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BPND changes across sessions in leptin-deficient patients and healthy control subjects. (a) Colored volumes-of-interest delineate the caudate nucleus (white), putamen (black), NAC (red) and GP (orange) within the right hemisphere of two coronal sections where a representative PET image is superimposed on the corresponding magnetic resonance image. (b) BPND values of all participants in the first and second PET sessions; for the three patients (data shown in red), the first and second sessions were conducted under ‘off-leptin’ and ‘on-leptin’ conditions, respectively. (c) Changes in BPND values obtained by subtracting the BPND value in session 1 from the BPND value in session 2. BPND, Binding potential; GP, globus pallidus; L, left hemisphere; PET, positron emission tomography; R, right hemisphere.Download Power Point slide (294 KB)
Source publication
The adipocyte-derived hormone, leptin, which plays a principal role in regulating feeding behavior and energy expenditure, modulates central dopamine systems at multiple levels.1, 2, 3 In ob/ob mice, which have a genetic mutation that renders them leptin-deficient, leptin administration was shown to increase dopamine D2/D3 receptor availability in...
Contexts in source publication
Context 1
... 2 /D 3 receptor binding was estimated in the nucleus accumbens (NAC), globus pallidus (GP), putamen, and caudate nucleus. VOIs were placed using the "FIRST" subcortical segmentation routines within the FSL software distribution (http:// www.fmrib.ox.ac.uk/fsl/first/index.html) (Figure 1a). Binding potential (BPND), which represents D 2 /D 3 receptor availability, was determined as described previously (10) (Figure 1b and 1c). ...
Context 2
... were placed using the "FIRST" subcortical segmentation routines within the FSL software distribution (http:// www.fmrib.ox.ac.uk/fsl/first/index.html) (Figure 1a). Binding potential (BPND), which represents D 2 /D 3 receptor availability, was determined as described previously (10) (Figure 1b and 1c). Z scores were calculated using the corresponding standard deviation from control subjects, averaged, and converted to one- tailed P values. ...
Context 3
... set 95% upper limits of 32%, 10%, 7% and 2% for the percentage BPND increase in the four regions. Figures 1b and 1c suggest, however, that changes in D 2 /D 3 receptor availability in the patients ranged from an increase after leptin replacement in the most ventral VOI (NAC) to a decrease in the most dorsal (caudate). ...
Citations
... Besides that, there is growing experimental results indicating that leptin also plays a significant role in other areas of the central nervous system (CNS) and is associated with several pathological and physiological mechanisms of neurological diseases, including neurodegenerative diseases and mood disorders [43,44]. Leptin influences neurotransmitters such as dopamine [45] and impacts gray matter plasticity [46]. It was found that neurological diseases occurred alongside leptin level alterations, suggesting that leptin might be a critical modulator of these diseases, and studying the specific relationship is of significance [47]. ...
Background
Depression is a leading cause of disability worldwide and a significant contributor to the global burden of disease. Altered leptin levels are known to be associated with depressive symptoms, however discrepancies in the results of increased or decreased levels exist. Due to various limitations associated with commonly used antidepressant drugs, alternatives such as exercise therapy are gaining more importance. Therefore, the current study investigates whether depressed patients have higher leptin levels compared to healthy controls and if exercise is efficient to reduce these levels.
Methods
Leptin levels of 105 participants with major depressive disorder (MDD; 45.7% female, age mean ± SEM: 39.1 ± 1.0) and 34 healthy controls (HC; 61.8% female, age mean ± SEM: 36.0 ± 2.0) were measured before and after a bicycle ergometer test. Additionally, the MDD group was separated into three groups: two endurance exercise intervention groups (EX) differing in their intensities, and a waiting list control group (WL). Leptin levels were measured pre and post a 12-week exercise intervention or the waiting period.
Results
Baseline data showed no significant differences in leptin levels between the MDD and HC groups. As expected, correlation analyses displayed significant relations between leptin levels and body weight (HC: r = 0.474, p = 0.005; MDD: r = 0.198, p = 0.043) and even more with body fat content (HC: r = 0.755, p < 0.001; MDD: r = 0.675, p < 0.001). The acute effect of the bicycle ergometer test and the 12-week training intervention showed no significant changes in circulating leptin levels.
Conclusion
Leptin levels were not altered in patients with major depression compared to healthy controls and exercise, both the acute response and after 12 weeks of endurance training, had no effect on the change in leptin levels.
Trial registration
The study was registered at the German register for clinical studies (DRKS) and the International Clinical Trials Registry Platform of the World Health Organization https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00008869 on 28/07/2015.
... Although the cerebellum is not traditionally regarded as an area responsible for the control of food intake, it may be involved in the suppression of motivational food-seeking, when leptin-sufficient individuals are not as hungry. Moreover, in positron emission tomography studies, we have shown that resumption of leptin treatment, after long-term replacement and shortterm removal, does not significantly increase striatal D2/D3 receptor availability [21]. ...
