RESUMEN
Exposure to maternal diabetes (DM) or hypertension (HTN) during pregnancy impacts offspring metabolic health in childhood and beyond. Animal models suggest that induction of hypothalamic inflammation and gliosis in the offspring's hypothalamus is a possible mechanism mediating this effect. We tested, in children, whether in utero exposures to maternal DM or HTN were associated with mediobasal hypothalamic (MBH) gliosis as assessed by brain magnetic resonance imaging (MRI). The study included a subsample of 306 children aged 9-11 years enrolled in the ABCD Study®; 49 were DM-exposed, 53 were HTN-exposed, and 204 (2:1 ratio) were age- and sex-matched children unexposed to DM and/or HTN in utero. We found a significant overall effect of group for the primary outcome of MBH/amygdala (AMY) T2 signal ratio (F(2,300):3.51, p = 0.03). Compared to unexposed children, MBH/AMY T2 signal ratios were significantly higher in the DM-exposed (ß:0.05, p = 0.02), but not the HTN-exposed children (ß:0.03, p = 0.13), findings that were limited to the MBH and independent of adiposity. We concluded that children exposed to maternal DM in utero display evidence of hypothalamic gliosis, suggesting that gestational DM may have a distinct influence on offspring's brain development and, by extension, children's long-term metabolic health.
Asunto(s)
Diabetes Gestacional , Hipertensión , Embarazo , Niño , Femenino , Animales , Humanos , Gliosis/patología , Obesidad , Diabetes Gestacional/epidemiología , Adiposidad , Hipertensión/complicaciones , Hipertensión/epidemiologíaRESUMEN
Hypogonadism in males confers elevated cardiovascular disease (CVD) risk by unknown mechanisms. Recent radiological evidence suggests that low testosterone (T) is associated with mediobasal hypothalamic (MBH) gliosis, a central nervous system (CNS) cellular response linked to metabolic dysfunction. To address mechanisms linking CNS androgen action to CVD risk, we generated a hypogonadal, hyperlipidemic mouse model with orchiectomy (ORX) combined with hepatic PCSK9 overexpression. After 4 wk of high-fat, high-sucrose diet (HFHS) consumption, despite equal body weights and glucose tolerance, androgen-deficient ORX mice had a more atherogenic lipid profile and increased liver and leukocyte inflammatory signaling compared with sham-operated control mice. Along with these early CVD risk indicators, ORX markedly amplified HFHS-induced astrogliosis in the MBH. Transcriptomic analysis further revealed that ORX and high-fat diet feeding induced upregulation of inflammatory pathways and downregulation of metabolic pathways in hypothalamic astrocytes. To interrogate the role of sex steroid signaling in the CNS in cardiometabolic risk and MBH inflammation, central infusion of T and dihydrotestosterone (DHT) was performed on ORX mice. Central DHT prevented MBH astrogliosis and reduced the liver inflammatory signaling and monocytosis induced by HFHS and ORX; T had a partial protective effect. Finally, a cross-sectional study in 41 adult men demonstrated a positive correlation between radiological evidence of MBH gliosis and plasma lipids. These findings demonstrate that T deficiency in combination with a Western-style diet promotes hypothalamic gliosis concomitant with increased atherogenic risk factors and provide supportive evidence for regulation of lipid metabolism and cardiometabolic risk determinants by the CNS action of sex steroids.NEW & NOTEWORTHY This study provides evidence that hypothalamic gliosis is a key early event through which androgen deficiency in combination with a Western-style diet might lead to cardiometabolic dysregulation in males. Furthermore, this work provides the first evidence in humans of a positive association between hypothalamic gliosis and LDL-cholesterol, advancing our knowledge of CNS influences on CVD risk progression.
