leptin and Metabolism--Inborn-Errors

The landmark discoveries of leptin and adiponectin firmly established adipose tissue as a sophisticated and highly active endocrine organ, opening a new era of investigating adipose-mediated tissue crosstalk. Both obesity-associated hyperleptinemia and hypoadiponectinemia are important biomarkers to predict cardiovascular outcomes, suggesting a crucial role for adiponectin and leptin in obesity-associated cardiovascular disorders. Normal physiological levels of adiponectin and leptin are indeed essential to maintain proper cardiovascular function. Insufficient adiponectin and leptin signaling results in cardiovascular dysfunction. However, a paradox of high levels of both leptin and adiponectin is emerging in the pathogenesis of cardiovascular disorders. Here, we (1) summarize the recent progress in the field of adiponectin and leptin and its association with cardiovascular disorders, (2) further discuss the underlying mechanisms for this new paradox of leptin and adiponectin action, and (3) explore the possible application of partial leptin reduction, in addition to increasing the adiponectin/leptin ratio as a means to prevent or reverse cardiovascular disorders.

Topics: Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Bariatric Surgery; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Leptin; Metabolism, Inborn Errors; Obesity; Signal Transduction

Obesity is a global epidemic in developed countries accounting for many of the metabolic and cardiorespiratory morbidities that occur in adults. These morbidities include type 2 diabetes, sleep-disordered breathing (SDB), obstructive sleep apnea, chronic intermittent hypoxia, and hypertension. Leptin, produced by adipocytes, is a master regulator of metabolism and of many other biological functions including central and peripheral circuits that control breathing. By binding to receptors on cells and neurons in the brainstem, hypothalamus, and carotid body, leptin links energy and metabolism to breathing. In this comprehensive article, we review the central and peripheral locations of leptin's actions that affect cardiorespiratory responses during health and disease, with a particular focus on obesity, SDB, and its effects during early development. Obesity-induced hyperleptinemia is associated with centrally mediated hypoventilation with decrease CO

Topics: Adiponectin; Animals; Humans; Leptin; Metabolism, Inborn Errors; Obesity; Sleep Apnea Syndromes; Sleep Apnea, Obstructive

Chronic intermittent hypoxia (CIH) occurs frequently in premature infants who have apnea of prematurity. Immaturity of the respiratory network from low central respiratory drive and the greater contribution of the carotid body on baseline breathing leads to respiratory instability in premature infants presenting as apnea and periodic breathing. During the 2nd week after birth, the smallest and the youngest premature infants have increased frequency of apnea and periodic breathing and associated oxygen desaturations that can persist for weeks after birth. CIH increases the production of reactive oxygen species that causes tissue damage. Premature infants have decreased capacity to scavenge reactive oxygen species. Oxidative injury is the cause of many of the co-morbidities that are seen in premature infants. In this review we discuss who low fat mass and the resulting relative deficiencies in leptin and adiponectin could contribute to the increase frequency of oxygen desaturations that occurs days after birth in the smallest and youngest premature infants. Leptin is a central respiratory stimulant and adiponectin protects the lung from vascular leak, oxidative injury and vascular remodeling.

Topics: Adiponectin; Animals; Humans; Hypoxia; Infant; Infant, Premature; Leptin; Metabolism, Inborn Errors

The identification and characterization of monogenic obesity syndromes have improved our understanding of the inherited component of severe obesity and have had undoubted medical benefits. This knowledge has also helped to dispel the notion that obesity represents an individual defect in behaviour with no biological basis.. For individuals at highest risk for complications of severe obesity, such findings provide a starting point for providing more rational mechanism-based therapies, as has successfully been achieved for congenital leptin deficiency.

