Metabolomics of the obese.
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Adipose Tissue↗
Biomedical subjects
Z Hochberg
Publications and source records attributed to Z Hochberg.
Differences in infantile growth patterns in Turner syndrome girls with and without spontaneous puberty.
OBJECTIVE: The role of prepubertal estrogen in child growth was modeled using Turner's syndrome, comparing growth patterns of girls who later did or did not enter puberty spontaneously. The hypothesis was that TS patients with normal prepubertal estrogen levels would have a different growth pattern from those with subnormal estrogen levels. STUDY DESIGN: Growth data from 78 full-term patients with Turner's syndrome were collected retrospectively. 24/78 later developed spontaneous puberty, (+Pub), and their growth data were compared to TS patients without spontaneous puberty (-Pub). A nonlinear mixed model was fitted using the bi-exponential model. RESULTS: The growth velocity difference between the -Pub and +Pub groups suggests an early infantile growth advantage in the -Pub group, which disappears before the end of the first year of life; growth velocity remains similar (+/- 1 cm/y) for the next 6 years and declines at age 7-8 years in the +Pub group faster than it does in the -Pub group. Bi-exponential analysis showed that both the 1st (restrictive) and 2nd exponent (forward) were different (p = 0.0003). CONCLUSIONS: Comparison of girls with or without spontaneous puberty suggests a role for estrogen in child growth. Estrogens restrict infantile growth, as well as growth during the mid-childhood spurt.
Adolescent↗
Perspectives on the development of an international consensus on childhood obesity.
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Child↗
From bone biology to bone analysis.
Bone development is one of the key processes characterizing childhood and adolescence. Understanding this process is not only important for physicians treating pediatric bone disorders, but also for clinicians and researchers dealing with postmenopausal and senile osteoporosis. Bone densitometry has great potential to enhance our understanding of bone development. The usefulness of densitometry in children and adolescents would be increased if the physiological mechanisms and structural features of bone were given more consideration in the design and interpretation of densitometric studies. This review gives an overview on the most relevant techniques of quantitative noninvasive bone analysis. Furthermore it describes the relationship between bone biology, selected surrogates describing the biological processes and the possibilities of measuring these surrogates specifically and precisely by the different devices. The overall recommendation for researchers in this field is to describe firstly the biological process to be analyzed (bone growth in length, remodeling or modeling, or all together), secondly the bone parameter which describes this process, and thirdly the reason for selecting a special device.
Absorptiometry, Photon↗
Hypothalamic regulation of adiposity: the role of 11beta-hydroxysteroid dehydrogenase type 1.
Following extensive suprasellar operations for excision of hypothalamic tumors, some patients develop morbid obesity despite receiving replacement doses of glucocorticoids. Urine analysis of cortisol and cortisone metabolites show that 11-OH/11-oxo ratios are significantly higher in patients with hypothalamic obesity, indicating enhanced 11beta-HSD1 activity. This correlates with the visceral-to-subcutaneous fat ratio. The consequence of increased 11beta-HSD1 activity and a shift of the steroid inter-conversion towards cortisol may contribute to the effects of the latter in adipose tissue. The message from the hypothalamus to adipocyte 11beta-HSD-1 involves hormones, the sympathetic nervous system and cytokines. CRH and ACTH downregulate 11beta-HSD-1 activity and induce lipolysis. Tumor necrosis factor-alpha and interleukin-1beta upregulate 11beta-HSD-1 expression and activity, while enhancing lipolysis. The sympathetic nervous system exerts its effects through beta-adrenergic upregulation and alpha-adrenergic downregulation of 11beta-HSD-1 activity. Inhibition of 11beta-HSD-1 suppresses preadipocyte differentiation into mature adipocytes, and may provide a therapeutic tool.
11-beta-Hydroxysteroid Dehydrogenase Type 1↗
Associations between a polymorphism in the 11 beta hydroxysteroid dehydrogenase type I gene and body composition.