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Andrógenos , Enfermedades Cardiovasculares , Humanos , Ratones , Masculino , Animales , Proproteína Convertasa 9 , Dieta Alta en Grasa/efectos adversos , Gliosis , Orquiectomía , Estudios Transversales , Factores de Riesgo , DihidrotestosteronaRESUMEN
Posttraumatic stress disorder (PTSD) and eating disorders (ED) frequently co-occur, but the mechanisms underlying this association remain unclear. EDs are characterized by features of maladaptive eating behaviors including disinhibited eating and cognitive dietary restraint. Identifying the genetic overlap between PTSD symptoms and maladaptive eating behaviors may elucidate biological mechanisms and potential treatment targets. A community sample of 400 same-sex twins (102 monozygotic and 98 dizygotic pairs) completed the PTSD Checklist-Civilian (PCL-C) for PTSD symptoms and the Three-Factor Eating Questionnaire-Reduced (TFEQ-R18) for eating behaviors (uncontrolled eating, emotional eating, and cognitive dietary restraint). We used biometric modeling to examine the genetic and environmental relationships between PCL-C and TFEQ-R18 total and subscales scores. Heritability was estimated at 48% for PTSD symptoms and 45% for eating behavior overall. Bivariate models revealed a significant genetic correlation between PTSD symptoms and eating behavior overall (rg =.34; CI:.07,.58) and Uncontrolled Eating (rg =.53; CI:.24,.84), and a significant environmental correlation between PTSD symptoms and Emotional Eating (re =.30; CI:.12,.45). These findings suggest the influence of common etiology. Future research and clinical efforts should focus on developing integrated treatments.
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Trastornos de Alimentación y de la Ingestión de Alimentos , Trastornos por Estrés Postraumático , Emociones , Conducta Alimentaria , Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Humanos , Trastornos por Estrés Postraumático/genética , Encuestas y CuestionariosRESUMEN
BACKGROUND/OBJECTIVES: The salience network (SN) comprises brain regions that evaluate cues in the external environment in light of internal signals. We examined the SN response to meal intake and potential genetic and acquired influences on SN function. SUBJECTS/METHODS: Monozygotic (MZ; 40 pairs) and dizygotic (15 pairs) twins had body composition and plasma metabolic profile evaluated (glucose, insulin, leptin, ghrelin, and GLP-1). Twins underwent resting-state functional magnetic resonance imaging (fMRI) scans before and after a standardized meal. The strength of SN connectivity was analyzed pre- and post-meal and the percentage change elicited by a meal was calculated. A multi-echo T2 MRI scan measured T2 relaxation time, a radiologic index of gliosis, in the mediobasal hypothalamus (MBH) and control regions. Statistical approaches included intraclass correlations (ICC) to investigate genetic influences and within-pair analyses to exclude genetic confounders. RESULTS: SN connectivity was reduced by a meal ingestion (ß = -0.20; P < 0.001). Inherited influences on both pre- and post-meal connectivity were present (ICC MZ twins 26%, P < 0.05 and 47%, P < 0.001, respectively), but not percentage change in response to the meal. SN connectivity in response to a meal did not differ between participants with obesity and of normal weight (χ2(1) = 0.93; P = 0.33). However, when participants were classified as having high or low signs of MBH gliosis, the high MBH gliosis group failed to reduce the connectivity in response to a meal (z = -1.32; P = 0.19). Excluding genetic confounders, the percentage change in SN connectivity by a meal correlated to body fat percentage (r = 0.24; P < 0.01). CONCLUSIONS: SN connectivity was reduced by a meal, indicating potential participation of the SN in control of feeding. The strength of SN connectivity is inherited, but the degree to which SN connectivity is reduced by eating appears to be influenced by adiposity and the presence of hypothalamic gliosis.
Asunto(s)
Ingestión de Alimentos , Gliosis/fisiopatología , Hipotálamo/fisiología , Comidas/fisiología , Red Nerviosa/fisiología , Adulto , Ingestión de Alimentos/genética , Ingestión de Alimentos/fisiología , Femenino , Antecedentes Genéticos , Humanos , Masculino , Persona de Mediana Edad , Gemelos Dicigóticos/genética , Gemelos Dicigóticos/estadística & datos numéricos , Gemelos Monocigóticos/genética , Gemelos Monocigóticos/estadística & datos numéricos , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: Family-based behavioral treatment (FBT) is the recommended treatment for children with common obesity. However, there is a large variability in short- and long-term treatment response, and mechanisms for unsuccessful treatment outcomes are not fully understood. In this study, we tested if brain response to visual food cues among children with obesity before treatment predicted weight or behavioral outcomes during a 6-month behavioral weight management program and/or long-term relative weight maintenance over a 1-year follow-up period. SUBJECTS AND METHODS: Thirty-seven children with obesity (age 9-11 years, 62% male) who entered active FBT (attended two or more sessions) and had outcome data. Brain activation was assessed at pretreatment by functional magnetic resonance imaging across an a priori set of appetite-processing brain regions that included the ventral and dorsal striatum, mOFC, amygdala, substantia nigra/ventral tegmental area, and insula in response to viewing food images before and after a standardized meal. RESULTS: Children with more robust reductions in brain activation to high-calorie food cue images following a meal had greater declines in BMI z-score during FBT (r = 0.42; 95% CI: 0.09, 0.66; P = 0.02) and greater improvements in Healthy Eating Index scores (r = -0.41; 95% CI: -0.67, -0.06; P = 0.02). In whole-brain analyses, greater activation in the ventromedial prefrontal cortex, specifically by high-calorie food cues, was predictive of better treatment outcomes (whole-brain cluster corrected P = 0.02). There were no significant predictors of relative weight maintenance, and initial behavioral or hormonal measures did not predict FBT outcomes. CONCLUSIONS: Children's brain responses to a meal prior to obesity treatment were related to treatment-based weight outcomes, suggesting that neurophysiologic factors and appetitive drive, more so than initial hormone status or behavioral characteristics, limit intervention success.
