An Evolutionary Perspective on the Obesity Epidemic.

An evolutionary approach to obesity involves a genomic/anthropological dimension. For 1.8 Myr the lifestyle of hunter-gatherers (HGs) comprised intense physical activity and a high-protein/low-carbohydrate diet. Genomes of HGs were adapted to low insulin sensitivity. When the agrarian epoch began a new 'farmer diet' high in carbohydrates (CHO) emerged. Owing to periodic famines, the genome may not have adapted; they preserved a HG genome. Ever since the industrial revolution our genome is adapting rapidly to a CHO-rich diet. Individuals with preserved HG genome develop obesity at age 4-8 years and need a low-CHO diet. By contrast, those with a farmer genome become obese in infancy; they need a low-calorie diet. This knowledge prompts exploration of the two genomes and their clinical presentations.

Outcomes of pubertal development in girls as a function of pubertal onset age

BACKGROUND: The relationship between pubertal onset and tempo and pubertal growth is controversial. We hypothesized that the age at onset of girls' puberty predicts pubertal tempo and the rate of pubertal progression. METHODS: We analysed the data of 380 girls from the prospective Study of Early Child Care and Youth Development (SECCYD), who were recruited in the USA from 1991-2006 and followed from birth to age 15.5 years. We used the following indicators: thelarche age (Tanner stage B2), pubarche age (P2), menarche age (M), the age when breast (B5) and pubic hair (P5) became fully mature, pubertal growth, pubertal duration (time from B2 to B5), pubertal progression (time from B2 to M). We clustered the girls according to B2 age into early onset (EO;<9.4 years), intermediate (IO;9.4-10.5 years), late onset (LO;>10.5 years). RESULTS: All indicators of pubertal onset and conclusion occurred earlier in the EOs than in the LO; yet, the differences in the age at main pubertal milestones lessened as puberty progressed: two years for B2; -1.4 years for M; - one year for B5. In EO, puberty was one year (average) longer than in LO. Although EO grew 7 cm (average) more than LO, their heights at B5 were comparable. There was a significant relationship between the thelarche age and puberty tempo (r=0.23, P<0.0001). CONCLUSIONS: The study highlights the predictive nature of variation in the onset age of puberty on its progression and duration. These results are reassuring in this context and will add to clinicians' and parental understanding of the expected milestones of puberty.

Bone health in eating disorders.

Eating disorders (EDs) put adolescents and young adults at risk for impaired bone health. Low bone mineral density (BMD) with ED is caused by failure to accrue peak bone mass in adolescence and bone loss in young adulthood. Although ED patients diagnosed with bone loss may be asymptomatic, some suffer bone pains and have increased incidence of fractures. Adolescents with ED are prone to increased prevalence of stress fractures, kyphoscoliosis and height loss. The clinical picture of the various EDs involves endocrinopathies that contribute to impaired bone health. Anorexia nervosa (AN) is characterized by low bone turnover, with relatively higher osteoclastic (bone resorptive) than osteoblastic (bone formation) activity. Bone loss in AN occurs in both the trabecular and cortical bones, although the former is more vulnerable. Bone loss in AN has been shown to be influenced by malnutrition and low weight, reduced fat mass, oestrogen and androgen deficiency, glucocorticoid excess, impaired growth hormone-insulin-like growth factor 1 axis, and more. Bone loss in AN may not be completely reversible despite recovery from the illness. Treatment modalities involving hormonal therapies have limited effectiveness, whereas increased caloric intake, weight gain and resumption of menses are essential to improved BMD.

Modified anthropometry in prepubertal Israeli children while excluding the head's weight and height.

AIM: A methodological inadequacy in anthropometric measurements of children exists because of an age-dependent decelerating contribution of the head to body weight (Wt) and height (Ht). Hence, we aimed to assess the contribution of head measurements to anthropometry (Ht, Wt and BMI) in healthy prepubertal children. METHODS: This prospective study was conducted in 300 2- to 9-year-old typically growing children. Head-excluded (HE) Ht was determined by a stadiometer that measured the distance from the foot plate to the lower margin of protuberance occipitalis externa. Head's weight was calculated from the head volume using three different measurements of the head circumference. RESULTS: In the typically growing children, the HE/standard (STD) ratios for Wt and Ht increased significantly with age (p < 0.001 for both), but the HE/STD ratio for BMI did not increase with age. CONCLUSION: Measurement of body Wt and Ht while excluding the head's Wt and Ht provides a new dimension to standard anthropometry by eliminating the age-dependent head bias with its unique pattern of growth and minimal adipose tissue.

Hypothalamic obesity in children.

