Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0028754 (obesity)
124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has recently been demonstrated that > or = one-third of men with type 2 diabetes mellitus have low testosterone concentrations associated with inappropriately low luteinizing hormone and follicle-stimulating hormone concentrations. Hypogonadotropic hypogonadism in men with type 2 diabetes is associated with obesity but not duration of diabetes, elevated glycosylated hemoglobin, or the presence of microvascular complications of diabetes. Recent data show that hypogonadotropic hypogonadism is also observed frequently in nondiabetics with the metabolic syndrome or obesity, but it is not associated with type 1 diabetes. Low testosterone concentrations in men with type 2 diabetes have also been related to a higher C-reactive protein concentrations, lower hematocrit, increased total and regional adiposity, lower bone mineral density, and erectile dysfunction. This article discusses the pathophysiology of hypogonadotropic hypogonadism in men with type 2 diabetes and its signs and symptoms. Clinical trials are required to determine whether testosterone replacement therapy alleviates insulin resistance, inflammation, and symptoms related to sexual dysfunction care.
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PMID:Hypogonadotropic hypogonadism in men with type 2 diabetes. 1949 39

Genetic studies in patients with severe early-onset obesity have provided insights into the molecular and physiological pathways that regulate body weight in humans. We report a 19-year-old male with hyperphagia and severe obesity, mild learning difficulties and hypogonadism, in whom diagnostic tests for Prader-Willi syndrome (PWS) had been negative. We carried out detailed clinical and metabolic phenotyping of this patient and investigated the genetic basis of this obesity syndrome using Agilent 185 k array comparative genomic hybridization (aCGH) and Affymetrix 6.0 genotyping arrays. The identified deletion was validated using multiplex ligation-dependent probe amplification and long-range PCR, followed by breakpoint sequencing which enabled precise localization of the deletion. We identified a approximately 187 kb microdeletion at chromosome 15q11-13 that encompasses non-coding small nucleolar RNAs (including HBII-85 snoRNAs) which were not expressed in peripheral lymphocytes from the patient. Characterization of the clinical phenotype revealed increased ad libitum food intake, normal basal metabolic rate when adjusted for fat-free mass, partial hypogonadotropic hypogonadism and growth failure. We have identified a novel deletion on chromosome 15q11-13 in an individual with hyperphagia, obesity, hypogonadism and other features associated with PWS, which is normally caused by deficiency of several paternally expressed imprinted transcripts within chromosome 15q11-13, a region that includes multiple protein-coding genes as well as several non-coding snoRNAs. These findings provide direct evidence for the role of a particular family of non-coding RNAs, the HBII-85 snoRNA cluster, in human energy homeostasis, growth and reproduction.
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PMID:A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism. 1949 35

Prader-Willi syndrome is an uncommon multisystem genetic disorder caused by defects of chromosome 15 (15qll-ql3), often due to deletions or uniparental disomy The syndrome is characterized by neonatal hypotonia, dysmorphic facial features, short stature, motor and mental disabilities, behavioral changes, hyperphagia, precocious obesity and hypogonadotropic hypogonadism. We present a 17 year-old woman, with a previous genetic diagnosis of Prader-Willi syndrome and BMI of 74 Kg/m(2), that was admitted in anasarca, with marked cyanosis, dyspnea and oliguria. She presented high levels of blood urea, creatinine and aminotransferases, in addition to hyperkalemia and hyperuricemia. She had been in regular use of fluoxetine during the last six months, and evolved with severe high blood pressure and respiratory failure, which needed intensive care support. Moreover, sequels and clear signs of recent self-injuries were observed in her trunk, forearms and hands. The findings of morbid obesity, anasarca, self-injury, hyperuricemia and hypoxemia in Prader-Willi syndrome are emphasized.
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PMID:Morbid obesity in an adolescent with Prader-Willi syndrome. 1954 50

Previous evidence suggests that the testicular negative feedback control of gonadotropin-releasing hormone-luteinizing hormone (LH) secretion may change as men age, and may thereby contribute to the hypogonadism that occurs as men grow older. To pursue this idea, we analyzed the results for 35 men with primary hypogonadism who were participants in an open-label multicenter study of testosterone replacement. LH, sex hormone-binding globulin (SHBG), and total and free testosterone and estradiol concentrations were measured in blood samples at baseline and after 2% testosterone gel was applied daily for 2 weeks. A 24-hour pharmacokinetic profile for testosterone and estradiol was obtained at the end of week 2. Age was a strong predictor of LH suppression during testosterone replacement (r = -0.46), and the effect could not be explained by obesity, SHBG, or higher levels of total or non-SHBG testosterone or estradiol during treatment. In fact, both LH and non-SHBG testosterone levels were lower (P < .05) in older men receiving testosterone treatment. In addition, the strongest association overall was between the percentage decline in LH and non-SHBG estradiol concentrations (r = -0.39). These data provide further evidence that suppression of LH secretion during testosterone treatment is greater as men age, and are consistent with the hypothesis that the hypogonadism of aging men is partly due to a change in gonadotropin negative feedback regulation. These results further suggest that estrogen receptor signaling might contribute to this effect.
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PMID:LH and non-SHBG testosterone and estradiol levels during testosterone replacement of hypogonadal men: further evidence that steroid negative feedback increases as men grow older. 1995 27

