Ellen A. Schur

Obesity is associated with hypothalamic injury in rodents and humans

Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.

Activation in brain energy regulation and reward centers by food cues varies with choice of visual stimulus

Objective:To develop a non-invasive method of studying brain mechanisms involved in energy homeostasis and appetite regulation in humans by using visual food cues that are relevant to individuals attempting weight loss.Design:Functional magnetic resonance imaging (fMRI) was used to compare brain activation in regions of interest between groups of food photographs.Participants:Ten healthy, non-obese women who were not dieting for weight loss.Measurements:Independent raters viewed food photographs and evaluated whether the foods depicted should be eaten by individuals attempting a calorically-restricted diet. Based on their responses, we categorized photographs into ‘non-fattening’ and ‘fattening’ food groups, the latter characterized by high-caloric content and usually also high-fat or high-sugar content. Blood oxygen level-dependent (BOLD) response was measured by fMRI while participants viewed photographs of ‘fattening’ food, ‘non-fattening’ food, and non-food objects.Results:Viewing photographs of fattening food compared with non-food objects resulted in significantly greater activation in the brainstem; hypothalamus; left amygdala; left dorsolateral prefrontal cortex; left orbitofrontal cortex; right insular cortex; bilateral striatum, including the nucleus accumbens, caudate nucleus, and putamen; bilateral thalamus; and occipital lobe. By comparison, only the occipital region had greater activation by non-fattening food than by object photographs. Combining responses to all food types resulted in attenuation of activation in the brainstem, hypothalamus, and striatum.Conclusion:These findings suggest that, in non-obese women, neural circuits engaged in energy homeostasis and reward processing are selectively attuned to representations of high-calorie foods that are perceived as fattening. Studies to investigate hormonal action or manipulation of energy balance may benefit from fMRI protocols that contrast energy-rich food stimuli with non-food or low-calorie food stimuli.

Feeling Bad in More Ways than One: Comorbidity Patterns of Medically Unexplained and Psychiatric Conditions

BackgroundConsiderable overlap in symptoms and disease comorbidity has been noted among medically unexplained and psychiatric conditions seen in the primary care setting, such as chronic fatigue syndrome, low back pain, irritable bowel syndrome, chronic tension headache, fibromyalgia, temporomandibular joint disorder, major depression, panic attacks, and posttraumatic stress disorder.ObjectiveTo examine interrelationships among these 9 conditions.DesignUsing data from a cross-sectional survey, we described associations and used latent class analysis to investigate complex interrelationships.Participants3,982 twins from the University of Washington Twin Registry.MeasurementsTwins self-reported a doctor’s diagnosis of the conditions.ResultsComorbidity among these 9 conditions far exceeded chance expectations; 31 of 36 associations were significant. Latent class analysis yielded a 4-class solution. Class I (2% prevalence) had high frequencies of each of the 9 conditions. Class II (8% prevalence) had high proportions of multiple psychiatric diagnoses. Class III (17% prevalence) participants reported high proportions of depression, low back pain, and headache. Participants in class IV (73% prevalence) were generally healthy. Class I participants had the poorest markers of health status.ConclusionsThese results support theories suggesting that medically unexplained conditions share a common etiology. Understanding patterns of comorbidity can help clinicians care for challenging patients.

Chronic Pain, Overweight, and Obesity: Findings from a Community-Based Twin Registry