Topics: Child; Humans; Hypothalamus; Leptin; Melanocortins; Metabolism, Inborn Errors; Obesity, Morbid; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Leptin

To determine the association among bone mineral density (BMD), inflammatory markers, and alterations in fat and lean mass in untreated HIV-infected individuals.. Cross-sectional analysis of antiretroviral therapy-naive persons enrolled into a randomized clinical trial.. Dual-energy x-ray absorptiometry for BMD and lean and fat mass and a laboratory assessment were performed. Soluble biomarkers included adipocytokines (leptin and adiponectin), inflammatory markers (high-sensitivity C-reactive protein and interleukin 6), and markers related to bone metabolism [osteoprotegerin (OPG)], receptor activator of nuclear factor κB ligand. BMD at the lumbar spine, total hip, and femoral neck was expressed as a Z score (number of standard deviations away from age-, race-, and sex-matched reference population).. Three hundred thirty-one subjects had a median (Q1, Q3) age of 36 (28, 45) years, were 89% men, and 44% white. The prevalence of low BMD (Z score ≤ -2 at any of the 3 sites) was 10%. No associations were detected between Z scores and high-sensitivity C-reactive protein, interleukin 6, or receptor activator of nuclear factor κB ligand (P ≥ 0.1). In a linear model adjusting for age, gender, race, and total fat mass, lower lumbar spine Z scores were associated with lower total lean mass, higher serum adiponectin, and lower OPG. Results at the total hip or femoral neck were similar.. Among antiretroviral therapy-naive HIV-infected individuals, lower BMD was associated with lower lean mass, higher adiponectin, and lower OPG, but not HIV disease variables or any of the inflammatory markers. These findings may have implications for bone metabolism in untreated HIV, in which hypoadiponectinemia and higher OPG may mitigate bone loss.

Topics: Adiponectin; Adult; Body Composition; Body Mass Index; Bone Density; C-Reactive Protein; Cross-Sectional Studies; Female; HIV Infections; HIV-1; Humans; Inflammation; Interleukin-6; Leptin; Male; Metabolism, Inborn Errors; Middle Aged; Osteoprotegerin; RANK Ligand

Leptin receptor (LEPR) deficiency is a rare genetic disorder that affects the body's ability to regulate appetite and weight. For patients and their families, the disorder seriously disrupts daily life; however, little is published about this impact. We here report the experiences of a 10.5-year-old girl with leptin receptor deficiency and her family. The diagnosis of this rare genetic obesity had a deep impact on the life of the child and her family. It led to a better understanding of the cause of the impaired appetite regulation and early-onset obesity with subsequently less judgement by others and improved cooperation of their social network and school on maintaining a healthy lifestyle for this girl. A strict eating regimen and lifestyle measures resulted in the first year after diagnosis in a significantly decreased body mass index (BMI), followed by BMI stabilization, still categorized as obesity class three. However, the troublesome challenge of how to manage the disruptive behaviour due to hyperphagia remained. Eventually, due to treatment with targeted pharmacotherapy, i.e., melanocortin-4 receptor agonists, her BMI continued to decrease due to resolving hyperphagia. The daily routine of the family and the atmosphere at home positively changed as they were no longer dominated by the food-focused behaviour of the child and the adherence to the strict eating regimen. This case report demonstrates the importance and impact of a rare genetic obesity disorder diagnosis in a family. Additionally, it highlights the value of genetic testing in patients with a high suspicion of a genetic obesity disorder as it can eventually lead to personalized treatment, such as guidance by specialized healthcare professionals and educated caregivers or targeted pharmacotherapy.

Topics: Body Mass Index; Child; Female; Humans; Hyperphagia; Leptin; Metabolism, Inborn Errors; Obesity; Precision Medicine; Receptor, Melanocortin, Type 4; Receptors, Leptin

Leptin replacement therapy (LRT) has drastically improved the prognosis of patients with lipodystrophy, but pro-inflammatory properties of leptin could become evident in the long term. Here, we report a 30-year-old Japanese woman with generalized lipodystrophy-associated progeroid syndrome due to a heterozygous LMNA variant (c.29C > T; p.T10I), who was diagnosed with severe aortic stenosis (AS) after more than a decade of LRT, which required transcatheter aortic valve implantation. Given her marked hypoadiponectinemia and the LMNA variant, our patient might have been susceptible to progeria-associated disorders, including aortic stenosis, which could have been exaggerated by the prolonged 'imbalanced adipokines' caused by LRT between pro-inflammatory leptin and anti-inflammatory adiponectin. Thus, long-term LRT could be associated with AS in patients with the LMNA variant to cause generalized lipodystrophy-associated progeroid syndrome and hypoadiponectinemia.

