The hypothalamic arcuate nucleus is involved in the control of energy intake and expenditure and may participate in the pathogenesis of eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN). Two systems are of particular interest in this respect, synthesizing ␣-melanocyte-stimulating hormone (␣-MSH) and synthesizing neuropeptide Y, respectively. We report here that 42 of 57 (74%) AN and͞or BN patients studied had in their plasma Abs that bind to melanotropes and͞or corticotropes in the rat pituitary. Among these sera, 8 were found to bind selectively to ␣-MSH-positive neurons and their hypothalamic and extrahypothalamic projections as revealed with immunostaining on rat brain sections. Adsorption of these sera with ␣-MSH peptide abolished this immunostaining. In the pituitary, the immunostaining was blocked by adsorption with ␣-MSH or adrenocorticotropic hormone. Additionally, 3 AN͞BN sera bound to luteinizing hormonereleasing hormone (LHRH)-positive terminals in the rat median eminence, but only 2 of them were adsorbed with LHRH. In the control subjects, 2 of 13 sera (16%) displayed similar to AN͞BN staining. These data provide evidence that a significant subpopulation of AN͞BN patients have autoantibodies that bind to ␣-MSH or adrenocorticotropic hormone, a finding pointing also to involvement of the stress axis. It remains to be established whether these Abs interfere with normal signal transduction in the brain melanocortin circuitry͞LHRH system and͞or in other central and peripheral sites relevant to food intake regulation, to what extent such effects are related to and͞or could be involved in the pathophysiology or clinical presentation of AN͞BN, and to what extent increased stress is an important factor for production of these autoantibodies.A norexia nervosa (AN) and bulimia nervosa (BN) are two officially recognized eating disorders that affect Ϸ3% of women during their lifetime (1). Both illnesses usually make their debut at young age and are characterized by hyperactivity and exaggerated concern about body shape and weight, and they often occur in the same patients (2). AN is manifested by an aversion to food, often resulting in life-threatening weight loss and amenorrhea, whereas BN includes large uncontrolled eating episodes followed by compensatory vomiting without significant change in body weight. Even if the cause(s) of AN and BN is still unclear, a body of data exists suggesting a primary neurobiological origin (3), and neuropeptides also have been implicated in these disorders (4). These assumptions are paralleled by growing evidence for a role of hypothalamic peptidergic neurons in conditions associated with energy deprivation or energy excess, providing a concept for central mechanisms controlling food intake and body weight (5-7). In a search of possible mechanisms implicating hypothalamic peptidergic neurons in the etiology and pathogenesis of AN͞BN, we hypothesized that hypothalamic systems responsible for the regulation of food intake could be targeted by autoantibodies...
BackgroundAlcohol abuse is associated with sleep problems, which are often linked to circadian rhythm disturbances. Previous studies have separately examined the effects of mutations in the clock gene PER2 on alcohol consumption and sleep problems. Here we hypothesized that an allelic variation in the PER2 gene is associated with alcohol consumption in interaction with sleep problems among adolescents.MethodsThe Survey of Adolescent Life and Health in Västmanland 2006, a Swedish county, including 1254 students 17–18 years old, was used as a population-representative sample of adolescents. We investigated the PER2 Single Nucleotide polymorphism (SNP) 10870 (A/G) in the cohort together with an assessment of alcohol consumption according to the AUDIT-C questionnaire, and sleep problems using a survey consisting of 18 items. Furthermore, we carried out an exploratory analysis on the PER2 Single Nucleotide Polymorphism 10870 polymorphism in a group of severely alcoholic females.ResultsWe found a significant association of the SNP 10870 in adolescent boys, where the genotype AA, in the presence of several and frequent sleep problems, was associated with increased alcohol consumption. Among adolescent girls, only sleep problems were related to alcohol consumption. A non-significant trend was observed among the severely alcoholic females, with the G allele being over-represented in the severely alcoholic females group in comparision to the control females.ConclusionThese results indicate that PER2 gene variation is associated with alcohol consumption in interaction with sleep problems among Swedish adolescent boys.
Major changes in psychiatric phenotypes due to genetic factors are seldom the result of single gene polymorphisms, but more often the result of several genetic mechanisms. In this millennium article we discuss the notion that the expression of numerous candidate genes could be regulated by the same transcription factors, and that polymorphisms in transcription factor genes might explain some phenotypes. We describe recent results of studies on the biological marker thrombocyte monoamine oxidase (trbc MAO) and the transcription factor AP-2. Low levels of trbc MAO is associated with temperamental characteristics such as sensation seeking and impulsiveness, and the enzyme is genetically regulated by specific transcriptional mechanisms. Transcription factor AP-2 is important for the development of midbrain structures and AP-2 has several binding sites in the regulatory regions of genes encoding key proteins in the monoamine transmitter systems. We have recently shown AP-2 to be linked to personality, binge-eating disorder, treatment with antidepressant drugs, and also to trbc MAO. Regardless of whether transcriptions factors, such as AP-2, regulate the expression of eg, the number of monoamine neurons or a variety of candidate genes within the monoamine systems, or both, we would like to emphasize the role of transcription factors, besides polymorphisms in monoaminergic candidate genes, when explaining inter-individual differences in temperament and psychiatric vulnerability. Molecular Psychiatry (2001) 6, 503-510.
The importance of an interaction between environment and biological factors for the expression for a particular behaviour is illustrated by results from a series of adolescents in which effects of platelet MAO activity and psychosocial environment on criminality was investigated. In a favourable environment platelet MAO-B activity was not associated with criminality, while a very strong association was found in adolescents from a bad psychosocial environment. Essentially similar findings were obtained when a MAO-A promoter polymorphism was analysed instead of platelet MAO-B activity. In boys, presence of the low functioning allele seemed to be protective against criminal activity in combination with a good environment, while it predisposed for criminality in a bad psycho-social environment. In girls, instead, homozygosity for the high activity MAO-A allele interacted with environment to predict criminality. Possible mechanisms underlying the role of monoamine oxidases for behaviour are discussed.
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