When Leptin Is Not There: A Review of What Nonsyndromic Monogenic Obesity Cases Tell Us and the Benefits of Exogenous Leptin.

Obesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies.

Plantar Flexor Function in Adults with and without Prader-Willi Syndrome.

PURPOSE: Prader-Willi Syndrome (PWS) is a form of congenital obesity characterized by excessive body fat, hypotonia, muscle weakness, and physical/cognitive disability. However, the sources of muscle dysfunction and their contribution to mobility are unclear. The purposes of this study were to 1) compare plantar flexor function between adults with and without PWS; and 2) to examine the relationship between plantar flexor function and gait speed in adults with PWS. METHODS: Participants included 10 adults with PWS, 10 adults without PWS and with obesity, and 10 adults without PWS and without obesity (matched on age and sex). Plantar flexor function was assessed using isokinetic dynamometry (peak torque [PT], early/late rate of torque development [RTD]), Hoffman reflex (H/M ratio), ultrasound imaging (cross-sectional area [CSA], echo intensity, pennation angle, and fascicle length), and peak propulsive force and plantar flexor moment during gait. Outcomes were compared between groups using one-way MANOVA. Associations between plantar flexor outcomes and gait speed were assessed using Pearson correlation in the PWS group. RESULTS: Adults with PWS had lower absolute and normalized early RTD, and lower H/M ratio than controls with and without obesity; lower absolute PT and late RTD than controls with obesity (all P < 0.05). Cross-sectional area, propulsive force, and plantarflexor moment were lower, and echo intensity was higher, in adults with PWS compared with controls without obesity (all P < 0.05). Greater absolute PT (r = 0.64), absolute early RTD (r = 0.62), absolute late RTD (r = 0.64), gastrocnemii CSA (r = 0.55), and propulsive force (r = 0.58) were associated with faster gait speed (all P < 0.05). CONCLUSIONS: Adults with PWS have impaired plantar flexor function likely attributable to reduced neuromuscular function and altered muscle morphology, which are associated with slower gait speeds.

Leptin-Mediated Changes in the Human Metabolome.

CONTEXT: While severe obesity due to congenital leptin deficiency is rare, studies in patients before and after treatment with leptin can provide unique insights into the role that leptin plays in metabolic and endocrine function. OBJECTIVE: The aim of this study was to characterize changes in peripheral metabolism in people with congenital leptin deficiency undergoing leptin replacement therapy, and to investigate the extent to which these changes are explained by reduced caloric intake. DESIGN: Ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) was used to measure 661 metabolites in 6 severely obese people with congenital leptin deficiency before, and within 1 month after, treatment with recombinant leptin. Data were analyzed using unsupervised and hypothesis-driven computational approaches and compared with data from a study of acute caloric restriction in healthy volunteers. RESULTS: Leptin replacement was associated with class-wide increased levels of fatty acids and acylcarnitines and decreased phospholipids, consistent with enhanced lipolysis and fatty acid oxidation. Primary and secondary bile acids increased after leptin treatment. Comparable changes were observed after acute caloric restriction. Branched-chain amino acids and steroid metabolites decreased after leptin, but not after acute caloric restriction. Individuals with severe obesity due to leptin deficiency and other genetic obesity syndromes shared a metabolomic signature associated with increased BMI. CONCLUSION: Leptin replacement was associated with changes in lipolysis and substrate utilization that were consistent with negative energy balance. However, leptin's effects on branched-chain amino acids and steroid metabolites were independent of reduced caloric intake and require further exploration.

Genetically Inherited Obesity and High-Fat Diet-Induced Obesity Differentially Alter Spermatogenesis in Adult Male Rats.

Obesity is a multifactorial disorder with predominantly genetic and/or environmental causes. Our aim was to delineate effects of genetically inherited and high-fat diet-induced obesity on fertility and spermatogenesis using two Wistar rat models: genetically inherited obese (GIO) WNIN/Ob rats and diet-induced obese (DIO) rats, which received a high-fat diet. The terminal body weights were similar in both groups, but there was a significant difference in metabolic and hormone profiles between the groups. Fertility assessment revealed a significant decrease in the litter size due to increased pre- and postimplantation loss in the DIO group, whereas the rats in the GIO group were infertile due to lack of libido. Significantly decreased sperm counts were observed in the GIO group compared with the DIO group. Enumeration of testicular cells on the basis of ploidy and cell type-specific expression markers, to study the effect of obesity on spermatogenesis, demonstrated that the GIO and DIO states affected mitosis: spermatogonia and S-phase population were increased. However, distinctive effects were observed on meiosis and spermiogenesis in both the groups. Differential effects of GIO and DIO on fertility and spermatogenesis could be due to the significant difference in white adipose tissue accumulation between the groups and not due to high body weights. The differential effects of obesity suggest male obesity-induced infertility observed in humans could be a combination of genetic and environmental factors.

