Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation

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Interplay between stress response genes associated with attention‐deficit hyperactivity disorder and brain volume

The glucocorticoid receptor plays a pivotal role in the brain's response to stress; a haplotype of functional polymorphisms in the NR3C1 gene encoding this receptor has been associated with attention‐deficit hyperactivity disorder (ADHD). The serotonin transporter (5‐HTT) gene polymorphism 5‐HTTLPR is known to influence the relation between stress exposure and ADHD severity, which may be partly because of its reported effects on glucocorticoid levels. We therefore investigated if NR3C1 moderates the relation of stress exposure with ADHD severity and brain structure, and the potential role of 5‐HTTLPR. Neuroimaging, genetic and stress exposure questionnaire data were available for 539 adolescents and young adults participating in the multicenter ADHD cohort study NeuroIMAGE (average age: 17.2 years). We estimated the effects of genetic variation in NR3C1 and 5‐HTT, stress exposure and their interactions on ADHD symptom count and gray matter volume. We found that individuals carrying the ADHD risk haplotype of NR3C1 showed significantly more positive relation between stress exposure and ADHD severity than non‐carriers. This gene–environment interaction was significantly stronger for 5‐HTTLPR L‐allele homozygotes than for S‐allele carriers. These two‐ and three‐way interactions were reflected in the gray matter volume of the cerebellum, parahippocampal gyrus, intracalcarine cortex and angular gyrus. Our findings illustrate how genetic variation in the stress response pathway may influence the effects of stress exposure on ADHD severity and brain structure. The reported interplay between NR3C1 and 5‐HTT may further explain some of the heterogeneity between studies regarding the role of these genes and hypothalamic–pituitary–adrenal axis activity in ADHD.     

Hormones, nicotine, and cocaine: Clinical studies

Nicotine and cocaine each stimulate hypothalamic-pituitary-adrenal and -gonadal axis hormones, and there is increasing evidence that the hormonal milieu may modulate the abuse-related effects of these drugs. This review summarizes some clinical studies of the acute effects of cigarette smoking or IV cocaine on plasma drug and hormone levels and subjective effects ratings. The temporal covariance between these dependent measures was assessed with a rapid (2 min) sampling procedure in nicotine-dependent volunteers or current cocaine users. Cigarette smoking and IV cocaine each stimulated a rapid increase in LH and ACTH, followed by gradual increases in cortisol and DHEA. Positive subjective effects ratings increased immediately after initiation of cigarette smoking or IV cocaine administration. However, in contrast to cocaine's sustained positive effects (< 20 min), ratings of “high” and “rush” began to decrease within one or two puffs of a high-nicotine cigarette while nicotine levels were increasing. Peak nicotine levels increased progressively after each of three successive cigarettes smoked at 60 min intervals, but the magnitude of the subjective effects ratings and peak ACTH and cortisol levels diminished. Only DHEA increased consistently after successive cigarettes. The possible influence of neuroactive hormones on nicotine dependence and cocaine abuse and the implications for treatment of these addictive disorders are discussed.     

Prenatal exposure to maternal psychosocial stress and HPA axis regulation in young adults

Epidemiological studies have reported associations between measures of size and weight at birth and disease risk in later life. Alteration in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis in response to prenatal stress has been proposed as one underlying mechanism. The present study investigated in humans the association of prenatal psychosocial stress exposure with subsequent HPA axis regulation in adult life, with a focus on measures of response to challenge and feedback sensitivity. Healthy young adults whose mothers experienced severe stress during their pregnancy in form of major negative life events (e.g. death of someone close; prenatal stress (PS) group, n = 31) and an age-matched comparison group (CG, n = 30) underwent the Trier Social Stress Test (TSST) and a 1 μg ACTH_1-24 stimulation test. In addition, a diurnal cortisol profile was assessed. ACTH concentrations following a standardized behavioural challenge paradigm (TSST) were marginally significantly higher in PS subjects than in CG subjects (p = .06). Pre-TSST adrenocortical (cortisol) levels were lower (p = .007), whereas the increase in cortisol in response to the TSST was higher (p = .03) in PS subjects compared to CG subjects. Cortisol concentrations following a pharmacological stimulation test simulating pituitary activity (ACTH_1-24 test) were significantly lower in PS than in CG subjects (p = .006). No differences emerged between the two groups in basal diurnal cortisol levels. This study provides first evidence in humans of an association between prenatal psychosocial stress exposure and subsequent alterations in the regulation of the HPA axis.     