We investigated 11 beta hydroxysteriod dehydrogenase type 1 (11betaHSD-1) sequence variants in 103 healthy overweight (BMI >2 s.d.) and 160 nonoverweight (BMI -2 to +2 SD) children to examine the associations between body composition and 11betaHSD-1 polymorphisms. A total of 4.3% of children were homozygous and 30.0% heterozygous for an adenine insertion in intron 3 (ins4436A). By ANCOVA (adjusting for age, sex, race, and height), BMI-s.d. differed according to ins4436A genotype (P<0.005), with the greatest BMI-SD for ins4436A homozygotes (mean +/-s.d., 3.4+/-3.4, vs heterozygotes, 0.8+/-5.5, or wild-type, 1.8+/-7.5). Homozygotes also had greater waist circumference, waist-to-hip ratio, and insulin resistance indices than heterozygote or wild-type children (all P<0.05), but no significant differences in trunk fat by DXA, or in serum lipids. We conclude an intronic 11betaHSD-1 gene polymorphism is associated with greater body mass, altered body composition, and insulin resistance in children. 11betaHSD-1 may be one of the genes relevant for pediatric-onset obesity and its complications.
11-beta-Hydroxysteroid Dehydrogenases↗
Relative abundance of growth hormone receptor isoforms in rhesus monkey tissues and human transformed lymphocytes.
The growth hormone receptor (GHR) is expressed as one active, full-sequence isoform and one truncated, inactive one that lacks the intracellular signaling domain. The aim of this study was to investigate the variation in the tissue expression of the full and truncated mRNA and protein. Epstein-Barr virus-transformed human B lymphocyte lines were established from 9 normal individuals with a height standard deviation score (SDS) of - 0.1 +/- 1.1 (mean +/- SD). Tissues were also collected from 3 Rhesus monkeys, whose GHR has 94.1 % homology with the human molecule. mRNA quantitation was determined by Real Time Quantitative PCR. Growth hormone receptor expression in transformed lymphocytes was also studied by fluorescence-activated cell sorter analysis. Both isoforms were expressed in transformed lymphocytes, but individual variation in the relative mRNA expression was small (truncated isoform percentage of total receptor mRNA: 17.1 +/- 4.4, mean +/- SD). There was no correlation between donors' height SDS and the expression of either isoform or the ratio between them. Protein expression by FACS analysis showed wider variation among the subjects; however, the relative ratio was similar in all the subjects. In monkey tissues, the truncated receptor showed a tissue-specific distribution. In conclusion, the expression of both isoforms in transformed lymphocytes from normal subjects shows small differences at the RNA or protein levels, and does not correlate with height SDS. Growth hormone splice isoforms show tissue specificity, suggesting local regulation of splicing. Tissues with relatively high expression of the truncated isoform are likely to be more resistant to the effects of GH due to the dominant negative effect of this isoform. In addition, the differential tissue expression might influence the levels of growth hormone binding protein in the immediate milieu of each tissue.
Adult↗
Transcriptional and translational regulation of the splicing isoforms of the growth hormone receptor by glucocorticoids.
Glucocorticoids exert multiple effects on the growth hormone IGF-I axis. The GH receptor is expressed as an active, full-sequence molecule and a truncated, inactive one that lacks the intracellular signaling domain. We used the HuH7 human hepatoma cell line to investigate the effect of glucocorticoids on growth hormone receptor mRNA and protein expression. cDNA quantification was performed by Real Time Quantitative PCR. Growth hormone receptor expression at the protein level was studied by fluorescence-activated cell sorter analysis using specific polyclonal antibodies raised against the two isoform unique C-terminal sequences. Cells were treated with pharmacologic doses of dexamethasone (Dex 10 -7 - 10 -5 M) to assess its acute (1 hour or overnight) and chronic effects (7 days). Dex induced a dose-dependent increase of both the full (427 %) and truncated (180 %) mRNAs. At the protein level, Dex upregulated the full sequence more (183 %) than the truncated (126 %) protein. For a better understanding of this regulation system, cells were incubated with Dex 10 -6 M for 24 h in the absence or presence of a transcriptional inhibitor, actinomycin D, or a translational inhibitor, cycloheximide. Actinomycin D had no effect on Dex-induced upregulation, while cycloheximide blocked the truncated mRNA but not the full sequence mRNA upregulation, suggesting that this effect of glucocorticoids is a post-transcriptional event. After 7 days of chronic treatment, Dex induced a dose-dependent downregulation of the active receptor without any changes in the expression of the truncated isoform either at the mRNA or protein levels. We conclude that short-term glucocorticoid treatment results in an enhancement of the growth hormone receptor expression, while long-term treatment has a suppressive effect, through both transcriptional and translational mechanisms ultimately influencing both isoforms of the receptor.