... No change in striatal D2/D3 receptor availability [21]. ...
Leptin, an adipokine synthesized and secreted mainly by the adipose tissue, has multiple effects on the regulation of food intake, energy expenditure, and metabolism. Its recently-approved analogue, metreleptin, has been evaluated in clinical trials for the treatment of patients with leptin deficiency due to mutations in the leptin gene, lipodystrophy syndromes, and hypothalamic amenorrhea. In such patients, leptin replacement therapy has led to changes in brain structure and function in intra- and extrahypothalamic areas, including the hippocampus. Furthermore, in one of those patients, improvements in neurocognitive development have been observed. In addition to this evidence linking leptin to neural plasticity and function, observational studies evaluating leptin-sufficient humans have also demonstrated direct correlation between blood leptin levels and brain volume and inverse associations between circulating leptin and risk for the development of dementia. This review summarizes the evidence in the literature on the role of leptin in neural plasticity (in leptin-deficient and in leptin-sufficient individuals) and its effects on synaptic activity, glutamate receptor trafficking, neuronal morphology, neuronal development and survival, and microglial function.
... Leptin, a 16-kDa adipokine of the obese (ob) gene product, is transported across the blood-brain barrier and affects neurotransmitters such as dopamine [10]. Although the exact neurobiological mechanisms of leptin associated with depression are not yet known, several clinical and experimental studies reported that leptin has been associated with the development of depression [11][12][13][14][15]. ...
... Although the exact neurobiological mechanisms of leptin associated with depression are not yet known, several clinical and experimental studies reported that leptin has been associated with the development of depression [11][12][13][14][15]. The effect of leptin in developing depression has been proposed via its modulatory effect on the hypothalamo-pituitary-adrenal (HPA) axis [10,12]. The concentration of the leptin levels in depression varies according to specific conditions, and the proper concentration is not measured. ...
... The hypothalamo-pituitary-adrenal axis is crucial for the adaptation response to stress. A chronically overactive HPA axis can result in severe psychiatric conditions, such as depression and anxiety disorders [10,12]. Recently, several studies have considered the relationship between leptin levels and depression, but with contradictory results. ...
Objective:
To investigate the question of whether serum leptin levels might be associated with post-stroke depression.
Methods:
We studied 130 patients who experienced a first episode of stroke of more than three months' duration, without any previous history of depression or speech disorders. Data were collected regarding the patient demographics, depressive mood (Diagnostic and Statistical Manual of Mental Disorders 4th edition [DSM-IV] criteria and Beck Depression Inventory) and serum leptin levels measured by an enzyme-linked immunosorbent assay (ELISA). In addition, the Korean version of Modified Barthel Index (K-MBI) and Korean version of Mini-Mental State Examination (K-MMSE) were used to assess the subjects' independence, in regard to the activities of daily living and cognition. A statistical analysis was performed to determine differences the serum leptin levels between patients with depression and those without depression, and to determine the difference in the MBI and K-MMSE scores between the groups separated according to the serum leptin levels.
Results:
Higher serum leptin levels were observed in patients with depression, compared with those without depression (38.5 ng/mL [range, 25.1-59.2 ng/mL] vs. 8.2 ng/mL [range, 4.9-17.8 ng/mL]; p<0.01. The serum leptin level showed an association with depression (odds ratio, 1.21; 95% confidence interval, 1.01-1.45; p=0.021). The K-MMSE and K-MBI improvement scores were lower, with statistical significance, in the group with the highest leptin level (>30 mg/dL), compared to the other two groups.
Conclusion:
High serum leptin levels are associated with depression after stroke, and patients with elevated serum leptin levels were disadvantaged in regard to functional and cognitive outcomes.
... The adipocyte-brain crosstalk is mediated to a large extent by adipokines and this circuit plays a pathophysiological role beyond obesity and cardiometabolic conditions (Nakamura et al., 2013;Paz-Filho et al., 2010). Leptin influences neurotransmitters such as dopamine (Ishibashi et al., 2012) and impacts gray matter plasticity (London et al., 2011). Consequently, a putative role for leptin, adiponectin and resistin in the pathophysiology of neuropsychiatric conditions associated with metabolic abnormalities, including MDD has emerged (vide infra) (Diniz et al., 2012;Liu et al., 2012;Lu et al., 2006;Weber-Hamann et al., 2007;Yamada et al., 2010). ...
... 20 A 7-minute transmission scan was performed using a rotating 68 Ge/ 68 Ga rod source. Dynamic data acquisition was initiated with a bolus injection of 18 F-fallypride 19,21,22 (< 185 MBq 6 5%, specific activity $ 37 GBq/mmol) and continued for 80 minutes. After a short break, another transmission scan was performed, and emission data collection continued for another 80 minutes. ...
