Event-related brain potentials in male hypogonadism

Özata, Metịn; Odabaşı, Zeki; Çağlayan, Suat; Beyhan, Zeynel; Vural, Okay; Ozdemir, Caglayan

doi:10.1007/bf03343601

Cited by 17 publications

(14 citation statements)

References 19 publications

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“…Similar results have been found in obese children with leptin gene mutations who have normal BP despite early-onset morbid obesity and many other features of the metabolic syndrome, including insulin resistance and dyslipidemia (19). These children had decreased rather than increased SNS activity as well as postural hypotension and attenuated RAAS responses to upright posture (19).…”

Section: Insulin Resistancesupporting

confidence: 70%

Obesity-induced Hypertension: Role of Sympathetic Nervous System, Leptin, and Melanocortins

Hall

Silva

Carmo

et al. 2010

Journal of Biological Chemistry

438

400

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Excess weight gain contributes to increased blood pressure in most patients with essential hypertension. Although the mechanisms of obesity hypertension are not fully understood, increased renal sodium reabsorption and impaired pressure natriuresis play key roles. Several mechanisms contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system, which appears to be mediated in part by increased levels of the adipocyte-derived hormone leptin, stimulation of pro-opiomelanocortin neurons, and subsequent activation of central nervous system melanocortin 4 receptors.The worldwide prevalence of obesity and associated cardiometabolic diseases have increased dramatically in the past 2-3 decades, rapidly becoming major challenges to the health care systems of most industrialized countries. Current estimates indicate that Ͼ1 billion people in the world are overweight or obese (1). In the United States, at least 65% of adults are overweight, and approximately one-third of adults are obese with a body mass index (defined as kilograms of weight/m 2 of height) of Ͼ30 (2). In children, the prevalence of obesity has also risen rapidly in parallel with increasing obesity in adults; a recent report indicates that 18.4% of 4-year-old children in the United States are obese, with significantly higher rates of obesity in Hispanic, black, and Native American children (3).Associated with obesity is a cascade of metabolic and cardiovascular disorders, including hypertension, a primary mediator of obesity-induced cardiovascular disease. Population studies show that excess weight gain predicts future development of hypertension, and the relationship between body mass index and blood pressure (BP) 2 appears to be nearly linear in diverse populations throughout the world (4). Some studies suggest that excess weight gain may account for 65-75% of human essential hypertension (5). Moreover, clinical studies indicate that weight loss is effective in primary prevention of hypertension and in reducing BP in most hypertensive subjects (6).Although the importance of obesity as a major cause of essential hypertension is well established, the physiological and molecular mechanisms that mediate the BP effects of excess weight gain are only beginning to be elucidated. Excess Weight Gain Increases Renal SodiumReabsorption and Impairs Pressure Natriuresis Table 1 summarizes some of the changes in cardiovascular, neurohormonal, and renal function that occur in obese humans and experimental animals (4,7,8). Notable changes, in addition to increased BP, include increases in cardiac output and heart rate as well as activation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS). Rapid weight gain also stimulates renal tubular sodium reabsorption, and obese subjects require higher than normal BP to maintain balance between intake and renal excretion of sodium, indicating impaired renal pressure natriuresis (4).Three factors are especially important in increasing re...

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Section: Insulin Resistancesupporting

confidence: 70%

Obesity-induced Hypertension: Role of Sympathetic Nervous System, Leptin, and Melanocortins

Hall

Silva

Carmo

et al. 2010

Journal of Biological Chemistry

438

400

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“…At baseline, before leptin replacement, patient A had clinical features of hypogonadism, as previously reported (10). His baseline measurements of testosterone and free testosterone were below the normal range for his age (10).…”

Section: Resultsmentioning

confidence: 51%

“…We have previously demonstrated that genetically based leptin deficiency due to a nonconservative missense leptin gene mutation (Cys-to-Thr in codon 105) in a highly consanguineous extended Turkish pedigree is associated with morbid obesity and hypogonadism (7,10). We prospectively studied the effects of leptin replacement therapy with recombinant methionyl human leptin (r-metHuLeptin) in three adult homozygous patients from this family who are the only three adult leptin-naive individuals identified in the world so far.…”

