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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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Salum, Rolando, Zembrzuski, Carneiro, Mello, Maya-Monteiro, Bozza, Kohlrausch and da Fonseca.)

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.

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., (© Endocrine Society 2020.)

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.

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.

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., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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.

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.

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.

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., (Copyright 2005 S. Karger AG, Basel.)

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.

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.

The outcome of delivery of infants weighing more than 4000 g born during two time periods 15 years apart was studied retrospectively. The increased use of cesarean section and other obstetric advances did not reduce the risk of fetal asphyxia and trauma associated with large fetal size. Maternal factors were identified for risk categorization of fetal macrosomia during pregnancy. Macrosomia was rare at 37 weeks and increasingly common thereafter. Fetal size assessment by ultrasound at 36 to 38 weeks' gestation would permit induction of labor for the macrosomic infant before the size became excessive or would make the accoucheur aware of the dangers that may arise during delivery.

Obesity can be reversed in ob/ob mice by parabiosis to lean littermates, by islet transplantation, and by injection of pancreatic polypeptide. These observations suggest that obese mice have functioning satiety centers but lack a circulating satiety factor of pancreatic origin which could be pancreatic polypeptide. This hypothesis has been difficult to test because antisera currently available do not cross-react with rodent pancreatic polypeptide. We have raised an antiserum against the biologically active carboxyl-terminal hexapeptide that measures mouse pancreatic polypeptide specifically. This antiserum has been used to compare circulating and tissue concentrations of pancreatic polypeptide in obese and lean mice. Although pancreatic contents were significantly (p less than 0.01) increased in obese mice (237 +/- 34 pmol/g) compared with lean littermates (107 +/- 20 pmol/g), no postprandial increase in circulating concentrations was observed in obese mice. The hypothesis that obese mice lack a satiety factor of pancreatic origin could be explained by the failure of release of pancreatic polypeptide.

Medical-genetic investigations were carried out in isolated population of Nokhurlis inhabiting some villages of Ashkhabad and Krasnovodsk provinces. A high coefficient of inbreeding, high endogamy, and low coefficients of migration were found for this population. Two hereditary disorders are relatively frequent among the Nokhurlis and lacking in neighboring populations. The frequency of the autosomal dominant gene for congenital cataract is 0.26% and that of the autosomal recessive gene for a peculiar form of obesity is 2.47%. In both cases, the main factor affecting gene accumulation appears to be the result of genetical drift effect. The total load of hereditary diseases of higher in Nokhurlis than in other Turkmen populations. The connection between the population structure of Nokhurlis and the accumulation of hereditary disorders is discussed.

This study compares the early (30-d) with the late (14-month) effects of small intestinal bypass on hepatic lipid accumulation in congenitally obese Zucker rats. Heterozygote, lean and homozygote, obese Zucker rats underwent sham operations and homozygote obese rats underwent bypass of 90 percent of their small intestine. Evaluation of hepatic lipid content at 30 d following the operation demonstrated increased hepatic triglyceride content in homozygote obese rats compared to heterozygote lean rats; however, the homozygote rats with small intestinal bypass did not have significantly different hepatic triglyceride content from that present in the homozygote obese sham operated rats. Fourteen months following the operations hepatic lipid content increased from 63 +/- 14 mg/g liver in homozygote, obese sham operated rats to 132 +/- 55 mg/g in homozygote, obese rats with small intestinal bypass. The increased lipid was secondary to increased hepatic triglyceride content. Histologic evaluations of liver specimens demonstrated no increased inflammation, granuloma formation or fibrosis when sham operated rat liver tissue was compared to liver tissue from rats with intestinal bypass. These data indicate that at a late stage following small intestinal bypass, the obese Zucker rat develops hepatic steatosis, as do humans, and can serve as an experimental model for evaluation of methods to decrease the triglyceride accumulation.

The endocrine pancreata of five overweight newborns (birthweight ranging from 3,800 g to 4,500 g) have been studied. Basal blood glucose and insulin levels were normal in these newborns. A marked and widespread B-cell nesidioblastosis was observed in relation to ten controls (birthweight ranging from 2,900 to 3,500 g). Morphometric analysis showed in the overweight newborns an increase in endocrine tissue, with special reference to B cells. These morphological aspects of the endocrine pancreas in relation to the birthweight were discussed.

1. Measurements were made of energy balance by direct calorimetry, and of nitrogen balance in groups of lean and congenitally obese ('fatty') Zucker rats at body-weights of 200 and 350 g given a highly digestible semisynthetic diet at 14-0 or 18-4 g/rat per 24 h. 2. Losses of food energy and N in faeces were very small. The fatty rats lost much more N in urine than did lean rats. Despite this the proportion of gross energy that was metabolized was 0-92 for both fatty and lean rats. 3. In all trials, fatty rats lost a smaller proportion of metabolizable energy (ME) as heat and deposited less as protein than thin rats but deposited much more as fat. 4. The amounts of ME required to deposit 1 kJ of protein and 1 kJ of fat respectively were shown by regression analysis to be 2-25 (+/-0-16) and 1-36 (+/-0-06) kJ respectively. These values agree extremely closely with recent, more tentative, estimates based on assumptions as to maintenance requirement which the present experiments were able to circumvent. It may be concluded with confidence that the energy costs of depositing 1 g of protein or fat are almost identical at 53 kJ ME/g.

Four women with the Bardet-Biedl syndrome had ophthalmoscopic findings compatible with a severe rod-cone degeneration. The patients were legally blind (visual acuity, 20/200 or worse) in one or both eyes before the age of 30 years. Two patients with early involvement had macular bull's-eye pigment epithelial changes. Two other patients had more advanced disease with geographic atrophy of the macular pigment epithelium and underlying choriocapillaris. Bone spicule formation was variable. Electrophysiologic findings were consistent with severe derangement of both the rod and cone systems. All four patients had intraretinal capillary leakage along the vascular arcades and from the optic nerve without cystoid macular edema. Extensive endocrinologic evaluation showed no objective evidence of hypogenitalism in the three patients tested. Three patients had renal disease, secondary to vesicoureteral reflux, or hypertension, or both.