Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin inhibits appetite by activating several neuroendocrine systems, including the hypothalamo-pituitary-adrenal cortical (HPA) axis. In turn, chronically elevated glucocorticoids increase circulating leptin. HPA axis hyperactivity occurs in 30-50% of patients with major depression, but the few prior reports of leptin measurements in this illness have shown inconsistent results. We, therefore, measured plasma leptin in 12 female and 8 male unipolar major depressives and 12 female and 8 male individually matched normal controls administered low-dose physostigmine (PHYSO) and arginine vasopressin (AVP) to stimulate the HPA axis. The subjects underwent four test sessions 5-7 days apart: PHYSO (8 microg/kg IV); AVP (0-08 U/kg IM); PHYSO+AVP; and saline control. Serial blood samples were taken before and after pharmacologic challenge and analyzed for leptin, ACTH(1-39), cortisol and AVP. Estradiol and testosterone also were measured at each test session. PHYSO and AVP produced no side effects in approximately half the subjects and predominantly mild side effects in the other half, with no significant patient-control differences. Correlations between side effects (absent or present) after PHYSO or AVP and the corresponding leptin responses were non-significant in all groups. Baseline plasma leptin concentrations (mean+/-S.D.) were significantly higher in the female patients compared to the female controls (22.5+/-13.9 ng/ml vs. 12.3+/-9.7 ng/ml), whereas they were similar in the male patients and the male controls (3.9+/-1.4 ng/ml vs. 3.6+/-2.0 ng/ml). Leptin concentrations following PHYSO remained unchanged from baseline, indicating that the short-lived ACTH and cortisol increases produced by PHYSO did not affect leptin secretion. In contrast, AVP administration, while also increasing ACTH and cortisol, significantly suppressed leptin, more so in the women than in the men. Baseline leptin and the leptin decrease after AVP were moderately positively correlated with the Hamilton Depression Scale 'somatization' factor in the female patients (r=0.50) and more strongly correlated with the 'mood-depression' factor in the male patients (r=0.81). These findings indicate a sexual diergism (functional sex difference) in plasma leptin measures between major depressives and matched normal controls.
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PMID:Sexual diergism of baseline plasma leptin and leptin suppression by arginine vasopressin in major depressives and matched controls. 1255 82

Low cholesterol levels have been reported in patients with manic episodes. Leptin seems to be strongly associated with lipid metabolism. In the present study, therefore, serum total cholesterol and leptin levels were compared in 16 patients with manic episodes, 16 with bipolar I disorder in full remission and 16 healthy controls. The serum total cholesterol and leptin levels were measured and Young Mania Rating (YMRS) and Hamilton Depression Rating Scales (HAM-D) were administered for each subject. Both the patients with manic episodes and the patients with bipolar I disorder in full remission had markedly low serum cholesterol and leptin levels compared with controls, though the difference was more obvious in patients with manic episodes. In addition, there were negative correlations between YMRS scores and serum cholesterol or leptin levels in the patients with manic episodes. Our results suggest that the patients with manic episodes and those with bipolar I disorder in full remission seem to be associated with decreased serum cholesterol and leptin levels.
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PMID:Serum leptin and cholesterol levels in patients with bipolar disorder. 1256 33

Insulin resistance is a metabolic syndrome commonly seen in obesity. Leptin, the obese gene product, plays a role in the regulation of cardiac function. Elevated leptin levels have been demonstrated under insulin-resistant states such as obesity and hypertension, although their role in cardiac dysfunction is unknown. This study was designed to determine the impact of prediabetic insulin resistance on leptin levels and leptin-induced cardiac contractile response. Whole-body insulin resistance was generated with a 10-week dietary sucrose feeding. Contractile and intracellular Ca(2+) properties were evaluated in ventricular myocytes using an IonOptix system. The contractile indices analyzed included peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)), maximal velocity of shortening/relengthening (+/-dL/dt), fura-fluorescence intensity change (deltaFFI) and decay rate (tau). Sucrose-fed rats displayed significantly elevated body weight and plasma leptin levels, depressed PS, +/-dL/dt, shortened TPS, prolonged TR(90) and tau, as well as reduced deltaFFI compared to the starch-fed control group. Leptin (1-1000 nM) elicited a concentration-dependent depression of PS and deltaFFI in myocytes from both starch and sucrose groups. Leptin-induced contractile depression was abolished by the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyle ester, elevation of the extracellular Ca(2+) concentration, the Janus activated kinase 2 inhibitor AG-490 or the mitogen activated protein kinase inhibitor SB203580 in myocytes from both sucrose and starch groups. Moreover, AG-490 and SB203580 unmasked a positive response of PS in myocytes from both groups. These data indicate that insulin resistance directly induces hyperleptinemia and cardiac contractile dysfunction, without affecting leptin-mediated cardiac contractile function at the myocyte level.
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PMID:Insulin resistance induces hyperleptinemia, cardiac contractile dysfunction but not cardiac leptin resistance in ventricular myocytes. 1451 67

