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)

A 70-year-old woman was referred to our hospital for diagnosis and treatment of a pulmonary mass detected on a chest X-ray film. Small cell lung cancer was diagnosed from pathological examination of a specimen of the tumor obtained by transbronchial biopsy. Paraneoplastic Cushing's syndrome was diagnosed on the basis of an elevated serum ACTH level (2000 pg/ml), the serum cortisol level (171.9 micrograms/dl), elevated excretion of urinary 17-OHCS (67 mg/day), persistent hypokalemia, metabolic alkalosis, hyperglycemia, central obesity, hypertension, systemic pigmentation, and the lack of a history of diabetes mellitus. Immunohistochemical staining with a polyclonal anti-ACTH antibody of a biopsy specimen from a lymph node with metastasis showed that tumor cells were weakly positive. The patient responded well to intensive chemotherapy with VP-16 (100 mg/m2 day 103), CBDCA (100 mg/m2 day 1-3), and CDDP (80 mg/m2 day 1). Complete response was obtained after 6 courses of chemotherapy. The serum ACTH level decreased rapidly as the tumor shrank. The primary tumor, however, relapsed after 3 months and the patient died of progressive disease, 11 months after diagnosis.
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PMID:[Small cell lung cancer associated with ectopic ACTH syndrome]. 862 81

Certain differences in regional fat distribution might be explicable by subtle hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. We examined prospectively PA function relative to abdominal obesity defined by waist-to-hip circumference ratio (WHR) in 71 normotensive men aged 30-55 years. Basal PA activity was assessed by measurements of serum cortisol and plasma corticotropin (ACTH) concentrations during the oral glucose tolerance test (OGTT). Functional activity was examined by dexamethasone suppression and ACTH stimulation tests; responses of 17-hydroxyprogesterone (17-OHP), 11-deoxycortisol (S), cortisol, dehydroepiandrosterone (DHEA), and androstenedione were determined. When the subjects were divided into tertiles for the WHR, the ratio of mean ACTH to mean cortisol during the OGTT was increased (p < 0.05), and the ratio of urinary cortisol to body-mass index was decreased (p < 0.01), whilst the net increments of cortisol (p < 0.05) and 17-OHP (p < 0.05) from 0 to 60 min, as well as the ratio of 17-OHP to S increments (p < 0.05) after ACTH were elevated in the highest vs lowest WHR tertile. The ratio of mean ACTH to mean cortisol (r = 0.495; p < 0.001) during the OGTT, the ratio of net 17-OHP to S increments (r = 0.404; p < 0.001), and the net DHEA (r = 0.276; p = 0.020) and 17-OHP (r = 0.336; p = 0.005) responses to ACTH at 60 min correlated with WHR. In multivariate analyses the ratio of mean ACTH to cortisol, cortisol response to ACTH, and the ratio of net 17-OHP to S increments were all significant predictors of WHR independent of smoking, physical activity, and BMI explaining 49.0% of the variance in WHR. Thus, abdominal obesity may be associated with decreased activity of adrenal 21-hydroxylase. Either obesity-related functional alteration of 21-hydroxylase activity or the high carrier prevalence of genetic defects of this enzyme may explain these findings.
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PMID:Pituitary-adrenocortical function in abdominal obesity of males: evidence for decreased 21-hydroxylase activity. 880 94

Expression of CRF messenger RNA (mRNA) and heteronuclear RNA (hnRNA) as well as the mRNAs encoding the CRF receptors of type 1 (CRF1R) and type 2 alpha (CFR2R) in the brain has been investigated in lean (Fa/?) and obese (fa/fa) Zucker rats. Exonic and intronic in situ hybridization histochemistry was employed to measure the mRNA and hnRNA levels in rats killed before (resting state), during, and 120 min after a treadmill running session. The resting expression of CRF hnRNA in the hypothalamic paraventricular nucleus (PVN) of obese rats was minimal and comparable to that of lean rats. However, during treadmill running, this expression was higher in obese than in lean rats. In obese rats, the transcription of the CRF1R mRNA in the PVN was high under resting conditions, dropped considerably during running, and rose again to elevated levels 120 min after the treadmill session. In lean rats, CRF1R mRNA in the PVN was minimal before and during running, but rose to a value similar to that in obese rats 120 min after running. In the PVN of obese rats, expression of the CRF1R gene measured during resting conditions was comparable to the level seen after running and proved to be dependent upon the feeding state of the rats. Expression of the CRF2R transcript was reduced in the ventromedial nucleus of the hypothalamus (VMH) of the obese rat. Plasma ACTH concentrations during treadmill running were lower in obese than in lean animals. Basal and postrunning levels of circulating corticosterone were higher in fa/fa than in Fa/? rats. However, there was no difference in corticosterone levels between lean and obese animals during running. The present results provide evidence for differences between lean and obese rats in the expression of CRF and its receptor within selective hypothalamic nuclei. Given the anorectic and thermogenic properties of CRF and the roles of PVN and VMH in the regulation of energy balance, it can be argued that the observed alterations in the biosynthesis of CRF and its receptors within the PVN and VMH might be related to the development of obesity.
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PMID:Expression of corticotropin-releasing factor and its receptors in the brain of lean and obese Zucker rats. 889 48