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Terapia Conductista , Obesidad Infantil/terapia , Apetito , Encéfalo/diagnóstico por imagen , Niño , Señales (Psicología) , Femenino , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
BACKGROUND/OBJECTIVES: Hypothalamic neurons play a major role in the control of body mass. Obese subjects present radiologic signs of gliosis in the hypothalamus, which may reflect the damage or loss of neurons involved in whole-body energy homeostasis. It is currently unknown if hypothalamic gliosis (1) differs between obese nondiabetic (ND) and obese diabetic subjects (T2D) or (2) is modified by extensive body mass reduction via Roux-n-Y gastric bypass (RYGB). SUBJECTS/METHODS: Fifty-five subjects (all female) including lean controls (CT; n = 13), ND (n = 28), and T2D (n = 14) completed at least one study visit. Subjects underwent anthropometrics and a multi-echo MRI sequence to measure mean bilateral T2 relaxation time in the mediobasal hypothalamus (MBH) and two reference regions (amygdala and putamen). The obese groups underwent RYGB and were re-evaluated 9 months later. Analyses were by linear mixed models. RESULTS: Analyses of T2 relaxation time at baseline showed a group by region interaction only in the MBH (P < 0.0001). T2D had longer T2 relaxation times compared to either CT or ND groups. To examine the effects of RYGB on hypothalamic gliosis a three-way (group by region by time) mixed effects model adjusted for age was executed. Group by region (P < 0.0001) and region by time (P = 0.0005) interactions were significant. There was a reduction in MBH relaxation time by RYGB, and, although the T2D group still had higher T2 relaxation time overall compared to the ND group, the T2D group had significantly lower T2 relaxation time after surgery and the ND group showed a trend. The degree of reduction in MBH T2 relaxation time by RYGB was unrelated to clinical outcomes. CONCLUSION: T2 relaxation times, a marker of hypothalamic gliosis, are higher in obese women with T2D and are reduced by RYGB-induced weight loss.
Asunto(s)
Cirugía Bariátrica , Diabetes Mellitus Tipo 2/complicaciones , Gliosis , Hipotálamo , Obesidad , Femenino , Gliosis/diagnóstico por imagen , Gliosis/patología , Humanos , Hipotálamo/diagnóstico por imagen , Hipotálamo/patología , Imagen por Resonancia Magnética , Obesidad/complicaciones , Obesidad/cirugía , Resultado del TratamientoRESUMEN
OBJECTIVE: We sought to evaluate associations between postpartum plasma adipokine concentrations among women with a history of preeclampsia (PE) without severe features (MPE), PE with severe features (SPE), and no PE (NPE). We also investigated relationships between adipokines and computed tomography (CT)-quantified measures of visceral fat (VF) area (VFA) and subcutaneous fat area (SCFA). STUDY DESIGN: We performed a secondary analysis of data collected as part of a previously performed cross-sectional study at our institution. Women with and without a history of PE were recruited in 10 years after delivery. VFA and SCFA measures were performed by CT scan. Anthropometric data and peripheral blood samples from subjects were collected concurrently. RESULTS: Plasma adiponectin concentrations (µg/mL) were significantly lower among MPE (18.5 ± 7.1) compared with NPE (27.3 ± 13.8) and SPE (25.7 ± 9.6). Leptin (p = 0.32) and resistin (p = 0.93) concentrations were similar among the groups. Adiponectin concentrations more closely aligned with VFA (ß = -0.001, p = 0.03), while resistin concentrations trended toward correlating with SCFA (ß = 0.02, p = 0.05). Leptin was not preferential to VFA or SCFA. CONCLUSION: VF distribution may contribute to the variation in PE phenotype. Adiponectin specifically may be a promising marker representing VFA.