Alternative Splicing↗
Endocrine complications of thalassemia.
Growth, sexual development, fertility, bone mineral density, diabetes mellitus, hypothyroidism, hypoparathyroidism, and hypoadrenalism are the main issues to be addressed in the long-term follow-up of patients with thalassemia. During childhood, growth may be affected by anemia, and other potential endocrine complications. Puberty is the stage of the maximal growth insult. Beta thalassemia is associated with bone abnormalities characterized by bone marrow expansion of the medullary cavity, and osteopenia with cortical thickening and trabecular coarsening. Good nutrition with adequate vitamins and trace elements intake, along with calcium and vitamin D supplementation, can increase bone density and prevent bone loss. Endocrine abnormalities should be monitored carefully and a thorough endocrine evaluation should be carried out yearly in every patients to detect subclinical endocrinopaties.
Bone Diseases↗
Choosing an oestrogen replacement therapy in young adult women with Turner syndrome.
OBJECTIVE: Hormone replacement therapy (HRT) is prescribed to most patients with Turner syndrome (TS) although its use in adult TS patients has not been scientifically evaluated. The present study was performed to compare the short-term effects in adult women with Turner syndrome of low-dose oral conjugated oestrogen (0.625 mg, CE) with relatively high dose ethinyl oestradiol (30 microg, EE2); both combined with an oral progestin. DESIGN AND PATIENTS: After 4 months off HRT, 17 young, otherwise healthy women with TS were enrolled in a random, unblinded, crossover study of the two oestrogenic preparations, each given for 6 months. MEASUREMENTS: We compared parameters of oestrogenic activity that would cover immediate changes in hormone levels, biochemistry, bone turnover, uterine and cardiac variables, which constitute risk factors for later development of diabetes, atherosclerosis, osteoporosis and aortic dissection. RESULTS: Serum FSH returned to normal follicular phase levels only on the EE2 regimen. The hypotrophic endometria normalized with either of the two oestrogen regimens with no excessive hypertrophy. Hyperinsulinaemia was suppressed to normal by both EE2 and CE. PTH and 1,25-dihydroxyvitamin D levels increased on HRT (EE2 > CE), and phosphorus decreased. Alkaline phosphatase, osteocalcin and urinary deoxypyridinoline cross-links (DPD) were high off therapy; the former two suppressed to high-normal levels on the EE2 regimen, but not on CE, and DPD did not normalize with either HRT. Lipid profiles in these young TS patients were normal. Liver enzymes were mildly elevated off therapy and suppressed to normal levels on both regimens, but more so with EE2. CONCLUSIONS: The risk factors embodied in hyperinsulinaemia and enhanced bone turnover which, ultimately, have consequences for TS morbidity, are minimized by HRT. In the short term, neither regimen is effective for bone turnover in adult women with Turner syndrome.
Adolescent↗
The autosomal dominant trait of obesity, acanthosis nigricans, hypertension, ischemic heart disease and diabetes type 2.
OBJECTIVE: Among obese subjects, acanthosis nigricans in both males and females is not as uncommon as previously thought. Whereas this finding was extensively evaluated in females, mostly in the context of polycystic ovaries syndrome, little attention has been paid to obese males with acanthosis nigricans. As acanthosis seems to be a marker for insulin resistance, the present study was designed to evaluate the hypothesis that the clinical syndrome of obesity and acanthosis would take a different clinical course than that of simple obesity. METHODS: To characterize the course of acanthosis nigricans and obesity in males, we examined 22 children and adolescents with this complex, together with their parents and grandparents and found them to follow a detrimental sequence of the metabolic syndrome. We compared the findings to 13 age-matched males with obesity but no clinical apparent acanthosis nigricans. We analyzed the clinical course, fat distribution, glucose, insulin and C-peptide and lipoproteins. RESULTS: Onset of obesity in the metabolic syndrome group was at a mean age of 6.4 years, as compared to 2.3 years in the controls. The metabolic syndrome patients had a truncal (android) distribution of fat and their fasting blood glucose was significantly higher. HDL/total cholesterol was lower. Examination of the pedigrees suggested autosomal dominant inheritance of the obesity and acanthosis nigricans complex, extending to hypertension and ischemic heart disease in the parents' generation, and further extending to include diabetes type 2 in the grandparents' generation. CONCLUSIONS: This metabolic syndrome is inherited as an autosomal dominant trait, with onset of truncal obesity at age 6-7 years, acanthosis nigricans during childhood or adolescence, extending to hypertension and ischemic heart disease during young adulthood, and further extending to include diabetes type 2 in late adulthood. It is recommended that such children should be followed up as an 'at-risk' group, and would probably benefit from intensive weight reduction, which may prevent the later manifestations of the syndrome.
