Single nucleotide polymorphism identification in candidate gene systems of obesity.

We have constructed a large panel of single nucleotide polymorphisms (SNP) identified in 68 candidate genes for obesity. Our panel combines novel SNP identification methods based on EST data, with public SNP data from largescale genomic sequencing, to produce a total of 218 SNPs in the coding regions of obesity candidate genes, 178 SNPs in untranslated regions, and over 1000 intronic SNPs. These include new non-conservative amino acid changes in thyroid receptor beta, esterase D, acid phosphatase 1.

Synchronicity of frequently sampled thyrotropin (TSH) and leptin concentrations in healthy adults and leptin-deficient subjects: evidence for possible partial TSH regulation by leptin in humans.

Leptin signals the status of energy reserves to the brain. Leptin stimulates biosynthesis of TRH in vitro and influences the activity of the hypothalamic-pituitary-thyroid axis in vivo in rodents. Because blood levels of both leptin and TSH display diurnal variation with a distinct nocturnal rise, we sought to determine whether a relationship exists between fluctuations in circulating leptin and TSH.

Research and treatment approaches to depression.

Depression is a major cause of disability worldwide, but we know little about the underlying fundamental biology. Research is hindered by the difficulties of modelling a disorder of higher cognitive functions in animals. Depression can be understood as the interaction of genetic susceptibility and environmental factors; however, current classifications are purely descriptive.

A feedback-controlled ensemble model of the stress-responsive hypothalamo-pituitary-adrenal axis.

The present work develops and implements a biomathematical statement of how reciprocal connectivity drives stress-adaptive homeostasis in the corticotropic (hypothalamo-pituitary-adrenal) axis. In initial analyses with this interactive construct, we test six specific a priori hypotheses of mechanisms linking circadian (24-h) rhythmicity to pulsatile secretory output. This formulation offers a dynamic framework for later statistical estimation of unobserved in vivo neurohormone secretion and within-axis, dose-responsive interfaces in health and disease.

The neuroimmune-endocrine axis: pathophysiological implications for the central nervous system cytokines and hypothalamus-pituitary-adrenal hormone dynamics.

Cytokines are molecules that were initially discovered in the immune system as mediators of communication between various types of immune cells. However, it soon became evident that cytokines exert profound effects on key functions of the central nervous system, such as food intake, fever, neuroendocrine regulation, long-term potentiation, and behavior. In the 80's and 90's our group and others discovered that the genes encoding various cytokines and their receptors are expressed in vascular, glial, and neuronal structures of the adult brain.

Acute systemic inflammation up-regulates secretory sphingomyelinase in vivo: a possible link between inflammatory cytokines and atherogenesis.

Inflammation plays a critical role in atherogenesis, yet the mediators linking inflammation to specific atherogenic processes remain to be elucidated. One such mediator may be secretory sphingomyelinase (S-SMase), a product of the acid sphingomyelinase gene. The secretion of S-SMase by cultured endothelial cells is induced by inflammatory cytokines, and in vivo data have implicated S-SMase in subendothelial lipoprotein aggregation, macrophage foam cell formation, and possibly other atherogenic processes.

Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone.

Both stress-system activation and melancholic depression are characterized by fear, constricted affect, stereotyped thinking, and similar changes in autonomic and neuroendocrine function. Because norepinephrine (NE) and corticotropin-releasing hormone (CRH) can produce these physiological and behavioral changes, we measured the cerebrospinal fluid (CSF) levels each hour for 30 consecutive hours in controls and in patients with melancholic depression. Plasma adrenocorticotropic hormone (ACTH) and cortisol levels were obtained every 30 min.

Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects.

We have previously demonstrated that genetically based leptin deficiency due to a missense leptin gene mutation in a highly consanguineous extended Turkish pedigree is associated with morbid obesity and hypogonadism. We have now performed detailed assessments of endocrine, sympathetic, and immune function. We have also identified a new adult female homozygous patient in this extended family who is severely obese and amenorrheic.

The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection.

Depression represents a major public health problem. It is estimated that 13-20% of the population has some depressive symptoms at any given time and about 5% of the population is assumed to suffer from major depression. Known pathological processes include ischemia, neoplasia, necrosis, apoptosis, infection, and inflammation.

Circadian interleukin-6 secretion and quantity and depth of sleep.

Patients with pathologically increased daytime sleepiness and fatigue have elevated levels of circulating interleukin-6 (IL-6). The latter is an inflammatory cytokine, which causes sickness manifestations, including somnolence and fatigue, and activation of the hypothalamic-pituitary-adrenal axis. In this study, we examined: 1) the relation between serial measurements of plasma IL-6 and quantity and depth of sleep, evaluated by polysomnography; and 2) the effects of sleep deprivation on the nyctohemeral pattern of IL-6 secretion.

Chronic administration of the non-peptide CRH type 1 receptor antagonist antalarmin does not blunt hypothalamic-pituitary-adrenal axis responses to acute immobilization stress.

Antalarmin is a pyrrolopyrimidine compound that antagonizes corticotropin-releasing hormone (CRH) type 1 receptors (CRHR1). In order to assess the effects of antalarmin treatment on hypothalamic-pituitary-adrenal (HPA) function we measured the plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone in animals treated with either antalarmin or vehicle for 1 week or for 8 weeks. We found that antalarmin treatment for 1 week did not affect basal concentrations of ACTH or corticosterone.