Asunto(s)
Adipoquinas/sangre , Grasa Intraabdominal/metabolismo , Preeclampsia/metabolismo , Adulto , Biomarcadores/sangre , Estudios Transversales , Femenino , Humanos , Grasa Intraabdominal/diagnóstico por imagen , Modelos Lineales , Periodo Posoperatorio , Preeclampsia/sangre , Embarazo , Tomografía Computarizada por Rayos XRESUMEN
We studied the effects of multiple cycles of weight loss and regain on the defended body weight in rats. Thirty-six male Wistar rats were divided into three weight-matched groups: weight cyclers (n = 18), ad libitum-fed controls (n = 9), and maturity controls (n = 9). Cyclers underwent four rounds of 20% weight loss from 50% caloric restriction, each cycle followed by recovery to stable plateau weight on ad libitum feeding. Controls ate ad libitum. Maturity controls ate ad libitum and then weight cycled the final two rounds to evaluate the effect of age in later cycles. Cyclers' postdiet plateau weight became progressively lower than that of controls. With each weight loss, ghrelin increased, while insulin and leptin decreased; the magnitude of these changes did not differ across cycles. After four rounds, cyclers' weight (504 ± 7 vs. 540 ± 22 g; P < 0.05) and percent body fat (11.7 vs. 15.2%; P < 0.05) were lower than in controls. After a 4-mo follow-up period of ad libitum feeding, cyclers maintained a lower total fat-pad mass versus controls (8.6 ± 0.5 vs. 15.9 ± 3.6 g; P < 0.01) and a lower glucose area-under-the-curve on oral glucose tolerance tests (P < 0.05). Repeated weight-loss cycles exerted positive effects, durably lowering defended levels of body adiposity and improving glucose tolerance.
Asunto(s)
Peso Corporal/fisiología , Pérdida de Peso/fisiología , Adiposidad , Animales , Composición Corporal , Restricción Calórica , Dieta Reductora , Ghrelina/metabolismo , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Leptina/sangre , Masculino , Ratas , Ratas WistarRESUMEN
OBJECTIVE: We used quantitative genetic methods to evaluate whether sleep quality, pain, and depression symptoms share a common genetic diathesis, to estimate the genetic and environmental sources of covariance among these symptoms, and to test for possible causal relationships. METHODS: A community sample of 400 twins from the University of Washington Twin Registry completed standardized self-report questionnaires. We used biometric modeling to assess genetic and environmental contribution to the association between sleep quality measured by the Pittsburgh Sleep Quality Index, pain measured by the Brief Pain Inventory, and depression symptoms measured by the Brief Symptom Inventory. Trivariate Cholesky structural equation models were used to decompose correlations among the phenotypes. RESULTS: Heritability was estimated at 37% (95% confidence interval = 20%-51%) for sleep quality, 25% (9%-41%) for pain, and 39% (22%-53%) for depression. Nonshared environmental influences accounted for the remaining variance. The genetic correlation between sleep quality and pain had an rg value of .69 (95% confidence interval [CI] = 0.33-0.97), rg value of .56 (95% CI = 0.55-0.98) between pain and depression, and rg value of .61 (95% CI = 0.44-0.88) between depression and sleep quality. Nonshared environmental overlap was present between pain and sleep quality as well as depression and sleep quality. CONCLUSIONS: The link between sleep quality, pain, and depression was primarily explained by shared genetic influences. The genetic factors influencing sleep quality and pain were highly correlated even when accounting for depression. Findings support the hypothesis of a genetic link between depression and pain as well as potential causality for the association of sleep quality with pain and depression.
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Depresión/etiología , Depresión/genética , Dolor/etiología , Dolor/genética , Sistema de Registros , Trastornos del Sueño-Vigilia/etiología , Trastornos del Sueño-Vigilia/genética , Adulto , Anciano , Ambiente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: To test the relationship of anxiety to caloric intake and food cue perception in women and men. METHODS: Fifty-five twins (26 complete, 3 incomplete pairs; 51% women) underwent 2 functional magnetic resonance imaging (fMRI) scans (before and after a standardized meal) and then ate at an ad libitum buffet to objectively assess food intake. State and trait anxiety were assessed using the State-Trait Anxiety Inventory. During the fMRI scans, participants viewed blocks of fattening and nonfattening food images, and nonfood objects. RESULTS: In women, higher trait anxiety was associated with a higher body mass index (BMI) (r = 0.40, p = .010). Trait anxiety was positively associated with kilocalories consumed at the buffet (r = 0.53, p = .005) and percent kilocalories consumed from fat (r = 0.30, p = .006), adjusted for BMI. In within-pair models, which control for shared familial and genetic factors, higher trait anxiety remained associated with kilocalories consumed at the buffet (p = .66, p = .014), but not with BMI. In men, higher state anxiety was related to macronutrient choices, but not to total caloric intake or BMI. FMRI results revealed that women with high trait anxiety did not suppress activation by fattening food cues across brain regions associated with satiety perception after eating a standardized meal (low anxiety, mean difference = -15.4, p < .001; high anxiety, mean difference = -1.53, p = .82, adjusted for BMI). CONCLUSIONS: In women, trait anxiety may promote excess caloric consumption through altered perception of high-calorie environmental food cues, placing women with genetic predispositions toward weight gain at risk of obesity. TRIAL REGISTRATION: Clinicaltrials.govidentifier:NCT02483663.