Topics: Adiponectin; Adult; Aortic Valve Stenosis; Female; Humans; Lamin Type A; Leptin; Lipodystrophy; Lipodystrophy, Congenital Generalized; Metabolism, Inborn Errors

Hyperleptinemia is supposed to play a causal role in the development of obesity-associated hypertension, possibly via increased sympathetic tone. Hence patients with congenital leptin deficiency should be hypotensive and their low blood pressure should increase under leptin substitution.. To test this assumption, we examined ambulatory blood pressure, resting heart rate, Schellong test results, cold pressor test results, heart rate variability, catecholamine metabolites, and aldosterone levels in 6 patients with congenital leptin deficiency before as well as 2-7 days and 7-14 months after the start of leptin substitution. Ambulatory blood pressure was also examined in 3 patients with biallelic disease-causing variants in the leptin receptor gene.. Contrary to our expectations, even before leptin substitution, 1 patient with biallelic leptin receptor gene variants and 4 patients with leptin deficiency had been suffering from hypertension. Short-term substitution with leptin increased blood pressure further in 3 out of 4 patients (from 127.0 ± 11.7 to 133.8 ± 10.6 mm Hg), concomitant with an increase in resting heart rate as well as in heart rate during the Schellong test in all patients (from 87.6 ± 7.7 to 99.9 ± 11.0 bpm, p = 0.031, and from 102.9 ± 13.5 to 115.6 ± 11.3 bpm, p = 0.031, respectively). Furthermore, the systolic blood pressure response during the cold pressor test increased in 4 out of 6 patients. Unexpectedly, catecholamine metabolites and aldosterone levels did not increase. After long-term leptin substitution and weight loss, the resting heart rate decreased in 4 out of 6 patients compared to baseline, and in all patients below the heart rate seen immediately after the start of therapy (from 99.9 ± 11.0 to 81.7 ± 5.4 bpm; p = 0.031).. These results show that obesity-associated hypertension does not depend on the presence of leptin. However, short-term leptin substitution can increase the blood pressure and heart rate in obese humans with leptin deficiency, indicating that leptin plays at least an additive role in obesity-associated hypertension. The mechanisms behind this are not clear but might include an increase in regional sympathetic tone.

Topics: Adolescent; Adult; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Child; Cohort Studies; Female; Heart Rate; Hormone Replacement Therapy; Humans; Hypertension; Leptin; Male; Metabolism, Inborn Errors; Obesity; Receptors, Leptin; Weight Loss; Young Adult

Factors associated with plasma levels of adiponectin and leptin were studied in adult subjects without diabetes from Cotonou in Benin (West-Africa). Seventy (70) men and 45 women were included in the study. Anthropometric variables were measured and a venous blood sample was drawn from each subject, after an overnight fasting period, for measurement of plasma glucose, insulin, leptin, and adiponectin levels. HOMA-IR was determined to assess insulin resistance. Adiponectin and leptin levels were higher in women than in men (with adiponectin 18.48 ± 12.77 vs.7.8 ± 10.39 μg/mL, P < 0.0001, and leptin 30.77 ± 19.16 vs. 8.66 ± 8.24 ng/mL, P < 0.0001). Fasting insulin level and HOMA-IR were also higher in the females. Hyperleptinemia was observed in 66,96% of subjects and hypoadiponectinemia was present in 44.35% of subjects. In both men and women, leptin correlated with age (r = 0.2; P = 0.02), BMI (r = 0.572; P < 0.0001), waist circumference (r = 0.534; P < 0.0001), fasting insulin (r = 0.461; P < 0.001), and HOMA-IR (r = 0.430; P < 0.0001). No significant correlation was observed for adiponectin levels with these variables. Only in women, adiponectin was inversely correlated with fasting glucose (r = -0.423; P < 0.004). These data confirm previous descriptions of leptin but suggest that variations in factors determining serum adiponectin levels observed between ethnicities could also been seen between populations from the same ethnicity.

