Katherine M. Morrison

2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children [summary].

Obesity is now reaching epidemic proportions in both developed and developing countries and is affecting not only adults but also children and adolescents. Over the last 20 years, obesity has become the most prevalent nutritional problem in the world, eclipsing undernutrition and infectious disease

Serum levels of perfluoroalkyl compounds in human maternal and umbilical cord blood samples

Perfluoroalkyl compounds (PFCs) are end-stage metabolic products from industrial flourochemicals used in the manufacture of plastics, textiles, and electronics that are widely distributed in the environment. The objective of the present study was to quantify exposure to perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorodecanoic acid (PFDeA), perfluorohexane sulfonate (PFHxS), perfluoroheptanoic acid (PFHpA), and perfluorononanoic acid (PFNA) in serum samples collected from pregnant women and the umbilical cord at delivery. Pregnant women (n=101) presenting for second trimester ultrasound were recruited and PFC residue levels were quantified in maternal serum at 24-28 weeks of pregnancy, at delivery, and in umbilical cord blood (UCB; n=105) by liquid chromatography-mass spectrometry. Paired t-test and multiple regression analysis were performed to determine the relationship between the concentrations of each analyte at different sample collection time points. PFOA and PFOS were detectable in all serum samples analyzed including the UCB. PFOS serum levels (mean+/-S.D.) were significantly higher (p<0.001) in second trimester maternal serum (18.1+/-10.9 ng/mL) than maternal serum levels at delivery (16.2+/-10.4 ng/mL), which were higher than the levels found in UCB (7.3+/-5.8 ng/mL; p<0.001). PFHxS was quantifiable in 46/101 (45.5%) maternal and 21/105 (20%) UCB samples with a mean concentration of 4.05+/-12.3 and 5.05+/-12.9 ng/mL, respectively. There was no association between serum PFCs at any time point studied and birth weight. Taken together our data demonstrate that although there is widespread exposure to PFCs during development, these exposures do not affect birth weight.

Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis

Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue, but its thermogenic potential is reduced with obesity and type 2 diabetes for reasons that are not understood. Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved biogenic amine that resides in non-neuronal and neuronal tissues that are specifically regulated via tryptophan hydroxylase 1 (Tph1) and Tph2, respectively. Recent findings suggest that increased peripheral serotonin and polymorphisms in TPH1 are associated with obesity; however, whether this is directly related to reduced BAT thermogenesis and obesity is not known. We find that Tph1-deficient mice fed a high-fat diet (HFD) are protected from obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD) while exhibiting greater energy expenditure by BAT. Small-molecule chemical inhibition of Tph1 in HFD-fed mice mimics the benefits ascribed to Tph1 genetic deletion, effects that depend on UCP1-mediated thermogenesis. The inhibitory effects of serotonin on energy expenditure are cell autonomous, as serotonin blunts β-adrenergic induction of the thermogenic program in brown and beige adipocytes in vitro. As obesity increases peripheral serotonin, the inhibition of serotonin signaling or its synthesis in adipose tissue may be an effective treatment for obesity and its comorbidities.

Reproducibility of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) classification: a systematic review

Abstract Background: The classifications of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) represent glucose levels above normal, but below the decision threshold for diabetes. We sought to determine what the reproducibility of these classifications was when repeat tests were performed by conducting a systematic review of the literature. Methods: All primary studies published in English of any study design were included. Studies were excluded if they did not follow the World Health Organization or American Diabetes Association diagnostic criteria, used whole blood as the specimen type, a glucose meter for analysis, or performed repeat testing greater than 8 weeks apart. Results: Five papers had reproducibility data for IGT or IFG, two of which where from the same population but sampled differently. The κ coefficients, indicating agreement between repeat tests that exceeded chance, indicated poor to fair agreement for IGT (0.04, 0.22, 0.38, 0.42) and moderate agreement for IFG (0.44 and 0.56). Similarly, the observed reproducibility was slightly lower for IGT (33%, 44%, 47%, 48%) compared to IFG (51%, 64%). In two studies for which data were available for both IGT and IFG, the average reproducibility was lower (49%) for the prediabetes group compared to the diabetes group (73%) or the normal group (93%). Conclusions: Poor reproducibility of IGT and IFG classification suggests caution should be exercised when interpreting a single test result. Clin Chem Lab Med 2007;45:1180–5.