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Ansiedad , Índice de Masa Corporal , Encéfalo/fisiología , Ingestión de Energía/fisiología , Conducta Alimentaria/fisiología , Imagen por Resonancia Magnética/métodos , Saciedad/fisiología , Adulto , Ansiedad/diagnóstico por imagen , Ansiedad/fisiopatología , Ansiedad/psicología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Señales (Psicología) , Grasas de la Dieta , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
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 study's 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.
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Diabetes Mellitus/epidemiología , Trastornos Mentales/epidemiología , Readmisión del Paciente/estadística & datos numéricos , Adulto , Anciano , Trastorno Bipolar/epidemiología , Estudios de Cohortes , Comorbilidad , Femenino , Hospitalización/economía , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Readmisión del Paciente/economía , Trastornos Psicóticos/epidemiología , Estudios Retrospectivos , Esquizofrenia/epidemiología , Índice de Severidad de la Enfermedad , Estadística como Asunto , Washingtón/epidemiologíaRESUMEN
Glucagon-like peptide 1 (GLP-1) has incretin effects that are well-documented, but the independent role of GLP-1 action in human satiety perception is debated. We hypothesized that blockade of GLP-1 receptors would suppress postprandial satiety and increase voluntary food intake. After an overnight fast, eight normal weight participants (seven men, BMI 19-24.7 kg/m(2), age 19-29 year) were enrolled in a double-blind, placebo-controlled, randomized crossover study of the GLP-1 antagonist Exendin-[9-39] (Ex-9) to determine if the satiating effects of a meal are dependent on GLP-1 signaling in humans. Following a fasting blood draw, iv infusion of Ex-9 (600-750 pmol/kg/min) or saline began. Thirty minutes later, subjects consumed a standardized breakfast followed 90 min later (at the predicted time of maximal endogenous circulating GLP-1) by an ad libitum buffet meal to objectively measure satiety. Infusions ended once the buffet meal was complete. Visual analog scale ratings of hunger and fullness and serial assessments of plasma glucose, insulin, and GLP-1 concentrations were done throughout the experiment. Contrary to the hypothesis, during Ex-9 infusion subjects reported a greater decrease in hunger due to consumption of the breakfast (Ex-9 -62 ± 5; placebo -41 ± 9; P=0.01) than during placebo. There were no differences in ad libitum caloric intake between Ex-9 and placebo. Ex-9 increased glucose, insulin, and endogenous GLP-1, which may have counteracted any effects of Ex-9 infusion to block satiety signaling. Blockade of GLP-1 receptors failed to suppress subjective satiety following a standardized meal or increase voluntary food intake in healthy, normal-weight subjects.
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Ingestión de Alimentos/fisiología , Fragmentos de Péptidos/uso terapéutico , Periodo Posprandial/fisiología , Receptores de Glucagón/antagonistas & inhibidores , Saciedad/fisiología , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , Estudios Cruzados , Método Doble Ciego , Ingestión de Energía , Femenino , Péptido 1 Similar al Glucagón/sangre , Péptido 1 Similar al Glucagón/genética , Receptor del Péptido 1 Similar al Glucagón , Humanos , Hambre , Incretinas/sangre , Insulina/sangre , Masculino , Receptores de Glucagón/metabolismo , Transducción de Señal , Adulto JovenRESUMEN
BACKGROUND: The mediobasal hypothalamus (MBH) is a key brain area for regulation of energy balance. Previous neuroimaging studies suggest that T2-based signal properties indicative of cellular inflammatory response (gliosis) are present in adults and children with obesity, and predicts greater adiposity gain in children at risk of obesity. OBJECTIVES/METHODS: The current study aimed to extend this concept to the early life period by considering if, in full-term healthy neonates (up to n = 35), MRI evidence of MBH gliosis is associated with changes in early life (neonatal to six months) body fat percentage measured by DXA. RESULTS: In this initial study, neonatal T2 signal in the MBH was positively associated with six-month changes in body fat percentage. CONCLUSION: This finding supports the notion that underlying processes in the MBH may play a role in early life growth and, by extension, childhood obesity risk.