Topics: Adiponectin; Adult; Africa, Western; Blood Glucose; Body Mass Index; Fasting; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Metabolism, Inborn Errors; Waist Circumference

Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and cardiovascular diseases. However, consumption of beverages containing fructose is allowed during gestation. Recently, we found that an intake of fructose (10 % wt/vol) throughout gestation produces impaired fetal leptin signaling and hepatic steatosis. Therefore, we have investigated whether fructose intake during pregnancy produces subsequent changes in the progeny, when adult.. Fed 261-day-old male and female descendants from fructose-fed, control or glucose-fed mothers were used. Plasma was used to analyze glucose, insulin, leptin, and adiponectin. Hepatic expression of proteins related to insulin signaling was determined.. Fructose intake throughout pregnancy did not produce alterations in the body weight of the progeny. Adult male progeny of fructose-fed mothers had elevated levels of insulin without a parallel increase in phosphorylation of protein kinase B. However, they displayed an augmented serine phosphorylation of insulin receptor substrate-2, indicating reduced insulin signal transduction. In agreement, adiponectin levels, which have been positively related to insulin sensitivity, were lower in male descendants from fructose-fed mothers than in the other two groups. Furthermore, mRNA levels for insulin-responsive genes were not affected (phosphoenolpyruvate carboxykinase, glucose-6-phosphatase) or they were decreased (sterol response element-binding protein-1c) in the livers of male progeny from fructose-supplemented rats. On the contrary, adult female rats from fructose-fed mothers did not exhibit any of these disturbances.. Maternal fructose, but not glucose, intake confined to the prenatal stage provokes impaired insulin signal transduction, hyperinsulinemia, and hypoadiponectinemia in adult male, but not female, progeny.

Topics: Adiponectin; Animals; Animals, Newborn; Blood Glucose; Body Weight; Fatty Liver; Female; Fetus; Fructose; Glucose-6-Phosphatase; Hyperinsulinism; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Liver; Male; Maternal Nutritional Physiological Phenomena; Metabolism, Inborn Errors; Phosphoenolpyruvate Carboxykinase (ATP); Phosphorylation; Pregnancy; Prenatal Exposure Delayed Effects; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Sterol Regulatory Element Binding Protein 1

Gestational exposures such as dietary changes can alter offspring phenotype through epigenetic modifications and promote increased risk for specific diseases, such as metabolic syndrome. We hypothesized that high-fat diet (HFD) during late gestation would lead increased risk for insulin resistance and hyperlipidemia via associated epigenetic alterations in tissue adipocytokine genes.. Offspring mice of mothers fed a HFD during late gestation (HFDO) were weighed and their food intake measured weekly till age 20 weeks at which time glucose and insulin tolerance tests, plasma lipid and adipocytokine levels were assessed, as well as mRNA expression in visceral fat. Adipocytokine gene methylation levels in visceral fat, liver and muscle were also assayed.. HFDO mice had increased weight accrual and food intake, and exhibited insulin resistance, hyperlipidemia and hyperleptinemia, as well as hypoadiponectinemia. Furthermore, increased methylation of adiponectin and leptin receptor, and decreased methylation of leptin genes with unchanged glucagon-like peptide-1 methylation patterns emerged in HFDO mice.. Taken together, late gestational HFD induces increased risk of metabolic syndrome in the progeny, which is coupled with hypoadiponectinemia as well as with leptin resistance, and concomitant presence of selective tissue-based epigenetic changes among adipocytokine genes.

Topics: Acetylation; Adiponectin; Animals; Animals, Newborn; Body Weight; Diet, High-Fat; Epigenesis, Genetic; Female; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Liver; Male; Metabolic Syndrome; Metabolism, Inborn Errors; Mice; Mice, Inbred C57BL; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Time Factors

A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined.. We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives.. Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency.. The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.

