Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms.

Pathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. We examined exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists. We found that Sox2 was highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increased the levels of human kisspeptin luciferase (hKiss-luc) transcription, while SOX2 overexpression repressed hKiss-luc transcription. Further, 4 of the identified SOX2 variants prevented this SOX2-mediated repression of hKiss-luc. Together, these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, attesting to hypothalamic defects in the SOX2 disorder spectrum. Our study describes potentially novel mechanisms contributing to SOX2-related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.

GnRH-deficient phenotypes in humans and mice with heterozygous variants in KISS1/Kiss1.

CONTEXT: KISS1 is a candidate gene for GnRH deficiency. OBJECTIVE: Our objective was to identify deleterious mutations in KISS1. PATIENTS AND METHODS: DNA sequencing and assessment of the effects of rare sequence variants (RSV) were conducted in 1025 probands with GnRH-deficient conditions. RESULTS: Fifteen probands harbored 10 heterozygous RSV in KISS1 seen in less than 1% of control subjects. Of the variants that reside within the mature kisspeptin peptide, p.F117L (but not p.S77I, p.Q82K, p.H90D, or p.P110T) reduces inositol phosphate generation. Of the variants that lie within the coding region but outside the mature peptide, p.G35S and p.C53R (but not p.A129V) are predicted in silico to be deleterious. Of the variants that lie outside the coding region, one (g.1-3659C→T) impairs transcription in vitro, and another (c.1-7C→T) lies within the consensus Kozak sequence. Of five probands tested, four had abnormal baseline LH pulse patterns. In mice, testosterone decreases with heterozygous loss of Kiss1 and Kiss1r alleles (wild-type, 274 ± 99, to double heterozygotes, 69 ± 16 ng/dl; r(2) = 0.13; P = 0.03). Kiss1/Kiss1r double-heterozygote males have shorter anogenital distances (13.0 ± 0.2 vs. 15.6 ± 0.2 mm at P34, P < 0.001), females have longer estrous cycles (7.4 ± 0.2 vs. 5.6 ± 0.2 d, P < 0.01), and mating pairs have decreased litter frequency (0.59 ± 0.09 vs. 0.71 ± 0.06 litters/month, P < 0.04) and size (3.5 ± 0.2 vs. 5.4 ± 0.3 pups/litter, P < 0.001) compared with wild-type mice. CONCLUSIONS: Deleterious, heterozygous RSV in KISS1 exist at a low frequency in GnRH-deficient patients as well as in the general population in presumably normal individuals. As in Kiss1(+/-)/Kiss1r(+/-) mice, heterozygous KISS1 variants in humans may work with other genetic and/or environmental factors to cause abnormal reproductive function.

Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome.

OBJECTIVE: To determine if mutations in NELF, a gene isolated from migratory GnRH neurons, cause normosmic idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS). DESIGN: Molecular analysis correlated with phenotype. SETTING: Academic medical center. PATIENT(S): A total of 168 IHH/KS patients as well as unrelated control subjects were studied for NELF mutations. INTERVENTION(S): NELF coding regions/splice junctions were subjected to polymerase chain reaction (PCR)-based DNA sequencing. Eleven additional IHH/KS genes were sequenced in three patients with NELF mutations. MAIN OUTCOME MEASURE(S): Mutations were confirmed by sorting intolerant from tolerant, reverse-transcription (RT)-PCR, and Western blot analysis. RESULT(S): Three novel NELF mutations absent in 372 ethnically matched control subjects were identified in 3/168 (1.8%) IHH/KS patients. One IHH patient had compound heterozygous NELF mutations (c.629-21G>C and c.629-23C>G), and he did not have mutations in 11 other known IHH/KS genes. Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c.1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). In vitro evidence of these NELF mutations included reduced protein expression and splicing defects. CONCLUSION(S): Our findings suggest that NELF is associated with normosmic IHH and KS, either singly or in combination with a mutation in another gene.

WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.

By defining the chromosomal breakpoint of a balanced t(10;12) translocation from a subject with Kallmann syndrome and scanning genes in its vicinity in unrelated hypogonadal subjects, we have identified WDR11 as a gene involved in human puberty. We found six patients with a total of five different heterozygous WDR11 missense mutations, including three alterations (A435T, R448Q, and H690Q) in WD domains important for ß propeller formation and protein-protein interaction. In addition, we discovered that WDR11 interacts with EMX1, a homeodomain transcription factor involved in the development of olfactory neurons, and that missense alterations reduce or abolish this interaction. Our findings suggest that impaired pubertal development in these patients results from a deficiency of productive WDR11 protein interaction.

TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood.

CONTEXT: Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), but broader populations have not yet been tested and genotype-phenotype correlations have not been established. OBJECTIVE: A broad cohort of normosmic IHH probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. DESIGN AND SETTING: The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide. PATIENTS OR OTHER PARTICIPANTS: 345 probands, 18 family members, and 292 controls were studied. INTERVENTION: Reproductive phenotypes throughout reproductive life and before and after therapy were examined. MAIN OUTCOME MEASURE: Rare sequence variants in TAC3/TACR3 were detected. RESULTS: In TACR3, 19 probands harbored 13 distinct coding sequence rare nucleotide variants [three nonsense mutations, six nonsynonymous, four synonymous (one predicted to affect splicing)]. In TAC3, one homozygous single base pair deletion was identified, resulting in complete loss of the neurokinin B decapeptide. Phenotypic information was available on 16 males and seven females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and five of the seven females were assessed after discontinuation of therapy; six of the seven males and four of the five females demonstrated evidence for reversibility of their hypogonadotropism. CONCLUSIONS: Mutations in the neurokinin B pathway are relatively common as causes of hypogonadism. Although the neurokinin B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.

The effect of subclinical hypothyroidism on platelet parameters.

BACKGROUND: Hypothyroidism has a broad clinical spectrum. Today, physicians frequently encounter patients with very mild thyroid dysfunction instead of overt hypothyroidism. These patients have normal serum levels of thyroxine and triiodothyronine and only mildly elevated serum thyrotropin levels. Such patients are often identified through routine screening or in the course of an evaluation of common nonspecific symptoms. On the other hand, coronary heart disease is the leading cause of death in developed countries. There are studies, which suggest platelets play a role in the pathogenesis of atherosclerosis and coronary heart disease. AIM: The aim of this study is to compare the platelet count and other platelet parameters in subclinical hypothyroidic and euthyroidic healthy control group and to investigate whether these parameters have a predictive significance in patients with subclinical hypothyroidism. MATERIALS AND METHODS: Forty-seven patients with subclinical hypothyroidism and 30 euthyroidic healthy control group were enrolled into the study. RESULTS: Patients with subclinical hypothyroidism had higher mean platelet volume (MPV) and platelet distribution width (PDW) values than control group, which were statistically significant (p<0.001 and p<0.001), respectively. CONCLUSION: Our results indicate that MPV and PDW play an important predictive role in subclinical hypothyroidism.

Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.

CHARGE syndrome and Kallmann syndrome (KS) are two distinct developmental disorders sharing overlapping features of impaired olfaction and hypogonadism. KS is a genetically heterogeneous disorder consisting of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia, and is most commonly due to KAL1 or FGFR1 mutations. CHARGE syndrome, a multisystem autosomal-dominant disorder, is caused by CHD7 mutations. We hypothesized that CHD7 would be involved in the pathogenesis of IHH and KS (IHH/KS) without the CHARGE phenotype and that IHH/KS represents a milder allelic variant of CHARGE syndrome. Mutation screening of the 37 protein-coding exons of CHD7 was performed in 101 IHH/KS patients without a CHARGE phenotype. In an additional 96 IHH/KS patients, exons 6-10, encoding the conserved chromodomains, were sequenced. RT-PCR, SIFT, protein-structure analysis, and in situ hybridization were performed for additional supportive evidence. Seven heterozygous mutations, two splice and five missense, which were absent in > or = 180 controls, were identified in three sporadic KS and four sporadic normosmic IHH patients. Three mutations affect chromodomains critical for proper CHD7 function in chromatin remodeling and transcriptional regulation, whereas the other four affect conserved residues, suggesting that they are deleterious. CHD7's role is further corroborated by specific expression in IHH/KS-relevant tissues and appropriate developmental expression. Sporadic CHD7 mutations occur in 6% of IHH/KS patients. CHD7 represents the first identified chromatin-remodeling protein with a role in human puberty and the second gene to cause both normosmic IHH and KS in humans. Our findings indicate that both normosmic IHH and KS are mild allelic variants of CHARGE syndrome and are caused by CHD7 mutations.