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Adiposidad , Hipotálamo , Imagen por Resonancia Magnética , Obesidad Infantil , Humanos , Hipotálamo/diagnóstico por imagen , Adiposidad/fisiología , Masculino , Femenino , Recién Nacido , Obesidad Infantil/epidemiología , Lactante , Aumento de Peso , Absorciometría de Fotón , Índice de Masa CorporalRESUMEN
A hallmark of brain injury from infection, vascular, neurodegenerative, and other disorders is the development of gliosis, which can be detected by magnetic resonance imaging (MRI). In rodent models of diet-induced obesity (DIO), high-fat diet (HFD) consumption rapidly induces inflammation and gliosis in energy-regulating regions of the mediobasal hypothalamus (MBH), and recently we reported MRI findings suggestive of MBH gliosis in obese humans. Thus, noninvasive imaging may obviate the need to assess MBH gliosis using histopathological end points, an obvious limitation to human studies. To investigate whether quantitative MRI is a valid tool with which to measure MBH gliosis, we performed analyses, including measurement of T(2) relaxation time from high-field MR brain imaging of mice fed HFD and chow-fed controls. Mean bilateral T(2) relaxation time was prolonged significantly in the MBH, but not in the thalamus or cortex, of HFD-fed mice compared with chow-fed controls. Histological analysis confirmed evidence of increased astrocytosis and microglial accumulation in the MBH of HFD-fed mice compared with controls, and T(2) relaxation times in the right MBH correlated positively with mean intensity of glial fibrillary acidic protein staining (a marker of astrocytes) in HFD-fed animals. Our findings indicate that T(2) relaxation time obtained from high-field MRI is a useful noninvasive measurement of HFD-induced gliosis in the mouse hypothalamus with potential for translation to human studies.
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Gliosis/patología , Hipotálamo/patología , Imagen por Resonancia Magnética/métodos , Obesidad/patología , Animales , Composición Corporal/fisiología , Dieta Alta en Grasa , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/metabolismo , Hipotálamo/metabolismo , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismoRESUMEN
The University of Washington Twin Registry is a unique community-based registry of twin pairs who join specifically to participate in scientific research. It was founded in 2002 to serve as a resource for investigators throughout the scientific community. Current enrollment exceeds 7,200 pairs, and plans are in place to increase enrollment to 10,000 pairs by 2015. In addition to serving as a recruitment base for new research studies, the registry maintains extensive and continually expanding survey data on physical and mental health, as well as a biorepository that includes DNA from more than 8,800 individual twins. The registry is engaged in linking member data to birth records and to diagnostic and procedure variables for hospital-based care provided to members in Washington State. It also incorporates several innovative variables relevant to the built and social environments, which were created by geocoding twin addresses and linking the resulting coordinates to geospatial information systems databases. This combination of existing data and biospecimens, characterizing a group of twins who are willing to participate in research, is a valuable resource for the new wave of twin studies. These include 'omics', epigenetics, gene-by-environment interactions, and other novel methods to understand human health.