Fatores de risco cardiovascular: o diagnóstico e prevenção devem iniciar nas crianças e adolescentes / Cardiovascular risk factors: diagnosis and prevention muststart in children and adolescents

A infância e a adolescência são períodos que compreendem a transição para a vida adulta, no qual ocorrem mudanças no âmbito físico, psicológico, emocional e social. Nesse período tão crucial para o desenvolvimento, fatores ambientais e doenças aos quais os jovens estão expostos podem refletir na vida adulta, gerando maiores chances de desenvolvimento de doenças crônicas, incluindo a doença cardiovascular (DCV). A principal etiologia das doenças cardiovasculares é a aterosclerose, que tem seu início na infância. Dessa forma, é reconhecido atualmente que a prevenção cardiovascular primordial deve iniciar precocemente, na infância e adolescência, antes da instalação da doença de fato, de modo a diminuir a prevalência e incidência das DCV na idade adulta.

Childhood and adolescence constitute the transition to adult life, where changes occur in the physical, psychological, emotional and social spheres. In such a crucial period of deve-lopment, environmental factors and diseases to which young people are exposed may have repercussions in adulthood, increasing the chances of developing chronic diseases, including cardiovascular disease (CVD). The main etiology of cardiovascular diseases is atheroscle-rosis, which has its onset in childhood. Accordingly, it is currently recognized that primordial prevention of cardiovascular disease should begin early, i.e. in childhood and adolescence, prior to its actual onset, in order to reduce the prevalence and incidence of CVD in adulthood.

PEG-asparaginase induced severe hypertriglyceridemia

Asparaginase (ASP) is an effective chemotherapy agent extensively used in children with acute lymphocytic leukemia (ALL). There has been a recent interest in using ASP in adults with ALL, particularly the less toxic pegylated (PEG) formulation. Hypertriglyceridemia (HTG) is a rare complication of PEG-ASP therapy. We report two cases of obese patients who developed severe HTG after receiving PEG for ALL. Both patients were incidentally found to have severe HTG (TG of 4,330 and 4,420 mg/dL). In both patients, there was no personal or family history of dyslipidemia or hypothyroidism. There was no evidence of pancreatitis or skin manifestations of HTG. Both patients were treated with PEG cessation, low-fat diet and pharmacotherapy. Both patients were re-challenged with PEG, with subsequent increase in TG but no associated complications. TG returned to baseline after discontinuing PEG and while on therapy for HTG. A literature review of PEG-induced HTG in adults demonstrated similar results: asymptomatic presentation despite very severe HTG. HTG is a rare but clinically important adverse effect of PEG. Underlying obesity and/or diabetes may represent risk factors. Clinicians should monitor TG levels during PEG therapy to avoid TG-induced pancreatitis.

PEG-asparaginase induced severe hypertriglyceridemia.

Asparaginase (ASP) is an effective chemotherapy agent extensively used in children with acute lymphocytic leukemia (ALL). There has been a recent interest in using ASP in adults with ALL, particularly the less toxic pegylated (PEG) formulation. Hypertriglyceridemia (HTG) is a rare complication of PEG-ASP therapy. We report two cases of obese patients who developed severe HTG after receiving PEG for ALL. Both patients were incidentally found to have severe HTG (TG of 4,330 and 4,420 mg/dL). In both patients, there was no personal or family history of dyslipidemia or hypothyroidism. There was no evidence of pancreatitis or skin manifestations of HTG. Both patients were treated with PEG cessation, low-fat diet and pharmacotherapy. Both patients were re-challenged with PEG, with subsequent increase in TG but no associated complications. TG returned to baseline after discontinuing PEG and while on therapy for HTG. A literature review of PEG-induced HTG in adults demonstrated similar results: asymptomatic presentation despite very severe HTG. HTG is a rare but clinically important adverse effect of PEG. Underlying obesity and/or diabetes may represent risk factors. Clinicians should monitor TG levels during PEG therapy to avoid TG-induced pancreatitis.