Obesity causes complex metabolic and endocrine changes that may lead to adverse outcomes, including hypogonadism. We herein studied the reproductive axis function in male rats under a high-fat diet and analyzed the impact of changes in glycosylation of pituitary LH on the bioactivity of this gonadotropin. Rats were fed with a diet enriched in saturated fat (20% of total calories) and euthanized on days 90 or 180 of diet. Long-term (180 days), high-fat feeding rats exhibited a metabolic profile compatible with insulin resistance and metabolic syndrome; they concomitantly showed decreased intrapituitary and serum LH concentrations, low serum testosterone levels, and elevated serum 17beta-estradiol concentrations. A fall in biological to immunological ratio of intrapituitary LH was detected in 180 days control diet-treated rats but not in high-fat-fed animals, as assessed by a homologous in vitro bioassay. Chromatofocusing of pituitary extracts yielded multiple LH charge isoforms; a trend towards decreased abundance of more basic isoforms (pH 9.99-9.0) was apparent in rats fed with the control diet for 180 days but not in those that were fed the diet enriched in saturated fat. It is concluded that long-term high-fat feeding alters the function of the pituitary-testicular axis, resulting in hypogonadotropic hypogonadism. The alterations in LH function found in these animals might be subserved by changes in hypothalamic GnRH output and/or sustained gonadotrope exposure to an altered sex steroid hormone milieu, representing a distinctly different regulatory mechanism whereby the pituitary attempts to counterbalance the effects of long-term obesity on reproductive function.
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PMID:Reproductive axis function and gonadotropin microheterogeneity in a male rat model of diet-induced obesity. 2000 31

Obstructive sleep apnea syndrome (OSAS) is a serious, prevalent condition that has significant morbidity and mortality when untreated. It is strongly associated with obesity and is characterized by changes in the serum levels or secretory patterns of several hormones. Obese patients with OSAS show a reduction of both spontaneous and stimulated growth hormone (GH) secretion coupled to reduced insulin-like growth factor-I (IGF-I) concentrations and impaired peripheral sensitivity to GH. Hypoxemia and chronic sleep fragmentation could affect the sleep-entrained prolactin (PRL) rhythm. A disrupted Hypothalamus-Pituitary-Adrenal (HPA) axis activity has been described in OSAS. Some derangement in Thyroid-Stimulating Hormone (TSH) secretion has been demonstrated by some authors, whereas a normal thyroid activity has been described by others. Changes of gonadal axis are common in patients with OSAS, who frequently show a hypogonadotropic hypogonadism. Altogether, hormonal abnormalities may be considered as adaptive changes which indicate how a local upper airway dysfunction induces systemic consequences. The understanding of the complex interactions between hormones and OSAS may allow a multi-disciplinary approach to obese patients with this disturbance and lead to an effective management that improves quality of life and prevents associated morbidity or death.
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PMID:Neuroendocrine alterations in obese patients with sleep apnea syndrome. 2018 53

Mutations in the prokineticin 2 peptide (PROK2) and its seven-transmembrane domain type 2 receptor PROKR2 are newly identified molecular culprits in autosomal Kallmann syndrome (KS). Prok2 and prokr2 gene knockout mice both have agenesis or hypoplasia of the olfactory bulbs, associated with hypogonadotropic hypogonadism linked to abnormal GnRH neuron migration. Prok2-/- and prokr2-/- mice are the first murine models of this human disease. KS patients of both sexes have a variety of point mutations, missense mutations, frameshifts and nonsense mutations in the PROK2 and PROKR2 genes that lead to a loss of peptide or receptor function. When only one allele is affected, penetrance of the two main clinical features of KS may be incomplete: subjects with only one mutant allele may have (1) no symptoms, with normal olfaction and complete pubertal development, (2) congenital isolated (idiopathic) hypogonadotropic hypogonadism (IHH) but normal olfaction, (3) anosmia/hyposmia but normal pubertal development and gonadal function or (4) the two cardinal clinical KS signs, anosmia and IHH. These phenotypic dissociations can be seen in family members with the same PROK2/PROKR2 mutations. By contrast, patients with two mutant alleles almost always have the cardinal signs of KS. Even when monoallelic PROK2/PROKR2 mutations are associated with full-blown KS, the reproductive phenotype in males is less severe than in KS associated with biallelic mutations, evidenced by significantly lower frequency of cryptorchidism and micropenis, greater testicular volume, and higher serum levels of LH, FSH and testosterone. Moreover, at least some of these monoallelic cases are in fact digenic, in that they also carry mutations of other KS/IHH genes. Overall, these observations point towards a combination of mendelian autosomal recessive transmission, with more complex oligogenic transmission. Patients with this genetic form of KS have been reported to have a possible increased prevalence of obesity and sleep disorders, which may be related to the role of PROK2 and PROKR2 in food intake and circadian rhythms. However, diurnal variation of serum cortisol levels appears to be physiologically maintained.
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PMID:Kallmann syndrome caused by mutations in the PROK2 and PROKR2 genes: pathophysiology and genotype-phenotype correlations. 2038 90