Human maternal and umbilical cord blood concentrations of polybrominated diphenyl ethers

Polybrominated diphenyl ethers (PBDEs), widely used as flame retardants in commercial products, have become ubiquitous environmental contaminants. Although adult human exposure to PBDEs is well documented, developmental exposure is less well characterized. The objectives of this study were to measure maternal and fetal exposure to nine PBDE congeners and to investigate potential associations with birth weight. PBDE congeners were quantified in maternal serum at 24-28 weeks of pregnancy, delivery, and umbilical cord serum (UCS) by gas chromatography-mass spectrometry (GC/MS/MS). Complete blood sample sets were obtained from 97 pregnant women (mean age 33.1±0.5 years). PBDE-28, -47 and -99 were quantified in all samples tested and PBDE-47 was the most abundant congener measured in both maternal (mid-pregnancy and delivery samples geometric mean=26.9 and 26.9, respectively) and UCS (GM=56.0 ng g(-1) lipid). The UCS concentration for all congeners with the exception of PBDE-153 was higher vs. maternal delivery samples (p<0.001). Only the UCS concentration of PBDE-17 and -99 were significantly associated (β=-49.860, p=0.032, and β=-3.645, p=0.05) with birth weight. However, after adjustment for potential confounders only the association between PBDE-99 and birth weight remained significant (β=-3.951 and p=0.016). We conclude that: the fetus is exposed to PBDEs from at least the second trimester of pregnancy onward; PBDE congeners are higher in UCS compared to maternal serum samples collected at delivery; and that developmental PBDE exposure is potentially associated with lower birth weight.

Maternal nicotine exposure increases oxidative stress in the offspring.

Fetal and neonatal nicotine exposure causes beta-cell apoptosis and loss of beta-cell mass, but the underlying mechanisms are unknown. The goal of this study was to determine whether maternally derived nicotine can act via the pancreatic nicotinic acetylcholine receptor (nAChR) during fetal and neonatal development to induce oxidative stress in the pancreas. Female Wistar rats were given saline or nicotine (1 mg/kg/day) via subcutaneous injection for 2 weeks prior to mating until weaning (postnatal day 21). In male offspring, nAChR subunit mRNA expression was characterized in the developing pancreas and various oxidative stress markers were measured at weaning following saline and nicotine exposure. The nAChR subunits alpha2-alpha4, alpha6, alpha7, and beta2-beta4 were present in the pancreas during development. Fetal and neonatal exposure to nicotine significantly increased pancreatic GPx-1 and MnSOD protein expression, as well as islet ROS production. Furthermore, protein carbonyl formation was higher in nicotine-exposed offspring relative to controls, particularly within the mitochondrial fraction. There was also a nonsignificant trend toward higher serum 8-isoPG levels. These data suggest that beta-cell apoptosis in the fetal and neonatal pancreas may be the result of a direct effect of nicotine via its receptor and that this effect may be mediated through increased oxidative stress.

Fetal and neonatal nicotine exposure and postnatal glucose homeostasis: identifying critical windows of exposure.

Fetal and lactational exposure to nicotine at concentrations comparable with those in women who smoke causes impaired glucose tolerance in male offspring in postnatal life. It remains unknown whether there are critical windows of susceptibility to nicotine exposure. Female nulliparous Wistar rats were given saline vehicle or nicotine bitartrate (1 mg/kg per day) prior to pregnancy, which was then: A) discontinued during pregnancy and lactation; B) continued until parturition; C) continued until weaning; and D) discontinued during pregnancy and restarted from lactation until weaning. At 26 weeks of age, offspring in each group were challenged with an oral glucose load. Beta-cell mass, apoptosis, and proliferation were measured at birth, and at 4 and 26 weeks of age. The animals in group C (exposed to nicotine throughout pregnancy and lactation) had reduced beta-cell mass from birth through 26 weeks of age and impaired glucose homeostasis at 26 weeks of age. beta-Cell mass was also reduced at birth and at 4 weeks of age in animals exposed to nicotine during pregnancy alone (group B). However, enhanced proliferation following weaning led to recovery of this defect to 98% of control levels by week 26. The response to the glucose load in groups A, B, and D did not differ from controls. Continued exposure to nicotine from conception through lactation results in permanent beta-cell loss and subsequent impaired glucose tolerance. This model of type 2 diabetes requires that nicotine exposure occurs both in utero and during lactation.

