Farid F. Chehab

Leptin as a regulator of adipose mass and reproduction

Leptin, an adipocyte-derived hormone, informs neuroendocrine pathways about the status of energy stores in adipose tissue. The integration of this peripheral signal in hypothalamic networks results in activation of peripheral metabolic pathways that control energy build-up and expenditure. Firing of the reproductive cascade of hormones at puberty and its regulation in adults is tightly associated with energy metabolism and is thus regulated by leptin. This article provides an update of past and present theories that link nutrition and reproduction in light of new research.

Leptin and reproduction

Leptin, a hormone secreted from adipose tissue, plays an important role in reproductive physiology. It has been shown to stimulate the reproductive system by rescuing the sterility of leptin-deficient mice and advancing the onset of puberty in normal mice. Although leptin is not critical for the biology of pregnancy in mice, its ability to reduce food intake is blunted in mid-gestation suggesting that late pregnancy may be a leptin-resistant state. Modifier genes originating from the Balb/cJ genetic background profoundly alter the sterile-obese phenotype of ob/ob mice by reducing their obesity and stimulating their reproductive system despite the absence of leptin. The mechanism of leptins action on the reproductive system remains to be determined but is likely to be mediated by multiple factors.

Molecular basis of β thalassemia in South China

SummaryThe phenotype of β thalassemia can be caused by over 40 different mutations. To set up a prenatal diagnosis program using DNA analysis, it is important to determine the type and frequency of mutation in a particular geographic area. We have delineated the molecular lesions that cause β thalassemia in the Guangdong province of China, and found six mutations in four different haplotypes. The surprising finding that five of these mutations each occur in two different haplotypes suggests the occurrence of crossing over or gene conversion events at the β-globin locus. The delineation of the haplotypes and mutations will permit the choice of the appropriate probes for prenatal detection of β thalassemia in this part of China.

Age at diagnosis as an indicator of eligibility for BRCA1 DNA testing in familial breast cancer

This paper reports the results of 1428 β-thalassemia chromosomes studied in Sicily during a hemoglobinopathy control program starting in 1983. Molecular screening was performed by direct restriction enzyme analysis, allele specific oligonucleotide (ASO) hybridization, reverse dot blot analysis (RDB) and, for the rare or new mutations, by direct sequencing of polymerase chain reaction (PCR) products. Using these approaches 1410 (98.7%) out of 1428 β-globin gene defects were characterized, involving 22 different β-thalassemia mutations. Three of these were present at high frequency (β∘39, IVS1, 110 and IVS1,6); the other β-globin gene defects were found at low frequency. In the latter, we found a smaller group of mutations at a frequency lower than 10% (IVS1, 1, IVS2, 745, β S) and a larger one at a frequency lower than 2% [-87, IVS1,2, IVS2,1, fr 6, fr 8 (-AA), fr 44, fr 76, -101, IVS1, 116, IVS1, 3′end G-C, IVS1,5 G-A, IVS1,5 G-C, cod 30, Lepore, deltaβ, β C]. The possible origin of this very large number of mutations is discussed, taking into account the historical point of view. Moreover, this approach has made a first trimester prenatal diagnosis program possible in our region in practically all cases, with a great improvement in general thalassemia management.

Minireview : Obesity and LipOdystrophy-Where Do the Circles Intersect?

Adipose tissue is unique in that it can undergo significant hypertrophy and atrophy, resulting in wide ranges of obesities and lipodystrophies. At the base of this elasticity is the lipid-filled adipocyte, which can either overfill by storing large amounts of triglycerides or shrink to a tiny cell by depleting its lipids and as such is remarkable in sustaining insults. As a major energy reservoir, the adipocyte may hold considerable calories necessary for survival and reproduction, two functions that are essential for the survival of the species. This review will summarize some of the recent studies that have advanced our understanding of the central and peripheral mechanisms that are initiated by adipocyte-secreted factors such as leptin, adiponectin, resistin, and retinol-binding protein 4. The intersection of obesity and lipodystrophy results in insulin resistance, which may be unlocked by elucidating the roles of these factors in pathways that control insulin sensitivity and glucose uptake.

20 YEARS OF LEPTIN: Leptin and reproduction: past milestones, present undertakings, and future endeavors

The association between leptin and reproduction originated with the leptin-mediated correction of sterility in ob/ob mice and initiation of reproductive function in normal female mice. The uncovering of a central leptin pathway regulating food intake prompted the dissection of neuroendocrine mechanisms involving leptin in the metabolic control of reproduction. The absence of leptin receptors on GnRH neurons incited a search for intermediary neurons situated between leptin-responsive and GnRH neurons. This review addresses the most significant findings that have furthered our understanding of recent progress in this new field. The role of leptin in puberty was impacted by the discovery of neurons that co-express kisspeptin, neurokinin B, and dynorphin and these could act as leptin intermediates. Furthermore, the identification of first-order leptin-responsive neurons in the premammilary ventral nucleus and other brain regions opens new avenues to explore their relationship to GnRH neurons. Central to these advances is the unveiling that agouti-related protein/neuropeptide Y neurons project onto GnRH and kisspeptin neurons, allowing for a crosstalk between food intake and reproduction. Finally, while puberty is a state of leptin sensitivity, mid-gestation represents a state of leptin resistance aimed at building energy stores to sustain pregnancy and lactation. The mechanisms underlying leptin resistance in pregnancy have lagged; however, the establishment of this natural state is significant. Reproduction and energy balance are tightly controlled and backed up by redundant mechanisms that are critical for the survival of our species. It will be the goal of the following decade to shed new light on these complex and essential pathways.