Long-term stabilization effects of leptin on brain functions in a leptin-deficient patient.

CONTEXT: Congenital leptin deficiency, caused by a very rare mutation in the gene encoding leptin, leads to severe obesity, hyperphagia and impaired satiety. The only systemic treatment is the substitution with metreleptin leading to weight reduction based on hormonal changes. Several studies have also shown alterations in brain function after metreleptin therapy. In a previous study, we were able to show changes in homeostatic (hypothalamus) and reward-related brain areas (striatum, orbitofrontal cortex (OFC), substantia nigra/ventral tegmental area, amygdala) 3 days and 6 months after therapy start in a leptin-deficient adolescent girl. To further access the time course of functional brain activation changes, we followed the patient for 2 years after initiation of the therapy. DESIGN, PATIENT: Functional magnetic resonance imaging during visual stimulation with food (high- and low-caloric) and non-food pictures was performed 1 and 2 years after therapy start in the previously described patient. RESULTS: The comparison of 'food vs. non-food' pictures showed a stabilization of the long-term effects in the amygdala and in the OFC. Therefore, no significant differences were observed between 6 months compared to 12 and 24 months in these regions. Additionally, a reduction of the frontopolar cortex activity over the whole time span was observed. For the comparison of high- and low-caloric pictures, long-term effects in the hypothalamus showed an assimilating pattern for the response to the food categories whereas only acute effects after 3 months were observed in hedonic brain regions. CONCLUSION: This follow-up study shows that the long lasting benefit of metreleptin therapy is also associated with activation changes in homeostatic, hedonic and frontal control regions in congenital leptin deficiency.

Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort.

BACKGROUND & AIMS: Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. METHODS: We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. RESULTS: We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. CONCLUSIONS: In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption.

[An overview of diseases inducing secondary obesity].

Obesity is a heterogeneous syndrome. The pathophysiology of obesity seems to be simple because of a chronic excess of nutrient intake relative to the low level of energy expenditure. However, several pathogenic processes are involved in the development of obesity. Moreover, there are primary diseases that cause secondary obesity, also called symptomatic obesity, in process of those clinical explorations. The symptomatic obesity is classified as endocrine, central nervous-related, congenital and drug-induced obesity. Since simple obesity is diagnosed after excluding symptomatic obesity, we should understand pathophysiology and clinical characteristics of each of primary diseases that cause obesity.

Estudio de prevalencia de obesidad, sobrepeso y presiòn arterial elevada en niños de 10-14 años, en instituciones educativas de la ciudad de Asunciòn / Study of prevalence of obesity, overweight, high blood pressure in childrem aged 10-14 years, in educational institutions of the city of Assumption

La obesidad ha llegado a proporciones epidèmicas globalmente, la HAS (Hipertensiòn Arterial Sistèmica) y la obesidad son fuertes predictores para la apariciòn de aterosclerosis y, por ende, de morbimortalidad por accidentes cardiovasculares en la edad adulta.

Nasci de novo: sobrevivendo ao estigma da gordura: um estudo de caso sobre obesidade / I was born again: surviving to the stigma of fat a case based study on obesity