Leptin deficiency in ob/ob mice produces marked depression of the hypercapnic ventilatory response, particularly during sleep. We now extend our previous findings to determine whether 1) leptin deficiency affects the hypoxic ventilatory response and 2) blockade of the downstream excitatory actions of leptin on melanocortin 4 receptors or inhibitory actions on neuropeptide Y (NPY) pathways has an impact on hypercapnic and hypoxic sensitivity. We have found that leptin-deficient ob/ob mice have the same hypoxic ventilatory response as weight-matched wild-type obese mice. There were no differences in the hypoxic sensitivity between agouti yellow mice and weight-matched controls, or NPY-deficient mice and wild-type littermates. Agouti yellow mice, with blocked melanocortin pathways, exhibited a significant depression of the hypercapnic sensitivity compared with weight-matched wild-type controls during non-rapid eye movement sleep (5.8 +/- 0.7 vs. 8.9 +/- 0.7 ml x min(-1) x %CO(2)(-1), P < 0.01), but not during wakefulness. NPY-deficient transgenic mice exhibited a small increase in the hypercapnic ventilatory response compared with wild-type littermates, but this was only present during wakefulness. We conclude that interruption of leptin pathways does not affect hypoxic sensitivity during sleep and wakefulness but that melanocortin 4 blockade is associated with depressed hypercapnic sensitivity in non-rapid eye movement sleep.
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PMID:Impact of interrupted leptin pathways on ventilatory control. 1457 71

The melanocortin system coordinates the maintenance of energy balance via the regulation of both food intake and energy expenditure. Leptin, a key adipogenic hormone involved in the regulation of energy balance is thought to act by stimulating production, in the hypothalamic arcuate nucleus, of alpha-melanocyte stimulating hormone (alphaMSH), a potent agonist of MC3/4 melanocortin receptors located in the paraventricular nucleus of the hypothalamus. Additionally leptin inhibits release of agouti-related protein (AgRP), an MC4R antagonist. During periods of caloric restriction, weight loss is not sustained because compensatory mechanisms, such as reduced resting metabolic rate (RMR) are brought into play. Understanding how these compensatory systems operate may provide valuable targets for pharmaceutical therapies to support traditional dieting approaches. As circulating leptin is reduced during caloric restriction, it may mediate some of the observed compensatory responses. In addition to decreases in circulating leptin levels, circulating AgRP is increased during fasting in rodents while alphaMSH is decreased. As central administration of AgRP depresses metabolism, we hypothesised that the peripheral rise in AgRP might be involved in signalling the depression of RMR during food restriction. We hypothesised that changes in plasma AgRP and alphaMSH may coordinate the regulation of changes in energy expenditure acting through central MC4 melanocortin receptors via the sympathetic nervous system.We show here that acute peripherally administered AgRP at supra-physiological concentrations in both lean (C57BL/6) and obese leptin-deficient (ob/ob) mice does not depress RMR, possibly because it crosses the blood-brain barrier very slowly compared with other metabolites. However, in vitro AgRP can decrease leptin secretion, by approximately 40%, from adipocytes into culture medium and may via this axis have an effect on energy metabolism during prolonged caloric restriction. In contrast, peripheral [Nle4,D-Phe7]-alpha MSH produced a large and sustained increase in resting energy expenditure (0.15 ml O2/min; P < 0.05) with a similar response in leptin-deficient ob/ob mice (0.27 ml O2/min) indicating that this effect is independent of the status of leptin production in the periphery. In both cases respiratory exchange ratio and the levels of energy expended on spontaneous physical activity were unaffected by the administration of peripheral [Nle4,D-Phe7]-alpha MSH. In conclusion, alphaMSH analogues that cross the blood-brain barrier may significantly augment dietary restriction strategies by sustaining elevated RMR.
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PMID:Peripherally administered [Nle4,D-Phe7]-alpha-melanocyte stimulating hormone increases resting metabolic rate, while peripheral agouti-related protein has no effect, in wild type C57BL/6 and ob/ob mice. 1559 Oct 28

Impaired leptin signalling in obesity is increasingly implicated in cardiovascular pathophysiology. To explore mechanisms for leptin activity in the heart, we hypothesized that physiological leptin signalling participates in maintaining cardiac beta-adrenergic regulation of excitation-contraction coupling. We studied 10-week-old (before development of cardiac hypertrophy) leptin-deficient (ob/ob, n=12) and C57Bl/6 (wild-type (WT), n=15) mice at baseline and after recombinant leptin infusion (0.3 mg kg-1 day-1 for 28 days, n=6 in each group). Ob/ob-isolated myocytes had attenuated sarcomere shortening and calcium transients ([Ca2+]i) versus WT (P<0.01 for both) following stimulation of the beta-receptor (with isoproterenol (isoprenaline)) or at the post-receptor level (with forskolin and dibutryl-cAMP). In addition, sarcoplasmic reticulum (SR) Ca2+ stores were depressed. Leptin replenishment in ob/ob mice restored each of these abnormalities towards normal without affecting gross (wall thickness) or microscopic (cell size) measures of cardiac architecture. Immunoblots revealed alterations of several proteins involved in excitation-contraction coupling in the ob/ob mice, including decreased abundance of Gsalpha-52 kDa, as well as alterations in the expression of Ca2+ cycling proteins (increased SR Ca2+-ATPase, and depressed phosphorylated phospholamban). In addition, protein kinase A (PKA) activity in ob/ob mice was depressed at baseline and correctable towards the activity found in WT with leptin repletion, a finding that could account for impaired beta-adrenergic responsiveness. Taken together, these data reveal a novel link between the leptin signalling pathway and normal cardiac function and suggest a mechanism by which leptin deficiency or resistance may lead to cardiac depression.
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PMID:Leptin repletion restores depressed {beta}-adrenergic contractility in ob/ob mice independently of cardiac hypertrophy. 1576 Sep 36