Dominant mutations at the agouti locus induce several phenotypic changes in the mouse including yellow pigmentation (phaeomelanization) of the coat and adult-onset obesity. Nonpigmentary phenotypic changes associated with the agouti locus are due to ectopic expression of the agouti-signaling protein (ASP), and the pheomelanizing effects on coat color are due to ASP antagonism of alpha-MSH binding to the melanocyte MC1 receptor. Recently it has been demonstrated that pharmacological antagonism of hypothalamic melanocortin receptors or genetic deletion of the melanocortin 4 receptor (MC4-R) recapitulates aspects of the agouti obesity syndrome, thus establishing that chronic disruption of central melanocortinergic signaling is the cause of agouti-induced obesity. To learn more about potential downstream effectors involved in these melanocortinergic obesity syndromes, we have examined expression of the orexigenic peptides galanin and neuropeptide Y (NPY), as well as the anorexigenic POMC in lethal yellow (A(y)), MC4-R knockout (MC4-RKO), and leptin-deficient (ob/ob) mice. No significant changes in galanin or POMC gene expression were seen in any of the obese models. In situ hybridizations using an antisense NPY probe demonstrated that in obese A(y) mice, arcuate nucleus NPY mRNA levels were equivalent to that of their C57BL/6J littermates. However, NPY was expressed at high levels in a new site, the dorsal medial hypothalamic nucleus (DMH). Expression of NPY in the DMH was also seen in obese MC4-RKO homozygous (-/-) mice, but not in lean heterozygous (+/-) or wild type (+/+) control mice. This identifies the DMH as a brain region that is functionally altered by the disruption of melanocortinergic signaling and suggests that this nucleus, possibly via elevated NPY expression, may have an etiological role in the melanocortinergic obesity syndrome.
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PMID:Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in two models of the agouti obesity syndrome. 913 6

Melanocortin peptides (adrenocorticotropin (ACTH), alpha-,beta-, and gamma-melanocyte stimulating hormone (MSH), and fragments thereof) derived from proopiomelanocortin (POMC) have a diverse array of biological activities, many of which have yet to be fully elucidated. The recent cloning of a family of five distinct melanocortin receptors through which these peptides act has provided the tools to further our understanding of melanocortin peptide functions. Early work on melanocortin peptides focused on their roles in pigmentation, adrenocortical function, the immune, central and peripheral nervous systems. Although melanocortin peptides have long been known to affect lipolysis, characterisation of the melanocortin receptors has opened up several lines of evidence for important roles in the development of obesity, insulin resistance and type II diabetes. We present here a review of the current evidence for melanocortin peptides playing such a role, and based on this evidence, a model for melanocortin peptides and their receptors in maintaining energy balance.
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PMID:Obesity, diabetes and functions for proopiomelanocortin-derived peptides. 914 88

Little is known about the effects of intentional weight loss on the function of the hypothalamic-pituitary-adrenal (HPA) axis of obese individuals. We studied the HPA axis of 34 healthy obese women (body mass index, 40.2 +/- 7.9 kg/m2) before and after a 21.0 +/- 7.9-kg weight loss induced by a 26-week weight loss program that included 12 weeks of a 3350 kJ/day (800 Cal/day) liquid formula diet, 6 weeks of gradual refeeding, and 6 weeks of caloric stabilization at 5020-6280 kJ/day (1200-1500 Cal/day). Obese subjects were evaluated twice: before caloric restriction and during the last 3 weeks of caloric stabilization with a 3-h evening 1 microg/kg ovine CRH (oCRH) stimulation test. CRH-stimulated ACTH and cortisol values were compared to those of a control group of 12 normal weight women. Before caloric restriction, both ACTH and cortisol responses to oCRH were similar in obese women and normal weight controls. Weight loss did not significantly alter the ACTH response to oCRH; however, the total plasma cortisol response to oCRH decreased significantly with weight loss (area under the curve, 96,320 +/- 21,040 nmol/L x min before weight loss; 82,450 +/- 22,460 nmol/L x min after weight loss; P < 0.001). Cortisol-binding globulin also decreased significantly after weight loss (2,270 +/- 1,050 nmol/L) compared either to values obtained before weight loss (3,590 +/- 1,360 nmol/L; P < 0.001) or to those of normal weight controls (3,910 +/- 1,400 nmol/L; P < 0.001). Assay for plasma free cortisol, either before or 180 min after oCRH treatment, showed no significant changes in cortisol responses resulting from weight loss. As plasma free cortisol was not altered by weight reduction, the decrease in the total cortisol response to oCRH after weight loss appears to be secondary to significant decreases in cortisol-binding globulin. We conclude that when obese women lose large amounts of weight with a 3350 kJ/day, very low energy diet, such weight reduction does not significantly affect the HPA axis.
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PMID:Differences in corticotropin-releasing hormone-stimulated adrenocorticotropin and cortisol before and after weight loss. 917 99

