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The ventrolateral preoptic area (VLPO) and the orexin/hypocretin neuronal system are key regulators of sleep onset, transitions between vigilance states, and energy homeostasis. Reciprocal projections exist between the VLPO and orexin/hypocretin neurons. Although the importance of the VLPO to sleep regulation is clear, it is unknown whether VLPO neurons are involved in energy balance. The purpose of these studies was to determine if the VLPO is a site of action for orexin-A, and which orexin receptor subtype(s) would mediate these effects of orexin-A. We hypothesized that orexin-A in the VLPO modulates behaviors (sleep and wakefulness, feeding, spontaneous physical activity [SPA]) to increase energy expenditure.

Conventional treatments for patients with type 2 diabetes are often inadequate. We aimed to assess outcomes of diabetes control and treatment risks 2 years after adding Roux-en-Y gastric bypass to intensive lifestyle and medical management.

Holoprosencephaly (HPE) is a developmental anomaly characterized by inadequate or absent midline division of the embryonic forebrain and midline facial defects. It is believed that interactions between genes and the environment play a role in the widely variable penetrance and expressivity of HPE, although direct investigation of such effects has been limited. The goal of this study was to examine whether mice carrying a mutation in a gene encoding the bone morphogenetic protein (BMP) antagonist twisted gastrulation (Twsg1), which is associated with a low penetrance of HPE, are sensitized to retinoic acid (RA) teratogenesis. Pregnant Twsg1+/− dams were treated by gavage with a low dose of all-trans RA (3.75 mg/kg of body weight). Embryos were analyzed between embryonic day (E)9.5 and E11.5 by microscopy and geometric morphometric analysis by micro-computed tomography. P19 embryonal carcinoma cells were used to examine potential mechanisms mediating the combined effects of increased BMP and retinoid signaling. Although only 7% of wild-type embryos exposed to RA showed overt HPE or neural tube defects (NTDs), 100% of Twsg1−/− mutants exposed to RA manifested severe HPE compared to 17% without RA. Remarkably, up to 30% of Twsg1+/− mutants also showed HPE (23%) or NTDs (7%). The majority of shape variation among Twsg1+/− mutants was associated with narrowing of the midface. In P19 cells, RA induced the expression of Bmp2, acted in concert with BMP2 to increase p53 expression, caspase activation and oxidative stress. This study provides direct evidence for modifying effects of the environment in a genetic mouse model carrying a predisposing mutation for HPE in the Twsg1 gene. Further study of the mechanisms underlying these gene-environment interactions in vivo will contribute to better understanding of the pathogenesis of birth defects and present an opportunity to explore potential preventive interventions.

The current understanding of the effects of hypoxia on early embryogenesis is limited. Potential mediators of hypoxic effects include adenosine, which increases dramatically during hypoxic conditions and activates A1 adenosine receptors (A1ARs).To examine the influences of hypoxia and adenosine signaling on cardiac development, chicken embryos were studied. Real time RT‐PCR assay was used to examine the A1AR gene expression during embryogenesis and after siRNA‐ mediated knock down. Cell proliferation was determined by counting cell nuclei and PhosphoHistone H3 positive cells. Apoptosis was determined by TUNEL assay.A1ARs were found to be expressed in chicken embryos during early embryogenesis. Treatment of Hamburger and Hamilton stage 4 embryos with the A1AR agonist N6‐cyclopentyladenosine caused cardiac bifida and looping defects in 55% of embryos. Hamburger and Hamilton stage 4 embryos exposed to 10% oxygen for 6, 12, 18, and 24 h followed by recovery in room air until stage 11, exhibited cardia bifida and looping defects in 34, 45, 60, and 86% of embryos respectively. Hypoxia‐induced abnormalities were reduced when A1AR signaling was inhibited by the A1AR antagonist 1,3 dipropyl‐8‐cyclopentylxanthine or by siRNA‐targeting A1ARs. Hypoxia treatment did not increase apoptosis, but decreased embryonic cell proliferation.These data indicate that hypoxia adversely influences cardiac malformations during development, in part by A1AR signaling. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.

This report describes the prevalence of overweight and obesity and estimates the disease burden associated with excess weight in ambulatory Veterans Affairs (VA) patients.