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Bancos de Muestras Biológicas , Recolección de Datos , Enfermedades en Gemelos/epidemiología , Investigación Biomédica Traslacional , Gemelos Dicigóticos/genética , Gemelos Monocigóticos/genética , Adulto , Certificado de Nacimiento , Estudios de Cohortes , Enfermedades en Gemelos/genética , Enfermedades en Gemelos/psicología , Femenino , Humanos , Masculino , Salud Mental , Características de la Residencia , Universidades , Washingtón/epidemiologíaRESUMEN
BACKGROUND: Dopamine receptors are involved in midbrain reward circuit activation. Polymorphisms in two dopamine receptor genes, DRD2 and DRD4, have been associated with altered perception of food reward and weight gain. The objective of this study was to determine whether the same risk alleles were associated with overweight/obesity and with lower reduction of overweight after a 1-year lifestyle intervention. METHODS: In a longitudinal study the association of polymorphisms in DRD2 (rs18000497, risk allele: T, formerly A1 allele at the TaqI A1 polymorphism) and DRD4 (variable number of tandem repeats (VNTR); 48 bp repeat in exon III; risk alleles: 7 repeats or longer: 7R+) was tested on weight loss success following a 1-year lifestyle childhood obesity intervention (OBELDICKS). An additional exploratory cross-sectional case-control study was performed to compare the same DRD polymorphisms in these overweight/obese children and adolescents versus lean adult controls. Subjects were 423 obese and 28 overweight children participating in lifestyle intervention (203 males), age median 12.0 (interquartile range 10.0-13.7) years, body mass index - standard deviation score (BMI-SDS) 2.4 ± 0.5; 583 lean adults (232 males); age median 25.3 (interquartile range 22.5-26.8) years, BMI 19.1 ± 1.9 kg/m2. BMI, BMI-SDS and skinfold thickness measures were assessed at baseline and after 1 year; genotyping was performed for DRD2 risk variant rs1800497 and DRD4 exon III VNTR. RESULTS: The DRD2 genotype had a nominal effect on success in the weight loss intervention. The weakest BMI-SDS reduction was in children homozygous for two rs1800497 T-alleles (n = 11) compared to the combined group with zero (n = 308) or one (n = 132) rs1800497 T-allele (-0.08 ± 0.36 vs. -0.28 ± 0.34; p < 0.05). There was no association between the DRD4 VNTR alleles and genotypes and success in the weight loss intervention. No associations of the risk alleles of the DRD2 and DRD4 polymorphisms and obesity were observed in the cross-sectional part of the study. CONCLUSIONS: We did not find association between polymorphisms in DRD2 and DRD4 genes and weight status. However, obese carriers of two DRD2 rs1800497 T-alleles may be at risk for weak responses to lifestyle interventions aimed at weight reduction. TRIAL REGISTRATION: Obesity intervention program "Obeldicks" is registered at clinicaltrials.gov (NCT00435734).
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Obesidad/genética , Sobrepeso/genética , Polimorfismo Genético , Polimorfismo de Nucleótido Simple/genética , Receptores de Dopamina D2/genética , Receptores de Dopamina D4/genética , Pérdida de Peso/genética , Adolescente , Adulto , Alelos , Índice de Masa Corporal , Estudios de Casos y Controles , Niño , Femenino , Genotipo , Humanos , Estudios Longitudinales , Masculino , Repeticiones de MinisatéliteRESUMEN
OBJECTIVE: Using a twin study design, we sought to determine whether an early age at dieting onset is a risk factor for higher adult body mass index (BMI) or use of risky dieting practices, independent of genetic and familial factors. METHOD: Female twins ages 18-60 years (N=950) from the University of Washington Twin Registry completed 2 surveys an average of 3 years apart. Analyses of individual twins and within-twin pairs tested associations of self-reported age at dieting onset with (1) adult BMI at baseline, (2) change in BMI between the two surveys and (3) risky dieting behaviors at baseline. RESULTS: In analyses mimicking studies of unrelated individuals, an earlier age at dieting onset was associated with greater adult BMI (p=0.003), higher Restraint Scale scores (p<0.001), greater use of risky dieting behaviors (p=0.04) and more weight cycling episodes (p<0.001). In within-pair models that control for genetic and familial factors, the only significant association was between an earlier age at dieting onset and more weight cycling episodes (p=0.006). DISCUSSION: Underlying genetic and familial factors may influence associations of early dieting with higher adult BMIs and risky dieting practices in women.