High self-perceived stress and many stressors, but normal diurnal cortisol rhythm, in adults with ADHD (attention-deficit/hyperactivity disorder)

Attention-deficit/hyperactivity disorder (ADHD) in adults is associated with significant impairment in many life activities and may thus increase the risk of chronic stress in everyday life. We compared adults with a DSM-IV ADHD diagnosis (n = 28) with healthy controls (n = 28) regarding subjective stress and amounts of stressors in everyday life, diurnal salivary cortisol in the everyday environment and salivary cortisol before and after cognitive stress in a laboratory setting. The association between cortisol concentrations and impulsivity was also investigated. Consistent with assumptions, individuals with ADHD reported significantly more self-perceived stress than controls, and subjective stress correlated with the amount of stressors in everyday life. The two groups were comparable with respect to overall diurnal cortisol levels and rhythm, as well as in pre- and post-stress cortisol concentrations. Post-stress cortisol (but not baseline cortisol) concentration was positively correlated with impulsivity. The group with high post-stress cortisol also reported more symptoms of depression and anxiety, as well as self-perceived stress and stressors in every-day life. The diagnosis of ADHD significantly increased the risk of belonging to the group with high post-stress cortisol levels. The results in this study warrant a focus not only on the primary diagnosis of ADHD, but also calls for a broader assessment of stressors and subjective stress in everyday life, as well as support comprising stress management and coping skills.     

Structure and Specificity of a Binary Tandem Domain F-Lectin from Striped Bass (Morone saxatilis)

The plasma of the striped bass Morone saxatilis contains a fucose-specific lectin (MsaFBP32) that consists of two F-type carbohydrate recognition domains (CRDs) in tandem. The crystal structure of the complex of MsaFBP32 with l-fucose reported here shows a cylindrical  81-Å-long and  60-Å-wide trimer divided into two globular halves: one containing N-terminal CRDs (N-CRDs) and the other containing C-terminal CRDs (C-CRDs). The resulting binding surfaces at the opposite ends of the cylindrical trimer have the potential to cross-link cell surface or humoral carbohydrate ligands. The N-CRDs and C-CRDs of MsaFBP32 exhibit significant structural differences, suggesting that they recognize different glycans. Analysis of the carbohydrate binding sites provides the structural basis for the observed specificity of MsaFBP32 for simple carbohydrates and suggests that the N-CRD recognizes more complex fucosylated oligosaccharides and with a relatively higher avidity than the C-CRD. Modeling of MsaFBP32 complexed with fucosylated glycans that are widely distributed in prokaryotes and eukaryotes rationalizes the observation that binary tandem CRD F-type lectins function as opsonins by cross-linking “non-self” carbohydrate ligands and “self” carbohydrate ligands, such as sugar structures displayed by microbial pathogens and glycans on the surface of phagocytic cells from the host.     

The effect of rearing experience and TPH2 genotype on HPA axis function and aggression in rhesus monkeys: A retrospective analysis

Gene-environment (G × E) interactions contribute to the development of many neuropsychiatric disorders. Tryptophan hydroxylase-2 (TPH2) synthesizes neuronal serotonin and is closely related to the hypothalamic-pituitary-adrenal (HPA) axis, while early life experience is a critical environmental factor programming the HPA axis response to stress. This retrospective study investigated G × E interaction at the TPH2 locus in rhesus monkeys. Twenty-eight adult, male rhesus monkeys of Indian origin, either mother-reared or peer-reared as infants, were involved in this study. These monkeys have been previously genotyped for the functional A2051C polymorphism in rhTPH2, and had been physiologically and behaviorally characterized. rhTPH2 A2051C exerted a significant main effect (CC > AA&AC) on the cerebrospinal fluid (CSF) level of 5-hydroxyindole-3-acetic acid (5-HIAA; F_(1,14) = 6.42, p = 0.024), plasma cortisol level in the morning (F_(1,18) = 14.63, p = 0.002) and cortisol response to ACTH challenge (F_(1,17) = 6.87, p = 0.018), while the rearing experience showed a significant main effect (PR > MR) on CSF CRH (F_(1,20) = 11.66, p = 0.003) and cage shaking behavior (F_(1,27) = 4.45, p = 0.045). The effects of rhTPH2 A2051C on the afternoon cortisol level, plasma ACTH level, dexamethasone suppression of urinary cortisol excretion, and aggression were dependent upon the rearing experience. These results were not confounded by the functional C77G polymorphism in the mu-opioid receptor (MOR). The present study supports the hypothesis that rearing experience and rhTPH2 A2051C interact to influence central 5-HT metabolism, HPA axis function, and aggressive behaviors. Our findings strengthen the involvement of G × E interactions at the loci of serotonergic genes and the utility of the nonhuman primate to model G × E interactions in the development of human neuropsychiatric diseases.     

