal model of PCOS associated with the metabolic syndrome. Metabolic indices were measured at 6 and 12 wks, and reproductive parameters including ovarian morphology and estrous cyclicity were assessed at 12 wks or adulthood. At 6 wks of age, the cp/cp genotype of the JCR:LA-cp strain developed visceral obesity, IR, dyslipidemia (hypertriglyceridemia and hypercholesterolemia) compared to control animals. Serum testosterone (T) concentrations were not significantly different between groups at 6 wks of age. However at 12 wks, the cp/cp genotype had higher serum T concentrations, compared to control animals, and presented with oligoovulation, a decreased number of corpora lutea and an increased number of total follicles, in particular atretic and cystic follicles. The cardiometabolic risk factors in the cp/cp animals were exacerbated at 12 wks including obesity, insulin resistance and dyslipidemia. The results of this study demonstrate that the JCR:LA-cp rodent may be a useful PCOS-like model to study early mechanisms involved in the etiology of cardiometabolic risk factors in the context of both PCOS and the metabolic syndrome.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 07 November 2016. at 04:20 For personal use only. No other uses without permission. . All rights reserved.