Increased Pancreatic Beta-Cell Apoptosis following Fetal and Neonatal Exposure to Nicotine Is Mediated via the Mitochondria

In Canada, nicotine replacement therapy is recommended as a safe smoking cessation aid for pregnant women. However, we have shown in an animal model that fetal and neonatal nicotine exposure causes increased beta-cell apoptosis and loss of beta-cell mass, which leads to the development of postnatal dysglycemia and obesity. The goal of this study was to determine whether the observed beta-cell apoptosis is mediated via the mitochondrial and/or death receptor pathway. Female Wistar rats were given saline (control) or nicotine bitartrate (1 mg/kg/day) via sc injection for 2 weeks prior to mating until weaning (postnatal day 21). At weaning, pancreas tissue was collected for Western blotting, electron microscopy (EM), and immunohistochemistry. Key markers of each apoptotic pathway were examined in whole pancreas homogenates and mitochondrial/cytosolic pancreas fractions. In the death receptor pathway, Fas and soluble Fas ligand (FasL) protein were significantly increased in the nicotine-exposed offspring compared to control animals; there was no difference in the ratio of inactive/active caspase-8 or membrane-bound FasL expression. In the mitochondrial pathway, there was a significant increase in the ratio of Bcl2/Bax, Bax translocation to the mitochondria, cytochrome c release to the cytosol, and the ratio of active/inactive caspase-3 in nicotine-exposed offspring relative to control animals. Furthermore, increased mitochondrial swelling was observed by EM in the pancreatic beta cells of nicotine-exposed offspring. Taken together, these data suggest that beta-cell apoptosis following developmental nicotine exposure is mediated via the mitochondria.

Mental Health of Extremely Low Birth Weight Survivors in Their 30s

OBJECTIVE: To determine the risk for psychiatric disorders among extremely low birth weight (ELBW) survivors in their early to mid-30s and to determine whether those born small for gestational age or those exposed to a full course of antenatal corticosteroids (ACS) were at particularly high risk. METHODS: A prospective, longitudinal, population-based cohort of 84 ELBW survivors and 90 normal birth weight (NBW) control participants born in Ontario, Canada from 1977 to 1982 were assessed by interviewers naive to birth weight status using the Mini-International Neuropsychiatric Interview. RESULTS: ELBW survivors had lower odds of an alcohol or substance use disorder but higher odds of current non–substance-related psychiatric problems (odds ratio [OR] = 2.47; 95% confidence interval [CI], 1.19–5.14). Those born ELBW and SGA exhibited the same patterns with larger effects. ACS-exposed ELBW survivors had even higher odds of any current non–substance-related psychiatric disorder (OR = 4.41; 95% CI, 1.65–11.82), particularly generalized anxiety disorder (OR = 3.42; 95% CI, 1.06–11.06), the generalized type of social phobia (OR = 5.80; 95% CI, 1.20–27.99), and the inattentive subtype of attention-deficit/hyperactivity disorder (OR = 11.45; 95% CI, 2.06–63.50). CONCLUSIONS: In their early to mid-30s, ELBW survivors were less likely to have alcohol or substance use disorders but may be at greater risk for other psychiatric problems. Those exposed to ACS were at especially high risk and manifested no reduction in alcohol or substance use disorders. ELBW survivors exposed to ACS may be a special group at risk for psychopathology in adulthood.

The impact of obesity on quality of life

An important association exists between obesity and mental illness that impacts all aspects of an individuals quality of life. This association can begin early in the developmental trajectory and we do not yet completely understand all the mechanisms linking obesity and mental illness. What we e do know is that physical health factors that often occur secondary to obesity, combined with societal attitudes toward those that are obese coupled with iatrogenic treatment factors linked to psychiatric pharmacotherapy and a number of biologic mediators result in an important and increasing common comorbidity. Recognizing this association is essential for the proper management of both conditions. The following review addresses this issue and provides clinical pearls to help deal with this issue.