Acanthosis Nigricans↗
The importance of adrenocortical glucocorticoids for adrenomedullary and physiological response to stress: a study in isolated glucocorticoid deficiency.
Glucocorticoids are required for the normal functioning of chromaffin cells and their capacity to produce epinephrine. This was modeled in a unique clinical syndrome of isolated glucocorticoid deficiency due to unresponsiveness to ACTH. The working hypotheses were that in patients with isolated glucocorticoid deficiency, adrenomedullary epinephrine would be suppressed despite replacement therapy; that norepinephrine might show a compensatory response; and that the physiological response to stress would reflect these changes. Toward these hypotheses, patients with ACTH unresponsiveness on glucocorticoid replacement were subjected to three levels of acute stress: assumption of upright posture, cold pressor, and exercise. Their catecholamine and physiological response were monitored. Patients with isolated glucocorticoid deficiency of this study had severe adrenomedullary dysfunction, characterized by a minimal resting production of epinephrine (6 +/- 2 pg/ml compared with 64 +/- 22 pg/ml of the controls) and a minimal response to stress. A slight compensatory increase of norepinephrine was found in response to cold pressor test (754 +/- 200 pg/ml compared with 431 +/- 73 pg/ml of the control). The physiological response is characterized by low systolic blood pressure and high pulse rate in rest and mild stress and in a pressor response to exercise (diastolic 87 +/- 5 mm Hg, compared with 73 +/- 2 mm Hg of the control). It is concluded that intra-adrenal glucocorticoids are essential for epinephrine secretion, that norepinephrine may be compensatory, and that these result in a distinct physiological response. The implications of the pressor response to exercise, the declining pulse pressure, and the increased pulse response insinuate a lower physical fitness in patients with adrenal insufficiency.
Adaptation, Physiological↗
The role of the vitamin D receptor in regulating vitamin D metabolism: a study of vitamin D-dependent rickets, type II.
In vitro studies and animal experiments suggest that the production of 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] and 24,25-(OH)(2)D is reciprocally controlled by 1,25-(OH)(2)D. To investigate the role of the vitamin D receptor (VDR) in controlling vitamin D metabolism in humans, we studied 10 patients with vitamin D-dependent rickets type II due to a defective VDR. After a period of high dose calcium therapy, 7 of the patients had normal serum calcium, phosphorus, alkaline phosphatase, and plasma PTH levels (PTH-N), and 3 showed increased serum alkaline phosphatase and plasma PTH (PTH-H). Serum calcium, phosphorus, alkaline phosphatase, PTH, vitamin D metabolites, urinary calcium/creatinine, and renal phosphate threshold concentration were compared with unaffected family members that comprised the control group. Vitamin D metabolites were measured before and after an oral load of 50,000 U/m(2) cholecalciferol. Compared with the control group, 1,25-(OH)(2)D levels were significantly higher and 24,25-(OH)(2)D levels were lower in the PTH-N group and even more so in the PTH-H group. 1alpha-Hydroxylase (1-OHase) and 24-OHase activities were estimated by the product/substrate ratio. In the PTH-N group, 1-OHase activity was higher and 24-OHase activity was lower than in controls. In the PTH-H group, 1-OHase activity was even higher, probably due to an additive effect of PTH. Thus, 1,25-(OH)(2)D-liganded VDR is a major control mechanism for vitamin D metabolism, and PTH exerts an additive effect. Assessment of the influence of 1,25-(OH)(2)D shows reciprocal control of enzyme activity in man, suppressing 1-OHase and stimulating 24-OHase activity.