UNLABELLED Chronic pain and obesity, and their associated impairments, are major health concerns. We estimated the association of overweight and obesity with 5 distinct pain conditions and 3 pain symptoms, and examined whether familial influences explained these relationships. We used data collected from 3,471 twins in the community-based University of Washington Twin Registry. Twins reported sociodemographic data, current height and weight, chronic pain diagnoses and symptoms, and lifetime depression. Overweight and obese were defined as body mass index of 25.0 to 29.9 kg/m(2) and >or= 30.0 kg/m(2), respectively. Generalized estimating equation regression models, adjusted for age, gender, depression, and familial/genetic factors, were used to examine the relationship between chronic pain, and overweight and obesity. Overall, overweight and obese twins were more likely to report low back pain, tension-type or migraine headache, fibromyalgia, abdominal pain, and chronic widespread pain than normal-weight twins after adjustment for age, gender, and depression. After further adjusting for familial influences, these associations were diminished. The mechanisms underlying these relationships are likely diverse and multifactorial, yet this study demonstrates that the associations can be partially explained by familial and sociodemographic factors, and depression. Future longitudinal research can help to determine causality and underlying mechanisms. PERSPECTIVE This article reports on the familial contribution and the role of psychological factors in the relationship between chronic pain, and overweight and obesity. These findings can increase our understanding of the mechanisms underlying these 2 commonly comorbid sets of conditions.

A twin study of depression and migraine: evidence for a shared genetic vulnerability.

Objective.— To determine if shared genetic or environmental vulnerabilities could underlie depression and migraine.

Hypothalamic Gliosis Associated With High-Fat Diet Feeding Is Reversible in Mice: A Combined Immunohistochemical and Magnetic Resonance Imaging Study

Gliosis, the activation of astrocyte and microglial cell populations, is a hallmark of central nervous system injury and is detectable using either immunohistochemistry or in vivo magnetic resonance imaging (MRI). Obesity in rodents and humans is associated with gliosis of the arcuate nucleus, a key hypothalamic region for the regulation of energy homeostasis and adiposity, but whether this response is permanent or reversible is unknown. Here we combine terminal immunohistochemistry analysis with serial, noninvasive MRI to characterize the progression and reversibility of hypothalamic gliosis in high-fat diet (HFD)-fed mice. The effects of HFD feeding for 16 weeks to increase body weight and adiposity relative to chow were nearly normalized after the return to chow feeding for an additional 4 weeks in the diet-reversal group. Mice maintained on the HFD for the full 20-week study period experienced continued weight gain associated with the expected increases of astrocyte and microglial activation in the arcuate nucleus, but these changes were not observed in the diet-reversal group. The proopiomelanocortin neuron number did not differ between groups. Although MRI demonstrated a positive correlation between body weight, adiposity, and the gliosis-associated T2 signal in the mediobasal hypothalamus, it did not detect the reversal of gliosis among the HFD-fed mice after the return to chow diet. We conclude that hypothalamic gliosis associated with 16-week HFD feeding is largely reversible in rodents, consistent with the reversal of the HFD-induced obesity phenotype, and extend published evidence regarding the utility of MRI as a tool for studying obesity-associated hypothalamic gliosis in vivo.

Gene expression changes in adipose tissue with diet- and/or exercise-induced weight loss

Adipose tissue plays a role in obesity-related cancers via increased production of inflammatory factors, steroid hormones, and altered adipokines. The impact of weight loss on adipose tissue gene expression may provide insights into pathways linking obesity with cancer risk. We conducted an ancillary study within a randomized trial of diet, exercise, or combined diet + exercise versus control among overweight/obese postmenopausal women. In 45 women, subcutaneous adipose tissue biopsies were conducted at baseline and after 6 months, and changes in adipose tissue gene expression were determined by microarray with an emphasis on prespecified candidate pathways as well as by unsupervised clustering of more than 37,000 transcripts (Illumina). Analyses were conducted first by randomization group and then by degree of weight change at 6-months in all women combined. At 6 months, diet, exercise, and diet + exercise participants lost a mean of 8.8, 2.5, and 7.9 kg (all P < 0.05 vs. no change in controls). There was no significant change in candidate gene expression by intervention group. In analysis by weight change category, greater weight loss was associated a decrease in 17β-hydroxysteroid dehydrogenase-1 (HSD17B1, Ptrend < 0.01) and leptin (LEP, Ptrend < 0.01) expression, and marginally significant increased expression of estrogen receptor-1 (ESR1, Ptrend = 0.08) and insulin-like growth factor–binding protein-3 (IGFBP3, Ptrend = 0.08). Unsupervised clustering revealed 83 transcripts with statistically significant changes. Multiple gene expression changes correlated with changes in associated serum biomarkers. Weight loss was associated with changes in adipose tissue gene expression after 6 months, particularly in two pathways postulated to link obesity and cancer, that is, steroid hormone metabolism and IGF signaling. Cancer Prev Res; 6(3); 217–31. ©2013 AACR.