Topics: Adult; Age of Onset; Basal Metabolism; Body Composition; Child; Diagnosis, Differential; Female; Genotype; Humans; Hyperphagia; Hypogonadism; Immunologic Deficiency Syndromes; Leptin; Lymphocyte Count; Male; Metabolism, Inborn Errors; Mutation; Obesity; Pedigree; Phenotype; Receptors, Cell Surface; Receptors, Leptin

The current biochemical definition of severe GH deficiency (stimulated peak GH < 3 micro g/liter) provides good separation of GH-deficient (GHD) adults from normal subjects, although it may not account for all patients with impaired GH secretion. The vast majority of normal subjects display a peak GH level in excess of 7 micro g/liter in response to the insulin tolerance test. Using a peak GH response of 7 micro g/liter as an arbitrary upper limit, we investigated the effects of partial GH deficiency (GH insufficiency, GHI; peak GH response of 3-7 micro g/liter) on the body composition of hypopituitary adults. GHD adults (n = 30, peak GH < 3 micro g/liter) were of shorter stature than the controls. Body mass index was not significantly increased, but waist/hip ratio (0.885 vs. 0.818, P = 0.001) and skinfold thickness (78.2 vs. 59.6 mm, P = 0.003) were greater than control subjects. Bioimpedance analysis revealed these patients to have reduced lean body mass (LBM) (44.4 vs. 51.2 kg, P = 0.023) and increased fat mass (FM) (25.7 vs. 18.4 kg, P = 0.039). Dual-energy x-ray absorptiometry (DXA) analysis of body composition confirmed reduced LBM (43.6 vs. 50.6 kg, P = 0.010) and increased FM (26.0 vs. 19.2 kg, P = 0.015). The excess FM was observed to be primarily truncal in distribution. Similarly, GHI adults were of shorter stature but with increased waist/hip ratio (0.871 vs. 0.818, P = 0.006) and skinfold thickness (80.8 vs. 59.6 mm, P = 0.003), compared with controls. Bioimpedance analysis revealed a reduction in LBM (44.9 vs. 51.2 kg, P = 0.020). DXA studies confirmed the reduced LBM (45.0 vs. 50.6 kg, P = 0.041) and additionally noted an increase in percent FM (32.9 vs. 27.4%, P = 0.019). All measures of body composition in the GHI patients were intermediate between those of the controls and GHD patients. Serum leptin levels were significantly elevated in both the GHD (41.5 vs. 20.7 ng/ml, P = 0.009) and GHI (36.7 vs. 20.7 ng/ml, P = 0.022) adults, compared with healthy controls. The excess FM observed using DXA in the GHD and GHI adults equated to 6.5 kg (8%) and 3.5 kg (5.5%), respectively, relative to healthy controls. In summary, we have shown that adults with GHI have abnormalities of body composition characteristic of GHD. The degree of abnormality of body composition lies between that of healthy subjects and GHD adults and correlates with the IGF-I level. Any future trials of GH replacement in patients with GHI must await further studies to establi

Topics: Absorptiometry, Photon; Adult; Anthropometry; Body Composition; Cohort Studies; Electric Impedance; Human Growth Hormone; Humans; Hypopituitarism; Insulin-Like Growth Factor I; Leptin; Metabolism, Inborn Errors; Skinfold Thickness