mentioning

confidence: 99%

Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults

Licinio

Çağlayan

Özata

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

450

372

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Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01-0.04 mg͞kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 ؎ 2.5 (mean ؎ SEM) at baseline to 26.9 ؎ 2.1 kg͞m 2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.T he increasing rates of obesity and consequent morbidity represent a major epidemic worldwide and threaten to bankrupt health care systems (1-3). While prevention is of great importance, it is medically relevant to identify biological pathways with the potential to treat obesity and related disorders, particularly in adults with fully established obesity and comorbid conditions, such as type 2 diabetes mellitus. Leptin, the product of the ob gene, plays a central role in the regulation of food intake and energy expenditure (4). Mutations in the leptin pathway can be a cause of human obesity (5-7). In children with complete leptin deficiency and who are still in the process of gaining weight and developing obesity, leptin replacement therapy can lead to substantial weight reduction (8,9).It is still unknown whether the leptin pathway is relevant to the treatment of established morbid obesity and its endocrine and metabolic consequences in adults. We addressed this question by treating three homozygous leptin-deficient adults with morbid obesity. Morbid obesity had been fully established for two to four decades in those patients, and they had been at a stable (but very high) weight for Ͼ10 years. They were hypogonadal, and one of them had type 2 diabetes mellitus. We report here the results of the first 18 months of replacement therapy with recombinant human leptin, showing that leptin is highly effective in dramatically reducing...

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“…Congenital complete leptin deficiency (3)(4)(5) or acute hypoleptinemia to Ͻ1 ng͞ml in leptinreplete humans induces changes in reproductive, thyroid, and IGF axes (10) and immune function (12), whereas increasing serum P value for nonparametric ANOVA across the three conditions. * , P Ͻ 0.05 by one-way ANOVA; †, P Ͻ 0.05 for fed vs. fasting ϩ placebo; ‡, P Ͻ 0.05 for fed vs. fasting ϩ r-metHuLeptin.…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans

Chan

Matarese

Shetty

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

192

158

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To elucidate whether the role of leptin in regulating neuroendocrine and immune function during short-term starvation in healthy humans is permissive, i.e., occurs only when circulating leptin levels are below a critical threshold level, we studied seven normal-weight women during a normoleptinemic-fed state and two states of relative hypoleptinemia induced by 72-h fasting during which we administered either placebo or recombinant methionyl human leptin (r-metHuLeptin) in replacement doses. Fasting for 72 h decreased leptin levels by Ϸ80% from a midphysiologic (14.7 ؎ 2.6 ng͞ml) to a low-physiologic (2.8 ؎ 0.3 ng͞ml) level. Administration of r-metHuLeptin during fasting fully restored leptin to physiologic levels (28.8 ؎ 2.0 ng͞ml) and reversed the fasting-associated decrease in overnight luteinizing hormone pulse frequency but had no effect on fasting-induced changes in thyroid-stimulating hormone pulsatility, thyroid and IGF-1 hormone levels, hypothalamic-pituitary-adrenal and renin-aldosterone activity. FSH and sex steroid levels were not altered. Shortterm reduction of leptin levels decreased the number of circulating cells of the adaptive immune response, but r-metHuLeptin did not have major effects on their number or in vitro function. Thus, changes of leptin levels within the physiologic range have no major physiologic effects in leptin-replete humans. Studies involving more severe and͞or chronic leptin deficiency are needed to precisely define the lower limit of normal leptin levels for each of leptin's physiologic targets.fasting ͉ reproductive D eficiency of the adipocyte-secreted hormone leptin (1) is associated with distinct abnormalities in energy-demanding processes such as neuroendocrine and immune function. Leptindeficient ob͞ob mice and humans with congenital complete leptin deficiency have abnormal neuroendocrine function, including hypogonadotropic hypogonadism, hypothalamic hypothyroidism, and͞or growth-hormone-axis abnormalities (2-6) and impaired cell-mediated immunity (4, 7), which are improved with leptin replacement (4,8). Similarly, starvation-induced decline of circulating leptin to very low levels in normal mice (9) and lean men (10) causes comparable neuroendocrine (9, 10) and immune defects (11, 12) that are significantly blunted or reversed with exogenous leptin.We have shown that an 80% decline of leptin levels from Ϸ2 to 0.3 ng͞ml in men mediates the fasting-induced suppression of gonadotropin and thyroid-stimulating hormone (TSH) pulsatility as well as sex steroid, insulin-like growth factor-1 (IGF-1), and thyroid hormone levels (10). Importantly, although observational studies have proposed that leptin regulates the hypothalamic-pituitarygonadal axis only when serum leptin levels fall below a ''threshold'' of Ϸ2 ng͞ml (13), the role of decreasing leptin levels to approximately, but not below, this threshold in leptin-replete humans with higher baseline leptin levels (e.g., normal-weight women) has not yet been directly studied.To elucidate whether such a threshold exists, below...

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Event-related brain potentials in male hypogonadism

Cited by 17 publications

References 19 publications

Obesity-induced Hypertension: Role of Sympathetic Nervous System, Leptin, and Melanocortins

Obesity-induced Hypertension: Role of Sympathetic Nervous System, Leptin, and Melanocortins

Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults

Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans

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