The crucial role of glucocorticoids in obesity and insulin resistance and the actions of the OB protein leptin on the hypothalamic-pituitary-adrenal (HPA) axis suggest that there is an important interaction of leptin with the glucocorticoid system. Therefore, we designed a study to test the effect of leptin directly on adrenocortical steroidogenesis. Primary cultures of bovine adrenocortical cells were incubated with increasing concentrations (10-1,000 ng/ml) of recombinant mouse leptin for 24 h, and the effects of leptin on basal and ACTH-stimulated cortisol secretion were determined. The accumulation of P450 17alpha mRNA following incubation with ACTH (10 nmol/l) and leptin (10-1,000 ng/ml) was analyzed by Northern blot. Adrenocortical cells were characterized by immunohistochemical staining for 17alpha-hydroxyprogesterone. Leptin (10-1,000 ng/ml) inhibited basal and ACTH-stimulated cortisol release. At a concentration that occurs in obese individuals in vivo (100 ng/ml), it reduced basal cortisol secretion to 52.7 +/- 37% (mean +/- SE). The rise in cortisol secretion following maximal ACTH stimulation (10 nmol/l) was blunted to 55.2 +/- 27%. At more physiological concentrations of ACTH (0.1 nmol/l), the inhibition of cortisol release by coincubation with low doses of leptin (10 ng/ml) was even more pronounced, leading to a reduction to 32.8% (1,248 +/- 134 vs. 410 +/- 157 nmol/l). Addition of OB protein (10-1,000 ng/ml) led to a dose-dependent reduction of ACTH-stimulated cytochrome P450 17alpha mRNA accumulation (from 80 to 45%), suggesting that leptin regulates adrenal steroidogenesis at the transcriptional level. These data clearly demonstrate that leptin inhibits cortisol production in adrenocortical cells and therefore appears to be a metabolic signal that directly acts on the adrenal gland.
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PMID:Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. 920 Jun 62

In the present study, we characterized the changes in plasma leptin levels in patients with pituitary Cushing's disease and in age- and sex-matched controls. Plasma levels of ACTH, cortisol, and leptin were measured before and after iv administration of ovine CRH in controls once and in patients twice (while they had active hypercortisolism and 10 days after successful surgery). Cushing's patients had elevated body mass indexes (34 +/- 1.9 vs. 22.9 +/- 0.8) and plasma leptin levels (35.6 +/- 3.4 vs. 9.2 +/- 1.9 ng/mL) compared to controls, which remained unchanged 10 days after successful transsphenoidal surgery and directly proportional to the body mass index. Plasma leptin levels were not affected by CRH infusion in either the controls or the patients despite clear-cut elevations in plasma ACTH and cortisol. These findings suggest that although acute changes in plasma cortisol do not affect plasma leptin, chronic hypercortisolism results in elevated leptin levels, probably by causing visceral obesity.
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PMID:Plasma leptin levels do not change in patients with Cushing's disease shortly after correction of hypercortisolism. 925 64

The mouse mutations mahogany (mg) and mahoganoid (md) are negative modifiers of the Agouti coat color gene, which encodes a paracrine signaling molecule that induces a swithc in melanin synthesis from eumelanin to pheomelanin. Animals mutant for md or mg synthesize very little or no pheomelanin depending on Agouti gene background. The Agouti protein is normally expressed in the skin and acts as an antagonist of the melanocyte receptor for alpha-MSH (Mc1r); however, ectopic expression of Agouti causes obesity, possibly by antagonizing melanocortin receptors expressed in the brain. To investigate where md and mg lie in a genetic pathway with regard to Agouti and Mc1r signaling, we determined the effects of these mutations in animals that carried either a loss-of-function Mc1r mutation (recessive yellow, Mc1re) or a gain-of-function Agouti mutation (lethal yellow, Ay). We found that the Mc1re mutation suppressed the effects of md and mg, but that md and mg suppressed the effects of Ay on both coat color and obesity. Plasma levels of alpha-MSH and of ACTH were unaffected by md or mg. These results suggest that md and mg interfere directly with Agouti signaling, possibly at the level of protein production or receptor regulation.
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PMID:Genetic studies of the mouse mutations mahogany and mahoganoid. 925 83

In a brief review of advances in endocrinology in the last two years the author discusses above all the vain expectations of a drug against obesity-the adipose tissue hormone leptin. Its elevated blood level in human obesity indicates that its secretion depends on the mass of adipose tissue and it is not certain whether leptin reduces the food intake in humans. Perhaps resistance to leptin is involved. New receptor diseases were revealed: mutation of LH receptors leads in both sexes to hypogonadism. Mutation of the calcium receptor in parathyroid cells leads to familial hypocalciuric hypercalcaemia or autosomal dominant hypocalcaemia. The complex regulation of the tonus of the vascular wall by endothelins is still the object of interest. Aquaporin is a renal protein which mediates the action of vasopressin. In the sphere of stress evidence is emerging on the participation of CRH in brain activity and the possibility to influence autoimmune inflammations and perhaps even AIDS by interference with the CRH-proopiomelanocortin-ACTH-cortisol system.
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PMID:[Endocrinology 1995-1996]. 926 67


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