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Índice de Masa Corporal , Dieta Reductora , Pérdida de Peso/fisiología , Adolescente , Adulto , Factores de Edad , Estudios Transversales , Conducta Alimentaria , Femenino , Humanos , Modelos Lineales , Estudios Longitudinales , Persona de Mediana Edad , Estudios Retrospectivos , Encuestas y Cuestionarios , Factores de Tiempo , Adulto JovenRESUMEN
Accumulated preclinical literature demonstrates that hypothalamic inflammation and gliosis are underlying causal components of diet-induced obesity in rodent models. This review summarizes and synthesizes available translational data to better understand the applicability of preclinical findings to human obesity and its comorbidities. The published literature in humans includes histopathologic analyses performed postmortem and in vivo neuroimaging studies measuring indirect markers of hypothalamic tissue microstructure. Both support the presence of hypothalamic inflammation and gliosis in children and adults with obesity. Findings predominantly point to tissue changes in the region of the arcuate nucleus of the hypothalamus, although findings of altered tissue characteristics in whole hypothalamus or other hypothalamic regions also emerged. Moreover, the severity of hypothalamic inflammation and gliosis has been related to comorbid conditions, including glucose intolerance, insulin resistance, type 2 diabetes, and low testosterone levels in men, independent of elevated body adiposity. Cross-sectional findings are augmented by a small number of prospective studies suggesting that a greater degree of hypothalamic inflammation and gliosis may predict adiposity gain and worsening insulin sensitivity in susceptible individuals. In conclusion, existing human studies corroborate a large preclinical literature demonstrating that hypothalamic neuroinflammatory responses play a role in obesity pathogenesis. Extensive or permanent hypothalamic tissue remodeling may negatively affect the function of neuroendocrine regulatory circuits and promote the development and maintenance of elevated body weight in obesity and/or comorbid endocrine disorders.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Masculino , Adulto , Niño , Humanos , Gliosis/etiología , Gliosis/patología , Estudios Transversales , Diabetes Mellitus Tipo 2/complicaciones , Estudios Prospectivos , Hipotálamo , Obesidad/complicaciones , InflamaciónRESUMEN
BACKGROUND: Cancer cachexia is associated with reduced body weight, appetite and quality of life (QOL) with no approved treatments. Growth hormone secretagogues like macimorelin have potential to mitigate these effects. METHODS: This pilot study assessed the safety and efficacy of macimorelin for 1 week. Efficacy was defined a priori as 1-week change in body weight (≥0.8 kg), plasma insulin-like growth factor (IGF)-1 (≥50 ng/mL) or QOL (≥15%). Secondary outcomes included food intake, appetite, functional performance, energy expenditure and safety laboratory parameters. Patients with cancer cachexia were randomized to 0.5 or 1.0 mg/kg macimorelin or placebo; outcomes were assessed non-parametrically. RESULTS: Participants receiving at least one of either macimorelin dose were combined (N = 10; 100% male; median age = 65.50 ± 2.12) and compared with placebo (N = 5; 80% male; median age = 68.00 ± 6.19). Efficacy criteria achieved: body weight (macimorelin N = 2; placebo N = 0; P = 0.92); IGF-1 (macimorelin N = 0; placebo N = 0); QOL by Anderson Symptom Assessment Scale (macimorelin N = 4; placebo N = 1; P = 1.00) or Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; macimorelin N = 3; placebo N = 0; P = 0.50). No related serious or non-serious adverse events were reported. In macimorelin recipients, change in FACIT-F was directly associated with change in body weight (r = 0.92, P = 0.001), IGF-1 (r = 0.80, P = 0.01), and caloric intake (r = 0.83, P = 0.005), and inversely associated with change in energy expenditure (r = -0.67, P = 0.05). CONCLUSIONS: Daily oral macimorelin for 1 week was safe and numerically improved body weight and QOL in patients with cancer cachexia compared with placebo. Longer term administration should be evaluated for mitigation of cancer-induced reductions in body weight, appetite and QOL in larger studies.
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Caquexia , Neoplasias , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Caquexia/etiología , Caquexia/complicaciones , Factor I del Crecimiento Similar a la Insulina , Calidad de Vida , Proyectos Piloto , Neoplasias/complicaciones , Peso CorporalRESUMEN
Obesity is increasing at an alarming rate. The effectiveness of currently available strategies for the treatment of obesity (including pharmacologic, surgical, and behavioral interventions) is limited. Understanding the neurobiology of appetite and the important drivers of energy intake (EI) can lead to the development of more effective strategies for the prevention and treatment of obesity. Appetite regulation is complex and is influenced by genetic, social, and environmental factors. It is intricately regulated by a complex interplay of endocrine, gastrointestinal, and neural systems. Hormonal and neural signals generated in response to the energy state of the organism and the quality of food eaten are communicated by paracrine, endocrine, and gastrointestinal signals to the nervous system. The central nervous system integrates homeostatic and hedonic signals to regulate appetite. Although there has been an enormous amount of research over many decades regarding the regulation of EI and body weight, research is only now yielding potentially effective treatment strategies for obesity. The purpose of this article is to summarize the key findings presented in June 2022 at the 23rd annual Harvard Nutrition Obesity Symposium entitled "The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets." Findings presented at the symposium, sponsored by NIH P30 Nutrition Obesity Research Center at Harvard, enhance our current understanding of appetite biology, including innovative techniques used to assess and systematically manipulate critical hedonic processes, which will shape future research and the development of therapeutics for obesity prevention and treatment.