Leptin is a product of the obese gene and plays an important role in the regulation of body weight and food intake. Weight and appetite are frequently altered in depression. So far, inconsistent results have been reported in terms of leptin levels in depression. Therefore, the authors investigated serum leptin levels in patients with depression and in healthy controls, and whether there was any alteration throughout antidepressant treatment. Female patients showed significantly higher leptin levels than those of the control females both before and after the response to antidepressant treatment, whereas no difference was found between the male patients and the male controls. The improvement from depression with antidepressant treatment caused a further elevation on the leptin levels, in both female and male patients. These findings confirm an increase in leptin levels in depressive patients and presence of a sexual dimorphism. Moreover, clinical response to antidepressant treatment seems to have an additional increasing effect on leptin levels.
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PMID:Effects of antidepressant treatment and of gender on serum leptin levels in patients with major depression. 1586 59

It is becoming apparent that the hormone leptin plays an important role in modulating hippocampal function. Indeed, leptin enhances NMDA receptor activation and promotes hippocampal long-term potentiation (LTP). Furthermore, obese rodents with dysfunctional leptin receptors display impairments in hippocampal synaptic plasticity. Here we demonstrate that under conditions of enhanced excitability (evoked in Mg2+-free medium or following blockade of GABA(A) receptors), leptin induces a novel form of long-term depression (LTD) in area CA1 of the hippocampus. Leptin-induced LTD was markedly attenuated in the presence of D-(-)-2-Amino-5-Phosphonopentanoic acid (D-AP5), suggesting that it is dependent on the synaptic activation of NMDA receptors. In addition, low-frequency stimulus-evoked LTD occluded the effects of leptin. In contrast, metabotropic glutamate receptors (mGluRs) did not contribute to leptin-induced LTD as mGluR antagonists failed to either prevent or reverse this process. The signalling mechanisms underlying leptin-induced LTD were independent of the Ras-Raf-mitogen-activated protein kinase signalling pathway, but were markedly enhanced following inhibition of either phosphoinositide 3-kinase or protein phosphatases 1 and 2A. These data indicate that under conditions of enhanced excitability, leptin induces a novel form of homosynaptic LTD, which further underscores the proposed key role for this hormone in modulating NMDA receptor-dependent hippocampal synaptic plasticity.
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PMID:Leptin induces a novel form of NMDA receptor-dependent long-term depression. 1608 87

Leptin is thought to be related to vegetative symptoms of depression such as alterations in food intake and weight. Fifty-seven drug-free patients and 26 healthy controls were enrolled in this study. We have found that the serum leptin levels were higher in patients with atypical depressive disorder than in controls, but not in patients with non-atypical depressive disorder, however, body mass index, age, and gender were not significantly different between these groups. Probably, these findings seem to be associated with some features of the atypical depressive disorders such as weight gain, a result of hyperphagia.
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PMID:High serum leptin levels in depressive disorders with atypical features. 1640 Dec 52

Leptin, a hormone secreted from adipose tissue, was originally discovered to regulate body weight. The localization of the leptin receptor in limbic structures suggests a potential role for leptin in emotional processes. Here, we show that rats exposed to chronic unpredictable stress and chronic social defeat exhibit low leptin levels in plasma. Systemic leptin treatment reversed the hedonic-like deficit induced by chronic unpredictable stress and improved behavioral despair dose-dependently in the forced swim test (FST), a model widely used for screening potential antidepressant efficacy. The behavioral effects of leptin in the FST were accompanied by increased neuronal activation in limbic structures, particularly in the hippocampus. Intrahippocampal infusion of leptin produced a similar antidepressant-like effect in the FST as its systemic administration. By contrast, infusion of leptin into the hypothalamus decreased body weight but had no effect on FST behavior. These findings suggest that: (i) impaired leptin production and secretion may contribute to chronic stress-induced depression-like phenotypes, (ii) the hippocampus is a brain site mediating leptin's antidepressant-like activity, and (iii) elevating leptin signaling in brain may represent a novel approach for the treatment of depressive disorders.
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PMID:Leptin: a potential novel antidepressant. 1642 96


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