25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
Shedding of growth hormone-binding protein is inhibited by hydroxamic acid-based protease inhibitors: proposed mechanism of activation of growth hormone-binding protein secretase.
The present study describes events postulated to be involved in the regulated mechanism of proteolytic shedding of growth hormone (GH)-binding protein (GHBP). Using Chinese hamster ovary (CHO) cell lines stably transfected either with the full-length human GH receptor (hGHR) or with the cytoplasmic domain-truncated hGHR (hGHR(tr)), we show that the phorbol ester, phorbol 12-myristate 13-acetate (PMA), caused a rapid time- and dose-dependent increase in GHBP secretion, which, as expected, was matched by a corresponding decrease in cell-surface GHR. Furthermore, PMA equally enhanced GHBP release from CHO/hGHR(tr) cells, suggesting that the cytoplasmic domain of hGHR is not essential for PMA-induced shedding. PMA is known to specifically activate protein kinase C and, indeed, the stimulatory effects of PMA in both cell lines were completely inhibited by the protein kinase inhibitor, staurosporine (100 nM), suggesting that activation of protein kinase C (PKC) may mediate PMA-induced GHBP shedding. Since proteolytic cleavage of several cell-surface proteins was shown to be stimulated by modulators of PKC activity and inhibited by metalloprotease inhibitors, we studied the effects of two hydroxamic acid-based inhibitors of zinc-dependent metalloproteases, BB-3103 and Ro31-9790, on GHBP proteolysis. Pretreatment of CHO/hGHR cells with both these inhibitors reduced PMA-enhanced shedding of GHBP, in a dose-dependent manner, with IC(50) values of approximately 0.41 microM for BB-3103 and approximately 0.97 microM for Ro31-9790. In addition, these inhibitors dose-dependently reduced the shedding enhanced by the sulfhydryl alkylator, N-ethylmaleimide (NEM), with IC(50) values of approximately 0.32 microM and approximately 0.58 microM for BB-3103 and Ro31-9790 respectively. It was of interest to find out that Ro31-9790 acted not only to modulate PMA- or NEM-induced shedding processes, but also markedly reduced the spontaneous, time-dependent accumulation of GHBP released from CHO/hGHR cells growing in serum-containing medium. Taken together, these results suggest that one or more zinc-dependent metalloprotease(s), acting at the cell surface, may be involved in GHBP secretase activity. A scheme is proposed whereby at least part of the regulated maturation and/or activation of the protease activity may involve a cysteine-switch mechanism and/or PKC-dependent phosphorylation. In the long run, specific inhibitors of these processes could be applied in the regulation of GHBP levels and, thus, of GH availability and/or activity.
Animals↗
Comparing thyroid ultrasonography to thyroid function in long-term survivors of childhood lymphoma.
BACKGROUND: We studied the value of thyroid ultrasonography as a follow-up tool in survivors of childhood lymphomas and correlated morphologic abnormalities with thyroid function tests. PROCEDURE: A prospective follow-up study of 45 long-term survivors of histology-proved childhood lymphomas was performed. Mean age at diagnosis was 9.1 years (range 2.1-16.4 years) and mean follow-up duration 10.9 years (range 3.9-22.2 years). RESULTS: Among the 26 survivors of Hodgkin disease (HD) who received mantle field irradiation, 14 (54%) had abnormal ultrasonograms. Elevated thyroid-stimulating hormone (TSH) concentrations were found in 14 (54%), and 6 of them (42%) had normal thyroid functions. Six of twelve patients with normal ultrasonograms had abnormal thyroid function, and 5 of 11 patients with normal function had abnormal sonograms. Among the 19 non-HD survivors who did not receive radiotherapy, 18 (95%) had both normal sonograms and normal function. Thus thyroid gland abnormalities were detected in 54% of HD survivors after mantle field irradiation. No correlation between the abnormalities detected on ultrasonography and serum levels of TSH and thyroid hormones were found. CONCLUSIONS: Both ultrasound and thyroid function tests independently provide clinically useful information; the former examines gland morphologogy and the latter evaluates hormonal changes associated with thyroid disease. The high frequency of thyroid abnormalities detected by ultrasonography suggests that periodic thyroid ultrasonography is advisable in the follow-up of patients treated with mantle irradiation to screen for morphologic changes that may presage malignant transformation.