-Endorphin (-END) and -melanocyte stimulating hormone (-MSH), neuropeptides derived from proopiomelanocortin (POMC), have opposite effects on eating behavior. We injected rats with -MSH (0.6 nmol) or -END (1 nmol) into the PVN (three times in a 26 h period). These doses of -MSH and -END decreased and increased feeding respectively. Following -MSH administration into the PVN, mRNA levels of POMC decreased by 17, whereas there was no significant change in gene expression of either proDynorphin or proEnkephalin. PVN injection of -END failed to alter gene expression of POMC, proDynorphin or proEnkephalin. These data suggest that a feedback pathway exists between the PVN and ARC for -MSH and POMC, but not for -END and POMC.

Cocaine and amphetamine regulated transcript (CART) decreases feeding and body weight after ventricular injection. CART mRNA and peptide are found in the paraventricular nucleus of the hypothalamus (PVN). The purpose of the present study was to determine effects of PVN-injected CART on feeding and thermogenic capacity. PVN-injected CART (55–102, 100 pmol) significantly decreased NPY-induced feeding at 1, 2 and 4 h, but did not significantly affect deprivation-induced feeding. CART induced gene expression of uncoupling protein 1 (UCP1), UCP2, and UCP3 in brown and white adipose tissue and biceps femoris muscle respectively. These results indicate the PVN as a specific site of CART action, and suggest that CART in the PVN may have an important influence on energy metabolism.

Hypocretin I (also referred to as orexin A) administered into the lateral hypothalamus (LH) stimulates feeding in rats. We undertook the present study to determine the brain regions activated by LH administration of hypocretin I. Hypocretin I administered into the LH significantly elevated cFos-immunoreactivity in the lateral septal area, the central nucleus of the amygdala, the shell of the nucleus accumbens, the bed nucleus of the stria terminalis, the LH, the posterior and dorsomedial hypothalamus, the perifornical, arcuate and paraventricular nuclei and the nucleus of the solitary tract. These data indicate that LH hypocretin I communicates with other key energy regulatory sites within the hypothalamus, the limbic region and the hindbrain, and suggest that these areas are important in the feeding-stimulatory actions of hypocretin I.

Objective:Individuals with hyperthyroidism lose weight despite increased appetite and food intake, and weight is regained after treatment of hyperthyroidism. We asked whether this weight regain is purely a function of lowered metabolic rate coincident with lowered thyroid hormone concentrations or if the weight gain is related to food-energy overconsumption.Methods:Ten unselected patients with hyperthyroidism treated with 131I were studied. The following measurements were made at 0, 1, 2, 3, 6, and 12 months: total food energy, carbohydrate, fat and protein consumption; serum thyroxine (T4); serum triiodothyronine (T3); T3resin uptake; serum thyroid stimulating hormone (TSH); weight; height; and 24-hour urinary urea excretion.Results:Inverse changes in body weight and food energy consumption/kg throughout the period of observation was a striking finding (mean initial weight 67.1 ± 5 kg, final weight 76.4 kg ± 3 kg, premorbid weight 77.1 ± 5 kg). The initial and final food energy intake was 3005 ± 199 and 2597 ± 137 Kcal/24 hrs, respectively. The thyroid hormone concentrations declined inversely relative to weight gain during the first months of the study, but later the thyroid hormones increased while weight gain continued. Initial serum T415.0 ± 1 value at three months was 4.0 ± 1.0 mg/dl, final T411.0 ± 1.Conclusion:We conclude that weight gain following treatment of hyperthyroidism is due to 1) reduction in metabolic rate consequent upon the decreased thyroid hormone concentrations and 2) food energy intake which was initially greater than required to maintain individuals’ premorbid weight. As body weight increased, food intake declined and both reached an asymptotic limit.