Conditions Comorbid with Chronic Fatigue in a Population-Based Sample

BACKGROUND Chronic fatigue syndrome (CFS) has been found to be comorbid with various medical conditions in clinical samples, but little research has investigated CFS comorbidity in population-based samples. OBJECTIVE This study investigated conditions concurrent with a CFS-like illness among twins in the population-based Mid-Atlantic Twin Registry (MATR), including chronic widespread pain (CWP), irritable bowel syndrome (IBS), and major depressive disorder (MDD). METHOD A survey was mailed to participants in the MATR in 1999. Generalized estimating equations were used to estimate odds ratios to assess associations between CFS-like illness and each comorbid condition. RESULTS A total of 4590 completed surveys were collected. Most participants were female (86.3%); mean age was 44.7 years. Among participants with a CFS-like illness, lifetime prevalences of CWP, IBS, and MDD were 41%, 16%, and 57% respectively. Participants reporting at least one of the three comorbid conditions were about 14 times more likely to have CFS-like illness than those without CWP, IBS, or MDD (95% confidence interval 8.1%-21.3%). Only MDD showed a temporal pattern of presentation during the same year as diagnosis of CFS-like illness. Age, gender, body mass index, age at illness onset, exercise level, self-reported health status, fatigue symptoms, and personality measures did not differ between those reporting CFS-like illness with and without comorbidity. CONCLUSION These results support findings in clinically based samples that CFS-like illness is frequently cormorbid with CWP, IBS, and/or MDD. We found no evidence that CFS-like illnesses with comorbidities are clinically distinct from those without comorbidities.

The Effect of Serious Mental Illness on the Risk of Rehospitalization Among Patients With Diabetes

BACKGROUND Medical-surgical rehospitalizations within a month after discharge among patients with diabetes result in tremendous costs to the US health care system. OBJECTIVE The studys aim was to examine whether co-morbid serious mental illness diagnoses (bipolar disorder, schizophrenia, or other psychotic disorders) among patients with diabetes are independently associated with medical-surgical rehospitalization within a month of discharge after an initial hospitalization. METHODS This cohort study of all community hospitals in Washington state evaluated data from 82,060 adults discharged in the state of Washington with any International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis indicating diabetes mellitus between 2010 and 2011. Data on medical-surgical hospitalizations were obtained from the Washington State Comprehensive Hospital Abstract Reporting System. Co-morbid serious mental illness diagnoses were identified based on International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes indicating bipolar disorder, schizophrenia, or other psychotic disorders. Logistic regression analyses identified factors independently associated with rehospitalization within a month of discharge. Cox proportional hazard analyses estimated time to rehospitalization for the entire study period. RESULTS After adjusting for demographics, medical co-morbidity, and characteristics of the index hospitalization, co-morbid serious mental illness diagnosis was independently associated with increased odds of rehospitalization within 1 month among patients with diabetes who had a medical-surgical hospitalization (odds ratio: 1.24, 95% confidence interval: 1.07, 1.44). This increased risk of rehospitalization persisted throughout the study period (up to 24 mo). CONCLUSIONS Co-morbid serious mental illness in patients with diabetes is independently associated with greater risk of early medical-surgical rehospitalization. Future research is needed to define and specify targets for interventions at points of care transition for this vulnerable patient population.

Radiologic evidence that hypothalamic gliosis is associated with obesity and insulin resistance in humans

To use quantitative magnetic resonance imaging (MRI) to test whether mediobasal hypothalamic (MBH) gliosis is associated with obesity and insulin resistance in humans.