TPH2 5′‐ and 3′‐regulatory polymorphisms are differentially associated with HPA axis function and self‐injurious behavior in rhesus monkeys

Tryptophan hydroxylase‐2 (TPH2) synthesizes neuronal serotonin and is linked to numerous behavioral traits. We have previously characterized the functionality of polymorphisms (especially 2051A>C) in 3’‐untranslated region (3’‐UTR) of rhesus monkey TPH2 (rhTPH2). This study further assessed the functionality of additional polymorphisms (–1605T>C, –1491Tn, –1485(AT)n, –1454A>G, –1325In>Del and –363T>G) in rhTPH2 5’‐flanking region (5’‐FR), and evaluated the effects of rhTPH2 5’ and 3’ genotypes on central serotonin turnover, hypothalamic–pituitary–adrenal (HPA) axis function and self‐injurious behavior (SIB) in 32 unrelated adult male monkeys of Indian origin. Haplotypes of the rhTPH2 5’‐FR polymorphisms exert a significant, cell‐dependent effect on reporter gene expression, primarily conferred by –1485(AT)n. The –1485(AT)n and 2051A>C polymorphisms interact to influence cerebrospinal fluid (CSF) 5‐HIAA and plasma adrenocorticotropic hormone (ACTH) in the afternoon. While –1485(AT)n exerts significant main effects on the afternoon cortisol level and nocturnal HPA negative feedback, 2051A>C has significant main effects on the morning cortisol level and cortisol response to ACTH challenge, as well as marginally significant main effects on the daytime HPA negative feedback and self‐biting rate. In addition, the genotype/allele frequency of the 5’‐FR –1325Ins>Del differed significantly between the self‐wounders and non‐wounders, whereas 3’‐UTR 2128S>L polymorphism differed significantly in genotype/allele frequency between the high‐ and low‐frequency biters. This study shows the functionality of rhTPH2 5’‐FR polymorphisms, and provides evidence for the differential association of rhTPH2 5’‐FR and 3’‐UTR polymorphisms with HPA axis function and SIB. Our findings shed light on the role of TPH2 gene variance in physiology and behavioral traits, and also contribute to the understanding of the pathophysiology and genetics of SIB     

应激性高血压犬鼠脑干及下丘脑-垂体-肾上腺轴中肾上腺髓质素及其受体mRNA表达的改变

采用逆转录- 聚合酶链式反应检测了慢性足底电击结合噪声应激致高血压大鼠下丘脑、延髓、中脑、垂体和肾上腺等组织中编码肾上腺髓质素的肾上腺髓质素前肽原(preproadrenomedullin, ppADM) 基因以及ADM 的特异性受体组件降钙素受体样受体(calcitonin-receptor-like receptor,CRLR)和受体活性调节蛋白2 和3(receptor-activity-modifying proteins, RAMP2 和RAMP3)表达的变化。我们观察到:与对照组相比,以 3- 磷酸甘油醛脱氢酶作为内参照,15 d 足底电击结合噪声应激引起下丘脑、垂体和肾上腺中ppADM mRNA表达上调,而在延髓和中脑表达明显下调(P<0.01 或 P<0.05); CRLR基因表达量正常时在下丘脑相对较高,应激15 d 后CRLR 表达在延髓、中脑和下丘脑下调(P<0.01 或 P<0.05), 而在垂体和肾上腺的表达无明显变化;应激后RAMP2 基因在延髓和下丘脑表达上调,而在肾上腺表达显著下调(P <0.01), 其他部位无明显变化;RAMP3 基因在对照组大鼠的中脑和下丘脑表达较高,在应激性高血压大鼠的下丘脑和垂体表达上调(P<0.01 或P<0.05), 而在中脑和肾上腺表达下调(P<0.05), 在延髓中的表达变化无统计学差异。上述结果提示:慢性足底电击结合噪声应激引起明显的中枢和下丘脑- 垂体-肾上腺轴ADM 及其受体组件CRLR/RAMP2 或CRLR/R