Opioid involvement in regulating the intake of highly palatable diets was studied by examining the effect of feeding either a cornstarch-based diet (CHO) or a high fat diet containing sucrose (Fat/Sucrose) on hypothalamic opioid levels. Rats received either CHO ad libitum, Fat/Sucrose ad libitum, Fat/Sucrose pair-fed to the caloric intake of CHO, or Fat/Sucrose at 60% of ad libitum Fat/Sucrose intake. Animals receiving Fat/Sucrose ad libitum consumed more calories and gained more weight than animals receiving CHO (P < 0.001). Relative to CHO, ad libitum intake of Fat/Sucrose elevated proDynorphin mRNA levels in the arcuate and Dynorphin A1–17 levels in the paraventricular nucleus (PVN) (P < 0.05), but did not affect arcuate mRNA levels of proEnkephalin or proOpiomelanocortin (POMC), or PVN levels of Met-Enkephalin or β-Endorphin. Pair-feeding the Fat/Sucrose diet to the level of intake of the CHO diet resulted in levels of proDynorphin and Dynorphin A1–17 that were similar in the two diet groups. Pair-feeding Fat/Sucrose reduced mRNA levels of proDynorpin, proEnkephalin and POMC, and Dynorphin A1–17 levels, relative to ad libitum feeding of Fat/Sucrose. Met-Enkephalin and β-Endorphin were not affected by dietary treatment. Feeding Fat/Sucrose at 60% of ad libitum intake resulted in mRNA levels of proDynorphin, proEnkephalin and POMC, and Dynorphin A1–17 levels that were similar to those observed in CHO group. Hypothalamic Dynorphin A1–17 and proDynorphin mRNA levels are stimulated by feeding a highly palatable diet rich in fat and sucrose. The increased synthesis may be due in part to a palatability-induced overconsumption of calories. Caloric restriction of the same diet decreases mRNA levels of proDynorphin, proEnkephalin and POMC, as well as levels of Dynorphin A1–17.

IT has long been known that opioids, whether administered exogenously or released endogenously, play a role in feeding behavior, and that blockade of opioid receptors with various antagonists can inhibit feeding. Recently, the orphan opioid receptor, ORL1, and its presumed ligand, orphanin FQ, have been identified in human and rodent brain, and show structural similarity to classical opioid receptors and peptides, respectively. While it has been shown that central administration of orphanin FQ induces hyperalgesia, the effects of this peptide on food intake have not been studied. In the present study, we report that central injection of orphanin FQ induces feeding in satiated rats and that this effect can be blocked by peripheral administration of the opioid antagonist naloxone.

OBJECTIVE: To report a case of neuroleptic malignant syndrome (NMS) associated with the use of olanzapine.CASE SUMMARY: A 67-year-old white man with bipolar disorder developed nausea and vomiting. After 12 days, he became confused, delirious, and manic. His only medications were olanzapine 10 mg/d and divalproex sodium 500 mg bid. He was admitted to a hospital and treated for dehydration and mania. Olanzapine was given on 6 of the first 7 hospital days. On hospital day 6, typical NMS developed with the body temperature increasing to 39.9 °C, obtundation, rigidity, tremor, diaphoresis, fluctuating pupillary diameter, labile tachycardia and hypertension, hypernatremia, and elevated serum creatine kinase. Olanzapine was stopped after hospital day 7, and the syndrome resolved by hospital day 12.DISCUSSION: The patient had all of the major manifestations of NMS. There was no other likely explanation for his illness and he received no other drug likely to be associated with the syndrome. This is the first case reported in which NMS was associated with olanzapine.

Artifactual hypoglycemia in patients with leukemia is well recognized. We report herein that patients with polycythemia vera and erythrocytosis demonstrate a similar spurious hypoglycemia caused by accelerated in vitro metabolism of glucose.(JAMA 1983;249:774-775)

In Reply.—In reaction to our observations on artifactual hypoglycemia in patients afflicted with polycythemia vera, Dr Lorber faults us for describing rather than explaining the phenomena. We believe strongly that the critical point for clinical medicine is the false hypoglycemia itself. For those who practice general medicine and endocrinology, knowledge of the conditions that interfere with interpretation of standard tests is important, and our study was intended for this purpose. We believed that the observation had special relevance in view of the absence of previous reports describing the potentially misleading in vitro effect.We do agree that understanding of biomedical mechanisms is desirable and something that all ultimately strive for. Dr Lorber no doubt understands as well as we do that the additional experiments he suggests could provide at best a modest refinement on our speculations. A more modern technique for exploring erythroycte metabolism than the one he mentions