Effects of leptin on intake of specific micro- and macronutrients in a woman with leptin gene deficiency studied off and on leptin at stable body weight.

In this report, we examine the effects of leptin on the intake of specific macro- and micronutrients in a female patient with leptin gene deficiency. The patient was studied off and on leptin at stable body weight, within the normal to mildly overweight range. The data were obtained by detailed dietary assessments, measuring dietary intakes by weighed food and fluid consumption records, and analyzed using nutrition analysis software. Overall, significant differences were found in the off versus on leptin treatment periods in the following categories: (i) macronutrients: kilocalories, protein, carbohydrates, monounsaturated fats, MFA 18:1 oleic and total fiber; (ii) vitamins: vitamin C, pyridoxine and pantothenic acid; (iii) minerals: potassium, magnesium, copper and chromium; and amino acids: threonine, lysine and histidine. The nutritional data from this study indicates a direct link between the effects of leptin and ingestion of several specific micronutrients. The mechanisms underlying these effects warrant further investigation and study.

KAL1 mutations are not a common cause of idiopathic hypogonadotrophic hypogonadism in humans.

Hypogonadotrophic hypogonadism results in the absence of puberty and if left untreated leads to infertility. Mutations in KAL1 are known to account for some of the cases of Kallmann syndrome. The aim of this study was to determine the prevalence of KAL1 mutations in a large number of patients with idiopathic hypogonadotrophic hypogonadism (IHH). One hundred and thirty eight patients (109 males and 29 females) with IHH were studied for mutations in KAL1. DNA from these patients was subjected to denaturing gradient gel electrophoresis or single strand conformation polymorphism to identify mutations. Sequencing was performed to confirm mutations detected. Four mutations were found in 109 males (3.7%). All four mutations were in anosmic/hyposmic men making the prevalence 4/63 (6.3%) in this group of patients. No mutations were found in the 29 female patients. KAL1 mutations are an uncommon cause of Kallmann syndrome.

LEPR, ADBR3, IRS-1 and 5-HTT genes polymorphisms do not associate with obesity.

Obesity is a growing problem and is associated with numerous medical conditions. In several genes coding for molecules involved in the regulation of body weight (fat mass) and thermogenesis, polymorphisms have been reported which possibly modify human obesity risk. The aim of this study was to determine the incidence of the following polymorphisms in the following genes in 262 obese (BMI > or = 30) and 138 control (BMI < or = 25) subjects: leptin receptor (LEPR)-Gln223Arg, B3-adrenergic receptor (B3-AR)-Trp64Arg, serotonin transporter (5-HTT)--a 44-base pair insertion/deletion functional polymorphism in the 5-HTTLPR and insulin receptor substrate-1 (IRS-1)-Gly972Arg. Our hypothesis was that these polymorphisms would occur more frequently in the obese population. The polymorphisms were determined by polymerase chain reaction (PCR) and restriction genotyping in study population. In our results, no strong associations were observed between BMI status and these polymorphisms. Weak, though significant, association coefficients obtained with HTT and LEPR loci indicate that the genotype numbers at these loci may depend on BMI status to some extent.

Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism.

OBJECTIVE: To determine the frequency of rare nucleotide variants in GNRHR and GPR54 in a large cohort of probands (n = 166) with normosmic idiopathic hypogonadotropic hypogonadism (nIHH), characterized by mode of inheritance, testicular volume, and presence or absence of endogenous LH pulsations. METHODS: Whenever possible, probands answered detailed questionnaires, underwent full physical exams, and underwent q 10-min frequent blood sampling for LH. Exons segments for GNRHR and GPR54 were screened for mutations. Nucleotide changes were identified as rare variants if they occurred at less than 1% frequency in an ethnically matched control population. RESULTS: Sixty-two percent of male probands were classified as sporadic, meaning that no other family members had delayed puberty or nIHH. In contrast, 61% of female probands were from familial pedigrees, with either autosomal dominant or autosomal recessive inheritance. Patients displayed a broad spectrum of disease severity based on testicular size and endogenous LH pulsations. Twenty-four rare variants were identified in GNRHR (within 15 probands) and seven rare variants in GPR54 (within five probands). CONCLUSIONS: Rare variants in GNRHR are more common than GPR54 in a nIHH population.

Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism.