A obesidade é definida como uma doença caracterizada pelo acúmulo excessivo de gordura corporal que acarreta para as pessoas diminuição na qualidade de vida, menor autonomia, diminuição da vitalidade e da capacidade funcional para as tarefas cotidianas. Além disso, os obesos tornam-se estigmatizados na medida em que não se enquadram nos padrões hegemônicos de beleza na sociedade contemporânea. O isolamento social e afetivo cresce, juntamente com a angústia, a depressão e a sensação de abandono. Esta pesquisa teve como objetivo a apreensão e interpretação de sentidos e significados que os alunos com sobrepeso ou obesidade atribuem às práticas corporais de saúde realizadas no Projeto de Exercício Físico Adaptado para Obesos (PEFAO) do Instituto de Educação Física e Desportos (IEFD) da Universidade do Estado do Rio de Janeiro (UERJ), no sentido de compreender os motivos que levam esses alunos a procurarem e a permanecerem neste Projeto de Extensão. Trata-se, pois, de um estudo de caso de natureza sócio-antropológica cuja estratégia metodológica adotada foi a articulação entre observação etnográfica (participante), entrevistas informais e formais (gravadas) e documentação fotográfica. Percebemos que os vínculos sociais e a ludicidade presentes nas aulas do PEFAO-UERJ levam os atores sociais a repensarem sua própria existência e resignificar o sofrimento. A partir da entrada no campo da Promoção da Saúde e da Qualidade de Vida, estruturado por um novo habitus inicialmente estranho aos obesos há um ritual de passagem que dá lugar à afirmação Eu nasci de novo. Esse novo nascimento simbólico se estabelece quando o aluno consegue ampliar sua vitalidade e valorizar sua existência enquanto ser humano, independente da quantidade de gordura no corpo. Aos poucos o estigma da gordura vai sendo resignificado e novos sentidos sobre a vida são produzidos coletivamente e partilhados pelo grupo social...

The obesity is defined as a disease characterized by the excessive body fataccumulation. It causes not only a decrease in quality of life and in vitality but also less autonomy and functional capacity on daily chores. Besides, the obese are stigmatized when they not fit in the present-day society's hegemonic standard of beauty. The social and affective isolation becomes higher and so the anguish, depression and sensation of abandonment. The purpose of this research has been theapprehension and interpretation of sense and meaning that the overweight or obese students give to the body health practices from the Physical Exercise Project Adapted to Obese ( PEFAO) taken place at Instituto de Educação Física e Desportos (IEFD) atthe Universidade do Estado do Rio de Janeiro (UERJ), in the way of understanding the reasons why these students look for this Projeto de Extensão and stay in it. So, thisresearch is about a socio-anthropological study, in which methodological strategy usedhas been the articulation between the ethnographic observation (participant), informal and formal interviews (recorded) and photographic documentation. We realize thatboth the social connection and educational games - seen at the PEFAO-UERJ classes - make the social actors think about their own existence and give a redefined suffering. From the inclusion on the field of the Health Promotion and Quality of Life, organized by a new habitus - at first unknown by the obese - there is a new rite of passage thatcauses the statement: "I was born again". This new birth - symbolic - is settle when a student is able to increase his vitality and to give value to his existence as a human being, no matter how high his body fat is. Gradually the body fat stigma gets a new sense and other ways of life's definition are produced collectively and shared by thesocial group. We conclude that the collective activities taken by individual...

Fish oils, phytosterols and weight loss in the regulation of lipoprotein transport in the metabolic syndrome: lessons from stable isotope tracer studies.

1. Dyslipoproteinaemia is a cardinal feature of the metabolic syndrome that accelerates atherosclerosis. It is characterized by high plasma concentrations of triglyceride-rich and apolipoprotein (apo) B-containing lipoproteins, with depressed concentrations of high-density lipoprotein (HDL). Dysregulation of lipoprotein metabolism in these subjects may be due to a combination of overproduction of very-low density lipoprotein (VLDL) apoB-100, decreased catabolism of apoB-containing particles and increased catabolism of HDL apoA-I particles. 2. Nutritional interventions may favourably alter lipoprotein transport in the metabolic syndrome. We review our collaborative studies, using stable isotopes and compartmental modelling, of the kinetic effects of fish oils, plant sterols (phytosterols) and weight reduction on the dyslipoproteinaemia in this disorder. 3. Fish oil supplementation diminished hepatic secretion of VLDL-apoB and enhanced conversion of VLDL to low-density lipoprotein (LDL)-apoB, without altering catabolism. 4. Plant sterols (phytosterols) did not have a significant effect on plasma concentrations of lipids and lipoprotein or the kinetics of apoB and apoA-I. 5. Modest weight reduction optimally decreased plasma triglyceride and LDL-cholesterol via reduction in hepatic apoB secretion and reciprocal upregulation of LDL catabolism. 6. The scope and potential of future studies using stable isotope tracers is discussed.

Inherited pericentric inversion (X)(p11.4q11.2) associated with delayed puberty and obesity in two brothers.