Detection of viral deoxyribonucleic acid in the amniotic fluid of low-risk pregnancies by polymerase chain reaction

OBJECTIVE The purpose of this study was to determine whether viral deoxyribonucleic acid is detectable in the amniotic fluid of pregnancies at low risk for fetal viral infection. STUDY DESIGN Amniotic fluid samples were prospectively collected from 277 patients. Selected primer pairs amplified deoxyribonucleic acid sequences unique to adenovirus, cytomegalovirus, herpes simplex virus, and parvovirus. Amplified deoxyribonucleic acid was detected by gel electrophoresis. Sensitivity of the adenovirus, cytomegalovirus, and herpes virus primers were determined by serial dilution of 10(3) PFU/ml controls. RESULTS Of the 277 extracted samples, 243 had detectable deoxyribonucleic acid. None of these samples had detectable viral deoxyribonucleic acid by polymerase chain reaction. The sensitivity of the adenovirus primer pairs was 10(-3) PFU/ml, cytomegalovirus 10(-2) PFU/ml, and herpes simplex virus 10(-1) PFU/ml. CONCLUSION This study did not detect viral deoxyribonucleic acid in a low-risk population, supporting the clinical significance of detecting viral deoxyribonucleic acid in pregnancies at risk for infection.

Effects of FoxO4 overexpression on cholesterol biosynthesis, triacylglycerol accumulation, and glucose uptake

The Forkhead transcription factors FoxO1, FoxO3a, and FoxO4 play a prominent role in regulating cell survival and cell cycle. Whereas FOXO1 was shown to mediate insulin sensitivity and adipocyte differentiation, the role of the transcription factor FoxO4 in metabolism remains ill defined. To uncover the effects of FoxO4, we generated a cellular model of stable FoxO4 overexpression and subjected it to microarray-based gene expression profiling. While pathway analysis revealed a disruption of cholesterol biosynthesis gene expression, biochemical studies revealed an inhibition of cholesterol biosynthesis, which was coupled with decreased mRNA levels of lanosterol 14α demethylase (CYP51). FoxO4-mediated repression of CYP51 led to the accumulation of 24,25 dihydrolanosterol (DHL), which independently and unlike lanosterol inhibited cholesterol biosynthesis. Furthermore, FoxO4-overexpressing cells accumulated lipid droplets and triacylglycerols and had an increase in basal glucose uptake. Recapitulation of these effects was obtained following treatment with CYP51 inhibitors, which also induce DHL buildup. Moreover, DHL but not lanosterol strongly stimulated liver X receptor α (LXRα) activity, suggesting that DHL and LXRα mediate the downstream effects initiated by FoxO4. Together, these studies suggest that FoxO4 acts on CYP51 to regulate the late steps of cholesterol biosynthesis.

Primary hydatid cyst of the pancreas causing obstructive jaundice

Primary hydatid cyst in the head of pancreas is rare. We report a case of a 26-year-old patient, who presented with obstructive jaundice. The imaging studies, while demonstrating a fusiform dilatation of the common bile duct, was unhelpful in identifying the etiology. A pancreatic head cyst was discovered at the time of surgery. Diagnosis was confirmed by subsequent serology and identification of scolices on microscopic examination. From the reported data, we discuss the diagnostic and therapeutic modalities of this rare disease.

Homozygous deletion of six olfactory receptor genes in a subset of individuals with Beta-thalassemia.

Progress in the functional studies of human olfactory receptors has been largely hampered by the lack of a reliable experimental model system. Although transgenic approaches in mice could characterize the function of individual olfactory receptors, the presence of over 300 functional genes in the human genome becomes a daunting task. Thus, the characterization of individuals with a genetic susceptibility to altered olfaction coupled with the absence of particular olfactory receptor genes will allow phenotype/genotype correlations and vindicate the function of specific olfactory receptors with their cognate ligands. We characterized a 118 kb β-globin deletion and found that its 3′ end breakpoint extends to the neighboring olfactory receptor region downstream of the β-globin gene cluster. This deletion encompasses six contiguous olfactory receptor genes (OR51V1, OR52Z1, OR51A1P, OR52A1, OR52A5, and OR52A4) all of which are expressed in the brain. Topology analysis of the encoded proteins from these olfactory receptor genes revealed that OR52Z1, OR52A1, OR52A5, and OR52A4 are predicted to be functional receptors as they display integral characteristics of G-proteins coupled receptors. Individuals homozygous for the 118 kb β-globin deletion are afflicted with β-thalassemia due to a homozygous deletion of the β-globin gene and have no alleles for the above mentioned olfactory receptors genes. This is the first example of a homozygous deletion of olfactory receptor genes in human. Although altered olfaction remains to be ascertained in these individuals, such a study can be carried out in β-thalassemia patients from Malaysia, Indonesia and the Philippines where this mutation is common. Furthermore, OR52A1 contains a γ-globin enhancer, which was previously shown to confer continuous expression of the fetal γ-globin genes. Thus, the hypothesis that β-thalassemia individuals, who are homozygous for the 118 kb deletion, may also have an exacerbation of their anemia due to the deletion of two copies of the γ-globin enhancer element is worthy of consideration.