OBJECTIVE: To characterize the phenotype, modes of inheritance, karyotype, and molecular basis of patients with idiopathic hypogonadotropic hypogonadism (IHH). DESIGN: Review of medical records, karyotyping, and collation of gene mutation analysis. SETTING: University molecular reproductive endocrinology laboratory. PATIENT(S): Patients with IHH. INTERVENTION(S): Review of medical records, laboratory studies, and molecular studies. MAIN OUTCOME MEASURE(S): Sense of smell, severity of IHH (complete vs. incomplete), associated anomalies, karyotype, mutation analysis, and genotype/phenotype correlations were studied. RESULT(S): Of 315 patients with IHH, 6.3% had one or more affected relatives. Autosomal recessive inheritance was likely in most of these familial cases, but autosomal-dominant and X-linked recessive inheritance patterns were likely in some families. Complete IHH was more commonly found in males (62%), whereas incomplete IHH was more commonly observed in females (54.3%). Anosmia was present in 31.3% of males and 27.9% of females. The karyotype was normal in all 19 females tested, but was abnormal in 3 of 57 (5.3%) of males tested. Although cryptorchidism did not differ among those who were anosmic vs. normosmic, it was approximately four times more common in patients with complete IHH than incomplete IHH (15.3% vs. 3.9%). Approximately 10% of the IHH patients tested had mutations in either the GNRHR or KAL1 gene. CONCLUSION(S): Idiopathic hypogonadotropic hypogonadism is a heterogeneous disorder affecting fertility, in which the number of familial cases is probably underestimated. Further study of genes that regulate hypothalamic-pituitary development and function will likely reveal important information regarding the development of normal puberty in humans.

Tissue levels of adiponectin, tumour necrosis factor-alpha, soluble intercellular adhesion molecule-1 and heart-type fatty acid-binding protein in human coronary atherosclerotic plaques.

BACKGROUND: There is little information available about any link between the levels of adiponectin, intercellular adhesion molecule-1 (ICAM-1), tumour necrosis factor-alpha (TNF-alpha) and heart-type fatty acid-binding protein (H-FABP) in coronary atherosclerotic plaque specimens. AIM: To analyse tissue levels of adiponectin, ICAM-1, TNF-alpha and H-FABP in the plaques obtained from coronary artery bypass grafting (CABG) and to evaluate whether there is any relationship between these variables and other characteristics. PATIENTS AND METHODS: Coronary artery specimens from 37 consecutive patients (28 men and nine women) at time of CABG procedure and preprocedural blood samples were obtained. Tissue concentrations of adiponectin, ICAM-1, TNF-alpha and H-FABP in the atherosclerotic plaques were measured. RESULTS: Blood glucose and tissue levels of TNF-alpha and ICAM-1 were negatively correlated with tissue levels of adiponectin, whereas TNF-alpha was positively correlated with ICAM-1 in atherosclerotic plaques. In addition, there was a positive correlation between blood glucose and tissue levels of both TNF-alpha and ICAM-1. TNF-alpha and ICAM-1 levels in atherosclerotic plaques appear to progressively increase whereas adiponectin levels progressively decrease with smoking status. Atherosclerotic tissue levels of these substances are also altered in diabetes. CONCLUSIONS: The data are in accord with those in prior publications on the detection and quantification of various inflammatory cytokines in atherosclerotic plaques. Our results indicate that diabetic state and smoking, in addition to other physiopathological mechanisms, may create a chronic inflammatory situation in the atherosclerotic process.

Evaluation of event-related potentials in Klinefelter syndrome and idiopathic hypogonadotrophic hypogonadism.

BACKGROUND: Many studies have evaluated patients with idiopathic hypogonadothropic hypogonadotropism (IHH), but few of these studies utilize event-related potentials (P300). AIMS: To assess the cognitive functions of hypergonadotropic vs. hypogonadotropic patients. SETTINGS AND DESIGN: The study group consisted of 41 untreated IHH patients, 32 untreated Klinefelter syndrome (KS) patients, and 30 healthy control subjects. METHODS AND MATERIAL: In this study, the latency and amplitude of P300 was evaluated in 41 untreated IHH and 32 untreated KS patients and compared to healthy control subjects (average age: 30 years). Also evaluated were the patients' hormone levels. RESULTS AND CONCLUSIONS: In this study, the amplitude of P300 was found to be reduced, and the latency prolonged in IHH patients in comparison to KS patients and control subjects. In KS patients, there was no difference in latency of P300, but the amplitude was reduced when compared with the control group. Cognitive dysfunction in patients with hypogonadotropism is related to androgen hormone levels. This deficiency can affect development of the central nervous system (CNS), causing defects of CNS to varying degrees during the perinatal period. Androgen deficiency is considered to exert its effects during the period of cognitive ability development, manifest in IHH patients but not KS patients.

Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Turkish with type 2 diabetes mellitus.

Insulin receptor substrate-1 (IRS-1) is an endogenous substrate for the insulin receptor tyrosine kinase, which plays a key role in insulin signaling. Recent studies have identified several polymorphisms in the human IRS-1 gene (Irs-1) that are increased in prevalence among type 2 diabetic patients. To determine whether variation in the Irs-1 contributes to genetic susceptibility to type 2 diabetes in Turkish people, PCR-RFLP and DNA sequencing method were utilized to analyze the coding region of Irs-1 in 70 subject and 116 control patients. Three missense mutations were detected (Gly972Arg, Ala512Pro, Ser892Gly). There was no significant association found with any of these variants and diabetes. The Gly972Arg mutation, however, was relatively more common in with 10/70 diabetic patients and 15/116 non-diabetic controls being heterozygous and 1/70 being and 0/116 non-diabetic controls being homozygous for this variant. As a conclusion, Ala512Pro, Ser892Gly mutations were rare and Met613Val, Ser1043Tyr and Cys1095Tyr mutations were not found in the populations studied. Gly972Arg is more common than other known mutations in our population but may not be a major determinant in genetic susceptibility to type 2 diabetes.

The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism.

OBJECTIVE: To determine the prevalence of GNRH receptor (GNRHR) gene mutations in a large cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH). DESIGN: Molecular analysis and genotype/phenotype correlations. SETTING: University molecular reproductive endocrinology laboratory. PATIENT(S): North American and Turkish patients with IHH. INTERVENTION(S): DNA from 185 IHH patients were subjected to denaturing gradient gel electrophoresis for exons and splice junctions of the GNRHR gene. Variant fragments were sequenced. MAIN OUTCOME MEASURE(S): GNRHR mutations were characterized and compared with the phenotype. The prevalence of GNRHR mutations was also determined. RESULT(S): Three of 185 (1.6%; confidence interval [CI] 0.3%-4.7%) total IHH patients demonstrated compound heterozygous GNRHR mutations. All three were identified from a cohort of 85 normosmic patients (3.5%, CI 0.73%-7.5%), and none were demonstrated in hyposmic or anosmic IHH patients. GNRHR mutations were identified in 1 of 15 (6.7%; CI 0.2%-32.0%) families with at least two affected siblings, and in 2 of 18 (11.1%; CI 1.4%-34.7%) normosmic females. None were found in presumably autosomal dominant families. CONCLUSION(S): GNRHR mutations account for approximately 3.5% of all normosmic and 7%-11% of presumed autosomal recessive IHH, suggesting that additional genes play an important role in normal puberty. We believe this to be the largest GNRHR gene mutation analysis performed to date in a population of IHH patients.

Evaluation of insulin sensitivity in patients with Klinefelter's syndrome: a hyperinsulinemic euglycemic clamp study.

Patients with Klinefelter's syndrome have a higher incidence of diabetes mellitus and the percentage of insulin resistance was reported to be high in these patients. However, little is known about the insulin sensitivity assessed by the hyperinsulinemic euglycemic clamp in these patients. In the present study, subjects included 13 newly diagnosed patients with Klinefelter's syndrome, and 9 age- and body mass index-matched healthy males. The hyperinsulinemic euglycemic clamp was performed in all patients and controls. Insulin resistance was present in five (38.5%) patients with Klinefelter's syndrome. Compared with control subjects, patients with Klinefelter's syndrome had elevated plasma concentrations of fasting insulin, follicle-stimulating hormone, luteinizing hormone, estradiol, and sex hormone-binding globulin, whereas they had reduced plasma free testosterone and total testosterone concentrations. The multivariate linear regression analysis showed that fasting glucose, fasting insulin, free testosterone, and total testosterone were independently associated with M-value. In conclusion, the present study by using hyperinsulinemic euglycemic clamp indicates the high prevalence of insulin resistance in Klinefelter's syndrome patients. However, these patients did not have reduced mean M-values compared with the controls, although their plasma insulin levels were significantly elevated. It is possible that hyperinsulinemia may be the primary metabolic abnormality rather than insulin resistance.