We report two brothers with hypogonadotropic hypogonadism (HH), obesity and short stature associated with a maternally inherited pericentric inversion (X)(p11.4q11.2). On the basis that either breakpoint might disrupt a gene whose function is critical to normal sexual development we mapped the chromosomal breakpoints using two-colour fluorescent in situ hybridisation (FISH). The position of both the Xp11.4 and Xq11.2 breakpoints was refined using a panel of ordered BAC clones. No known genes were shown to map to the breakpoint regions. While we cannot entirely exclude the possibility that association between the clinical and cytogenetic phenotypes in the family is coincidental, it is possible that the inversion is responsible for HH through alternative molecular mechanisms such as position effects.

Impaired expression and functional activity of the beta 3- and beta 1-adrenergic receptors in adipose tissue of congenitally obese (C57BL/6J ob/ob) mice.

Adipocytes from genetically obese (ob/ob) mice display an impaired response to beta-adrenergic stimulation, but the molecular defects have not been unequivocally identified. The expression and functional activity of the beta 1-, beta 2-, and beta 3-adrenergic receptor (AR) subtypes in white and brown adipose tissue from genetically lean and obese (ob/ob) mice were compared. Three beta 3AR transcripts of 2.1, 2.6, and 3.5 kilobases were identified in adipose tissue from lean mice by Northern blotting. All three beta 3AR mRNA species were dramatically reduced (by approximately 300-fold) in 12-week-old obese mice compared to those in lean animals. beta 1AR mRNA levels were also reduced (by approximately 4-fold) in obese mice, whereas beta 2AR mRNA levels were not significantly changed. The functional consequences of these changes in beta 3AR and beta 1AR expression were assessed by measuring beta-agonist-stimulated adenylyl cyclase activity in adipocyte plasma membranes with subtype-selective beta-adrenergic agonists and antagonists. Dose-response curves with epinephrine from lean mice were best fit to a two-component model comprised of 23% high affinity (K(act) = 1.42 x 10(-7) M) and 77% low affinity (K(act) = 1.67 x 10(-5) M) components, corresponding to activation of beta 1AR and beta 2AR conjointly, and beta 3AR, respectively. The beta 1AR-selective antagonist CGP20712A reduced the high affinity component to about 10%, whereas the nonselective beta-antagonist propranolol eliminated the high affinity component. The beta 3AR-selective agonist BRL37344 stimulated adenylyl cyclase activity in lean membranes to a slightly lesser extent than epinephrine, but was more potent (73% high affinity component; K(act) = 3.61 x 10(-8) M). In obese mice, stimulation of adenylyl cyclase by all agonists was severely blunted and was best fit to a single class of sites. Studies with CGP20712A or the beta 2AR-selective antagonist ICI118,551 indicated that this residual response was predominantly beta 2AR in character. Expression of beta AR subtypes in both brown and white adipose tissue of weanling obese mice (4-5-weeks of age) was also affected, but to a lesser extent, consistent with the progressive severity of obesity with age. Together the reduction in expression of the beta 3AR and beta 1AR impairs the beta-agonist-stimulated adenylyl cyclase response over a broad concentration range by greatly lowering the maximum stimulation and shifting the adrenergic sensitivity at low concentrations from a mixed beta 1AR/beta 2AR response to predominantly beta 2AR.

Perinatal hyperinsulinism and perinatal obesity as risk factors for hyperinsulinaemia in later life.

In the offspring of gestational or long-term diabetic mothers the following findings were obtained: (1) Immunoreactive plasma insulin levels on the first day of life were weakly correlated to the thickness of the skin-fold at the neck on the third day of life (n = 82; r = 0.27; P less than 0.05). (2) A significant correlation was found between the plasma insulin levels at birth and the basal as well as the maximal plasma insulin values after glucose loading (1.75 g/kg b. wt.) at 2 years of age (for basal values: n = 25; r = 0.53; P less than 0.01; and for maximal values: n = 21; r = 0.63; P less than 0.01). (3) A highly significant correlation was even observed between the thickness of the neck-fold at 3 days of age and the fasting plasma insulin levels at 3-8 years of age (n = 26; r = 0.61; P less than 0.001). These findings suggest that perinatal hyperinsulinism and perinatal obesity, induced by maternal hyperglycaemia and/or overnutrition during pregnancy, are risk factors for persistent hyperinsulinaemia predisposing to diabetes mellitus and cardiovascular disease in later life.