Hypothalamic obesity is an intractable form of obesity syndrome that was initially described in patients with hypothalamic tumours and surgical damage. However, this definition is now expanded to include obesity developing after a variety of insults, including intracranial infections, infiltrations, trauma, vascular problems and hydrocephalus, in addition to acquired or congenital functional defects in central energy homeostasis in children with the so-called common obesity. The pathogenetic mechanisms underlying hypothalamic obesity are complex and multifactorial. Weight gain results from damage to the ventromedial hypothalamus, which leads, variously, to hyperphagia, a low-resting metabolic rate; autonomic imbalance; growth hormone-, gonadotropins and thyroid-stimulating hormone deficiency; hypomobility; and insomnia. Hypothalamic obesity did not receive enough attention, as evidenced by rarity of studies in this group of patients. A satellite symposium was held during the European Congress of Obesity in May 2011, in Istanbul, Turkey, to discuss recent developments and concepts regarding pathophysiology and management of hypothalamic obesity in children. An international group of leading researchers presented certain aspects of the problem. This paper summarizes the highlights of this symposium. Understanding the central role of the hypothalamus in the regulation of feeding and energy metabolism will help us gain insights into the pathogenesis and management of common obesity.

Child health, developmental plasticity, and epigenetic programming.

Plasticity in developmental programming has evolved in order to provide the best chances of survival and reproductive success to the organism under changing environments. Environmental conditions that are experienced in early life can profoundly influence human biology and long-term health. Developmental origins of health and disease and life-history transitions are purported to use placental, nutritional, and endocrine cues for setting long-term biological, mental, and behavioral strategies in response to local ecological and/or social conditions. The window of developmental plasticity extends from preconception to early childhood and involves epigenetic responses to environmental changes, which exert their effects during life-history phase transitions. These epigenetic responses influence development, cell- and tissue-specific gene expression, and sexual dimorphism, and, in exceptional cases, could be transmitted transgenerationally. Translational epigenetic research in child health is a reiterative process that ranges from research in the basic sciences, preclinical research, and pediatric clinical research. Identifying the epigenetic consequences of fetal programming creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and the development of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs.

Expanding the definition of hypothalamic obesity.

Hypothalamic obesity (HyOb) was first defined as the significant polyphagia and weight gain that occurs after extensive suprasellar operations for excision of hypothalamic tumours. However, polyphagia and weight gain complicate other disorders related to the hypothalamus, including those that cause structural damage to the hypothalamus like tumours, trauma, radiotherapy; genetic disorders such as Prader-Willi syndrome; side effects of psychotropic drugs; and mutations in several genes involved in hypothalamic satiety signalling. Moreover, 'simple' obesity is associated with polymorphisms in several genes involved in hypothalamic weight-regulating pathways. Thus, understanding HyOb may enhance our understanding of 'simple' obesity. This review will claim that HyOb is a far wider phenomenon than hitherto understood by the narrow definition of post-surgical weight gain. It will emphasize the similarity in clinical characteristics and therapeutic approaches for HyOb, as well as its mechanisms. HyOb, regardless of its aetiology, is a result of impairment in hypothalamic regulatory centres of body weight and energy expenditure. The pathophysiology includes loss of sensitivity to afferent peripheral humoral signals, such as, leptin on the one hand and dysfunctional afferent signals, on the other hand. The most important afferent signals deranged are energy regulation by the sympathetic nervous system and regulation of insulin secretion. Dys-regulation of 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) activity and melatonin may also have a role in the development of HyOb. The complexity of the syndrome requires simultaneous targeting of several mechanisms that are deranged in the HyOb patient. We review the studies evaluating possible treatment strategies, including sympathomimetics, somatostatin analogues, triiodothyronine, sibutramine, and surgery.

In vitro fertilisation and use of ovulation enhancers may both influence childhood height in very low birthweight infants.