Microanalysis of eating behavior of three leptin deficient adults treated with leptin therapy.

Leptin deficiency has been associated with extreme obesity and hyperphagia in rodents and humans. A rare genetic disorder in humans yields the absence of the hormone leptin, extreme obesity, and a ravenous appetite. Reports on these rare cases have indicated that therapy using leptin injections can yield significant weight loss and changes in appetite. The aim of this report on acute leptin therapy in three leptin deficient adults was to provide a microanalysis of changes in eating behavior and ratings of hunger and satiety. In addition to substantial weight loss, 15 weeks of leptin therapy was associated with approximately 50% reduction in food intake and substantial changes in ratings of hunger and satiety before most meals. After short-term leptin therapy, the three participants ate until ratings indicated they were satiated, which was comparable to the ratings before leptin therapy. These findings suggest that one of the primary effects of acute leptin therapy may be to reduce the ravenous hunger associated with leptin deficiency, resulting in reduced food intake and significant weight loss. These results are discussed in the context of the scientific literature pertaining to leptin and its effects on appetite and obesity.

The association of plasma adiponectin levels with hypertensive retinopathy.

OBJECTIVE: Previous studies have demonstrated that low plasma adiponectin concentrations are associated with essential hypertension. It has also recently been shown that adiponectin plays an essential role in the modulation of angiogenesis. These data led us to hypothesize that adiponectin might contribute to end-organ damage in hypertension. METHODS: In the present study we have evaluated the relationship between plasma adiponectin concentrations and hypertensive retinopathy. One hundred and ten patients newly diagnosed with essential hypertension (EHT) (mean age, 46.79+/-5.0 years; body mass index (BMI), 26.47+/-2.23 kg/m(2); male/female ratio, 58/52) and 57 healthy normotensive control subjects (NT) (mean age, 46.84+/-5.4 years; BMI, 26.66+/-2.65 kg/m(2); male/female ratio, 33/24) were enrolled. RESULTS: Plasma adiponectin levels were significantly lower in EHT than in NT (P < 0.001). In addition, adiponectin concentrations were strongly correlated with systolic and diastolic blood pressures in EHT (r = -0.757, P < 0.001; r = -0.761, P < 0.001) while there was no correlation in the NT group. Plasma adiponectin in patients with grade 0 hypertensive retinopathy (n = 52) was significantly higher than that of the patients with grade 1 (n = 30) and 2 (n = 28) hypertensive retinopathy (P < 0.001 for each). Plasma adiponectin in patients with grade 0 hypertensive retinopathy was also significantly lower than that in the NT group (P < 0.001). The estimated threshold of plasma adiponectin concentration for hypertensive retinopathy was 17 microg/ml. This critical adiponectin level served largely to separate patients with retinopathy from those without. CONCLUSION: Our results have shown that plasma adiponectin concentrations decrease progressively with higher grades of hypertensive retinopathy even after correction for other atherogenic risk factors, suggesting that a critical adiponectin level is needed for the development of retinopathy.

Increased acylation stimulating protein concentrations in nonalcoholic fatty liver disease are associated with insulin resistance.

OBJECTIVES: As acylation stimulating protein (ASP) acts on adipocytes mainly as a paracrine factor to increase triglyceride synthesis and storage; hypothetically, it may play a similar role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). METHODS: Forty-six male patients with NAFLD (group A), age-matched 30 male patients with chronic viral hepatitis (group B) and 30 age-matched and body mass index (BMI)-matched healthy male subjects were enrolled in the study. RESULTS: Among the NAFLD patients, 10 patients (24.4%) had simple steatosis and 36 patients (69.6%) had nonalcoholic steatohepatitis (NASH). The mean levels of ASP, complement 3, insulin, C-peptide, HOMA-IR, triglyceride, and very low-density lipoprotein (VLDL) were significantly higher in group A patients than both controls and group B. ASP levels correlated significantly in a positive manner with BMI, insulin, and HOMA-IR. CONCLUSIONS: Dysregulation of the ASP pathway may have important metabolic consequences in NASH and is associated with insulin resistance.