Adolescent↗
Longitudinal analysis of growth over the first 3 years of life in Turner's syndrome.
OBJECTIVE: To evaluate longitudinal growth in Turner's syndrome (TS) over the first 3 years of life. METHODS: Growth of 47 patients with TS was compared with that of 40 age-matched control girls by using an analysis according to the Infancy-Childhood-Puberty and bi-exponential models. RESULTS: A mean of 1.2 SDs were lost before birth and a total of 3.0 SDs were lost by age 3 years. According to the Infancy-Childhood-Puberty model, intrauterine growth retardation contributed -1.24 SDs, a 5-month delay in childhood growth spurt contributed -0.96 SDs, and slow childhood growth contributed an additional -0.8 SDs by age 3 years. The bi-exponential analysis disclosed a quasi-linear first exponent and a confining second exponent, which merged at age 18 months in control subjects and 24 months in patients with TS. The first exponent confers an average annual growth rate of 8.4 cm/y in control subjects and 6.7 cm/y in patients with TS. CONCLUSIONS: Intrauterine growth retardation and the initial 3 years of life contribute most of the deficit in the final height of patients with TS. These data provide a reference of standards for longitudinal growth in patients with TS at age 3 months to 3 years.
Child, Preschool↗
Clinical review 112: Does serum growth hormone (GH) binding protein reflect human GH receptor function?
Previous observations raised the possibility that circulating GH-binding protein (GHBP) may serve as a useful index for tissue GH receptor (GHR) responsiveness in humans. Indeed, there are many examples to indicate that across a wide scope of comparative studies, ontogenic data, experimental systems, physiological conditions, nutritional states, and diseases there is a close relationship between the concentration of GHR and the level of serum GHBP. In the present review, we discuss various aspects that might affect differentially cellular GHR and circulating GHBP, based on species and tissue divergence, regulation of cell-surface GHR turnover, GHR cleavage mechanism, GHR mRNA splicing, and GH insensitivity (GHI) syndrome patients with normal or high serum GHBP levels. Most previous experimental data were collected through comparative analysis of human GHBP against GHR and GHBP determinations in animal models. Yet, GHBPs possess species-specific properties, and the mechanism for their generation and regulation display evolutionary divergence. Another important aspect is tissue divergence, in terms of GHR regulation and its cleavage to GHBP. Although GHBP is generated mainly from the liver GHR, many other tissues express GHRs and probably also contribute to the total GHBP level. Human GHBP is generated by proteolytic cleavage of GHR at the cell-surface and, thus, occupancy or modulation of GHR turnover/internalization would impact the level of cell-surface GHR that are available for proteolysis. An additional degree of complexity arises from recent reports, implicating a protein kinase C-regulated metalloprotease activity in GHBP generation. This suggests that the proteolytic system, which controls the specific cleavage mechanism and switch between GHR proteolysis and GHBP shedding, is a regulated process. Finally, differential splicing regulation to the full-length, active human GHR (hGHR) and the inactive truncated hGHRtr isoform messenger RNA transcripts might regulate both the production of GHBP and GHR bioactivity, as hGHRtr generates large amounts of GHBP but has a dominant negative effect on GH signaling. Several clinical GH-resistant conditions, such as liver cirrhosis, renal insufficiency, insulin-dependent diabetes mellitus, hypothyroidism, malnutrition, or critical illness are associated with reduced GHBP levels. However, this is not universally true, as in other conditions (e.g. early childhood, acromegaly) decreased GHBP levels are not associated with GHI. Divergence between serum GHBP and insulin-like growth factor I, such as which occur during puberty or obesity, also questions whether GHBP levels reflect GHR function. Even in patients with GHI syndrome, serum GHBP cannot be relied on to detect all GHR mutations. The correct assessment of GHR expression and GH functionality in an individual patient will require, in parallel to measurements of serum GHBP, additional detailed diagnostic screening of the entire GH-insulin-like growth factor I axis.
Animals↗
[Growth hormone in the search for stature].
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Body Height↗