Hypogonadism occurs commonly in men with type 2 diabetes (T2DM) and severe obesity. Current evidence points to a decreased secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus and thereby decreased secretion of gonadotropins from the pituitary gland as a central feature of the pathophysiology in these men. Hyperglycaemia, inflammation, leptin and oestrogen-related feedback have been proposed to make aetiological contributions to the hypogonadotropic hypogonadism of T2DM. However, the neuroendocrine signals that link these factors with modulation of GnRH neurons have yet to be identified. Kisspeptins play a central role in the modulation of GnRH secretion and, thus, downstream regulation of gonadotropins and testosterone secretion in men. Inactivating mutations of the kisspeptin receptor have been shown to cause hypogonadotropic hypogonadism in man, whilst an activating mutation is associated with precocious puberty. Data from studies in experimental animals link kisspeptin expression with individual factors known to regulate GnRH secretion, including hyperglycaemia, inflammation, leptin and oestrogen. We therefore hypothesise that decreased endogenous kisspeptin secretion is the common central pathway that links metabolic and endocrine factors in the pathology of testosterone deficiency seen in men with obesity and T2DM. We propose that the kisspeptin system plays a central role in integrating a range of metabolic inputs, thus constituting the link between energy status with the hypothalamic-pituitary-gonadal axis, and put forward potential clinical studies to test the hypothesis.
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PMID:Hypothesis: kisspeptin mediates male hypogonadism in obesity and type 2 diabetes. 2062 62

Congenital deficiency of the leptin receptor is a very rare cause of severe early-onset obesity. To date, only 9 families have been reported in the literature to have mutations in the leptin receptor gene. The clinical features include severe early onset obesity, severe hyperphagia, hypogonadotropic hypogonadism, and T cell and neuroendocrine/metabolic dysfunction. Here we report two cousins with severe early onset obesity and recurrent respiratory tract infections. Their serum leptin levels were elevated but they were within the range predicted by the elevated fat mass in both cousins. Direct sequencing of the entire coding sequence of the leptin receptor gene revealed a novel homozygous missense mutation in exon 6, P316T. The mutation was found in the homozygous form in both cousins and in the heterozygote state in their parents. This mutation was not found in 200 chromosomes from 100 unrelated normal weight control subjects of Egyptian origin using PCR-RFLP analysis. In conclusion, finding this new mutation in the LEPR beside our previous mutation in the LEP gene implies that monogenic obesity syndromes may be common in the Egyptian population owing to the high rates of consanguineous marriages. Further screening of more families for mutations in LEP, LEPR, and MC4 might confirm this assumption.
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PMID:Homozygosity for a novel missense mutation in the leptin receptor gene (P316T) in two Egyptian cousins with severe early onset obesity. 2130 29

Male breast cancer (MBC) is rare, with the peak age of onset at 71 years. BRCA2 mutations are more frequent than BRCA1 with 20% of cases giving a family history. Risk factors for MBC are poorly understood and include working in high-ambient temperatures and exhaust fume exposure. MBC is associated with hyperoestrogenic states found in liver disease, Klinefelter's syndrome, gonadal dysfunction or obesity. Most information on treatment of MBC is derived from large randomized trials carried out in female patients. The small numbers of MBC seen in any unit annually has precluded significant trials being carried out.Diagnosis and treatment of MBC is similar to that of female patients, but men tend to be treated with mastectomy rather than breast-conserving surgery. The mainstay of adjuvant therapy or palliative treatment for advanced disease is endocrine, mostly tamoxifen. Prognosis of male patients is equal to that of stage-matched women, but men tend to fare worse because of delay in presentation, leading to a large proportion of patients presenting with stage III or IV disease. Increased input is needed for psychological support for male breast cancer patients. Specific therapeutic questions about MBC need international trials to obtain meaningful answers.
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PMID:Male breast cancer: a review. 2227 5


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