GH secretion is regulated by hypothalamic and peripheral hormones under a very complex interplay. Superimposed on this regulation, signals of a metabolic nature connect GH secretion with the metabolic and energetic homeostasis of a given individual. GH secretion is enhanced in malnutrition and is severely impeded in obesity, but no information is available to explain why GH secretion is severely impeded or blocked in excess adiposity. Obesity is associated with high plasma levels of leptin, and leptin participates at the hypothalamic and pituitary levels in the regulation of GH secretion. Thus, it has been postulated that the inhibitory action of obesity on GH discharge may be mediated by excess leptin levels. The only situation in which obesity does not parallel leptin values is the rare case of morbid obesity due to leptin deficiency caused by missense mutation of the leptin gene. To understand the causes of GH blockade presented in obesity, patients with both homozygous and heterozygous mutations of the leptin gene and matched controls for both sex and body mass index (BMI) were studied. Three homozygous and 5 heterozygous patients with leptin gene mutations as well as 13 control subjects were studied. In all subjects basal levels of leptin and GH values stimulated by the combined administration of GHRH plus GH-releasing peptide-6 (GHRP-6) were analyzed. To analyze the effects of obesity and leptin levels, 5 groups were designed, all them matched by sex and adiposity. The number of subjects (n), leptin levels in micrograms per liter, and adiposity in BMI were as follows: nonobese subjects: n = 5, BMI = 22.1 +/- 0.9 kg/m2, leptin = 5.4 +/- 0.9; heterozygous patients: n = 5, BMI = 27.0 +/- 1.0 kg/m2, leptin = 2.3 +/- 0.1; controls for the heterozygous group: n = 5, BMI = 24.7 +/- 1.1 kg/m2, leptin = 5.7 +/- 1.2; homozygous patients: n = 3, BMI = 54.4 +/- 0.2 kg/m2, leptin = 1.0 +/- 0.2; and controls for the homozygous group: n = 3, BMI = 50.3 +/- 2.0 kg/m2, leptin = 35.0 +/- 6.6. In these matched groups, the GHRH- and GHRP-6-stimulated GH secretion (mean peak +/- SE; micrograms per liter) was: nonobese, 86.8 +/- 8.9 [significantly higher than heterozygous (28.6 +/- 4.9) and control for heterozygous (39.9 +/- 10.4)]; homozygous group, 9.4 +/- 3.0; control for homozygous, 9.3 +/- 1.0 (significantly lower than the heterozygous, control for heterozygous, and nonobese groups). Hence, it appeared that GH discharge was negatively conditioned by adiposity and wa

Topics: Adult; Body Mass Index; Female; Growth Hormone-Releasing Hormone; Hormones; Human Growth Hormone; Humans; Leptin; Male; Metabolism, Inborn Errors; Mutation; Obesity; Oligopeptides

The aim of this study was to evaluate the relationship between GH and leptin in a group of short children and adolescents. Leptin and GH serum levels were measured before and during pharmacological stimulation tests (arginine and insulin) in a group of 45 children (30 male, 15 female), mean age 8.6+/-3.9 yr, affected by idiopathic isolated GH deficiency (GHD), and in a group of 27 children (15 male, 12 female), age 10.9+/-3.3 yr, with constitutional growth delay. Results showed that basal and peak leptin levels as well as the AUC were significantly higher in GHD patients compared to controls (p<0.05) and correlated with BMI SDS (p<0.0001) in GHD patients. No change in leptin serum levels was observed during either stimulation test. No correlation was found, however, between basal leptin serum levels and basal, peak and the AUC of GH during the tests. Moreover, no correlation was found between the acute changes of serum GH concentration during both stimulation tests and leptin serum levels. The results suggest that leptin and GH secretion is not correlated and that leptin serum levels mainly reflect the amount of fat tissue, which is higher in GHD patients.

Topics: Arginine; Body Mass Index; Child; Control Groups; Female; Human Growth Hormone; Humans; Infusions, Intravenous; Insulin; Leptin; Male; Metabolism, Inborn Errors; Time Factors

Topics: Basal Metabolism; Child; Energy Intake; Energy Metabolism; Female; Follicle Stimulating Hormone; Humans; Hyperphagia; Leptin; Luteinizing Hormone; Metabolism, Inborn Errors; Obesity; Proteins; Recombinant Proteins; Weight Loss

Topics: Adipose Tissue; Energy Metabolism; Humans; Leptin; Metabolism, Inborn Errors; Obesity; Proteins

The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure. We know of no equivalent evidence regarding leptin's role in the control of fat mass in humans. We have examined two severely obese children who are members of the same highly consanguineous pedigree. Their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found. The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans.

Topics: Adult; Age of Onset; Animals; Body Composition; Child; Child, Preschool; CHO Cells; Consanguinity; Cricetinae; Female; Frameshift Mutation; Homozygote; Humans; Leptin; Male; Metabolism, Inborn Errors; Mice; Mice, Obese; Molecular Sequence Data; Obesity; Pedigree; Polymorphism, Single-Stranded Conformational; Proteins; Sequence Analysis, DNA; Transfection