CONTEXT: Term-born children conceived by in vitro fertilisation (IVF) are reportedly taller than naturally conceived (NC) children. High levels of growth promoting hormones and epigenetic imprinting have been suggested as pathogenetic mechanisms. HYPOTHESIS: Tall stature in prematurely born IVF-conceived (IVF-C) children suggests pre- or early implantation imprinting rather than a postnatal effect. METHODS: We studied 334 very low birthweight (VLBW: birth weight <1500 g) children born prematurely during 1995-1999 and obtained their anthropometric measures at 6-10 years of age. Perinatal and neonatal data were obtained from the Israeli VLBW database. We compared IVF-C, ovulating agents conceived (OA-C) and naturally conceived (NC) groups of children with respect to their and their parents' anthropometry and their perinatal/neonatal variables. RESULTS: Childhood height standard deviation scores (SDSs) were greatest in IVF-C (-0.12 (SD 1.25); p<0.022) and insignificantly greater in OA-C (-0.37 (SD 1.02)) as compared to NC (-0.58 (SD 1.36)) children. The IVF-C and NC groups were significantly different regarding 17 parental and perinatal variables; however, multiple regression analysis including these variables showed that, as compared with NC, IVF-C children had significantly older mothers at birth with earlier follow-up during pregnancy and more multi-fetal pregnancies. CONCLUSIONS: IVF-C and to a lesser extent OA-C prematurely born children are taller than otherwise NC children. After ruling out postnatal and parental causes, we speculate that pre- or early implantation factors might have contributed to the taller stature of IVF-C children.

Juvenility in the context of life history theory.

Homo sapiens is unique in having four prolonged and pronounced postnatal pre-adult life history stages: infancy, which lasts for 30-36 months and ends with weaning from breast feeding in traditional societies; childhood, which lasts for an additional 2-4 years and concludes in a degree of independence as regards protection and food provision; a juvenile stage of 3-4 years that terminates with readiness for sexual maturation; and adolescence, which lasts for 3-5 years and culminates in fertility. Juvenility implies two transitional periods which are only experienced by humans: a transition from childhood to juvenility and from juvenility to adolescence. Juvenility, "the age of reason and responsibility" and concrete operation, coincides with elementary school age and offers opportunities to prepare for the social complexity of adolescence. Here I define the transition to juvenility by three variables: adrenarche (the onset of adrenal androgen generation), growth pattern (decelerating from a linear childhood growth velocity) and adiposity rebound acceleration of body mass index. The data presented suggest that this period is endowed with programming/predictive adaptive responses of body composition to the environment.

Endocrinology of adipose tissue - an update.

Adipose tissue is the body's largest repository of energy and it plays an important role in total energy homeostasis. Moreover, it is now well recognized as an endocrine organ. A wide range of different factors including complex proteins as well as fatty acids, prostaglandins, and steroids are either synthesized de novo or converted in adipose tissue and released into the blood stream. These so-called adipokines contribute to the development of obesity-related disorders, particularly type-2 diabetes (T2D) and cardiovascular disease. In this review, we present an overview on the endocrine functions of adipose tissue with a special focus on discoveries reported within the past 5 years.

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.

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.

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.

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.

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.

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.

Human adipose tissue under in vitro inhibition of 11beta-hydroxysteroid dehydrogenase type 1: differentiation and metabolism changes.

In humans, oxoreducing 11beta-HSD-1 activity appears to be related to body fat distribution in male-type central obesity, but not in female-type peripheral obesity. We postulated that inhibition of 11beta-HSD-1 might have clinical therapeutic significance in oxoreducing mostly visceral fat and its metabolic activity. Our current study investigated the consequence at the cellular level of such inhibition. As an inhibitor of 11beta-HSD-1 activity, we used the licorice derivative carbenoxolone. Carbenoxolone has an inhibitory effect on the activity of both oxidizing 11beta-HSD-2, which converts cortisol to cortisone, and oxoreducing 11beta-HSD-1; yet, preadipocytes and adipocytes only express the latter. Preadipocytes were retrieved from omental and subcutaneous fat from healthy non-obese individuals and differentiated in vitro to mature adipocytes. Activity of 11beta-HSD-1 was assayed by measuring conversion of added 500 nM cortisone to cortisol. Expression of 11beta-HSD-1 mRNA was determined by real-time PCR, while lipolytic effects were determined by measuring glycerol and triglyceride concentration in the culture medium. Carbenoxolone decreased 11beta-HSD-1 activity in a dose-dependent manner with an IC-50 of 5X10 -6 M, but did not affect the expression of 11beta-HSD-1 mRNA. Cortisone stimulated subcutaneous, but not omental preadipocytes proliferation, an effect that was not abolished by carbenoxolone. Dexamethasone had a stimulatory effect on the maturation of both omental and subcutaneous preadipocytes. Carbenoxolone per se, either with or without cortisone, had a negative effect on preadipocyte maturation. Inhibiting 11beta-HSD-1 activity by carbenoxolone had no impact on leptin secretion. Thus, carbenoxolone has no effect on preadipocyte proliferation, but a dramatic inhibitory effect on preadipocyte differentiation into mature adipocytes. The mechanism is only partly related to its inhibitory effect on 11beta-HSD-1 activity. The present observations lend support to the presence of an intracrine loop of a hormone that is both produced from a precursor and active within the preadipocyte and adipocyte.