The development of high-affinity radiotracers for positron emission tomography (PET) has allowed for quantification of dopamine receptors in extrastriatal and striatal regions of the brain. As these new radiotracers have distinctly different kinetic properties than their predecessors, it is important to examine the suitability of kinetic models to represent their uptake, distribution, and in vivo washout. Using the simplified reference tissue model, we investigated the influence of reference region choice on the striatal binding potential of 18F-fallypride, a high-affinity dopamine D2/D3 receptor ligand. We compared the use of the visual cortex and a white matter region (superior longitudinal fasciculus) to the cerebellum, a commonly used reference tissue, in a PET-fallypride study of healthy and methamphetamine-dependent subjects. Compared to the cerebellum, use of the visual cortex produced significantly greater sample variance in binding potential relative to nondisplaceable uptake (BPND). Use of the white matter region was associated with BPND values and sample variance similar to those obtained with the cerebellum and a larger effect size for the group differences in striatal BPND between healthy and methamphetamine-dependent subjects. Our results do not support the use of the visual cortex as a reference region in 18F-fallypride studies and suggest that white matter may be a reasonable alternative to the cerebellum as it displays similar statistical and kinetic properties.
... Baseline DA D2/3 BPeq was not related to circulating leptin levels after full correction for multiple comparisons. These data are in line with a recent report using [ 18 F]fallypride PET in a small sample of patients diagnosed with hereditary lipodystrophy where replacement with leptin failed to alter DA D2/3 availability (Ishibashi et al., 2012). However, the use of more liberal thresholds of significance (p = 0.01 uncorrected for multiple comparisons), revealed positive correlations with leptin (controlling for sex, BMI, and AIMs) and DA D2/3 BPeq observed in the ventral basal ganglia bilaterally (data not shown). ...
... Dopaminergic neurotransmission in the ventral basal ganglia plays an integral role in the response to salient rewarding stimuli including drugs of abuse, sex, social bonding, and food (Berridge and Robinson, 1998). Further, the dopaminergic system appears to be influenced by an individual's metabolic phenotype as obese individuals show lower levels of DA D2 receptor binding compared to lean (Volkow et al., 2008) and leptin influences the neuronal response to salient stimuli related to food in the diseased state (Farooqi et al., 2007; Rosenbaum et al., 2008; Stice et al., 2008; Stice et al., 2011; Ishibashi et al., 2012). ...
Neural systems that identify and respond to salient stimuli are critical for survival in a complex and changing environment. In addition, interindividual differences, including genetic variation and hormonal and metabolic status likely influence the behavioral strategies and neuronal responses to environmental challenges. Here, we examined the relationship between leptin allelic variation and plasma leptin levels with DAD2/3R availability in vivo as measured with [(11)C]raclopride PET at baseline and during a standardized pain stress challenge. Allelic variation in the leptin gene was associated with varying levels of dopamine release in response to the pain stressor, but not with baseline D2/3 receptor availability. Circulating leptin was also positively associated with stress-induced dopamine release. These results show that leptin serves as a regulator of neuronal function in humans and provides an etiological mechanism for differences in dopamine neurotransmission in response to salient stimuli as related to metabolic function. The capacity for leptin to influence stress-induced dopaminergic function is of importance for pathological states where dopamine is thought to play an integral role, such as mood, substance-use disorders, eating disorders, and obesity.
Background: Depression is a leading cause of disability worldwide and a significant contributor to the global burden of disease. Altered leptin levels are known to be associated with depressive symptoms, however discrepancies in the results of increased or decreased levels exist. Due to various limitations associated with commonly used antidepressant drugs, alternatives such as exercise therapy are gaining more importance. Therefore, the current study investigates whether depressed patients have higher leptin levels compared to healthy controls and if exercise is efficient to reduce these levels.
Methods: Leptin levels of 105 participants with major depressive disorder (MDD; 45.7% female, age mean ± SEM: 39.1 ± 1.0) and 34 healthy controls (HC; 61.8% female, age mean ± SEM: 36.0 ± 2.0) were measured before and after a bicycle ergometer test. Additionally, the MDD group was separated into three groups: two endurance exercise intervention groups (EX) differing in their intensities, and a waiting list control group (WL). Leptin levels were measured pre and post a 12-week exercise intervention or the waiting period.
Results: Baseline data showed no significant differences in leptin levels between the MDD and HC groups. As expected, correlation analyses displayed significant relations between leptin levels and body weight (HC: r = 0.474, p = 0.005; MDD: r = 0.198, p = 0.043) and even more with body fat content (HC: r = 0.755, p < 0.001; MDD: r = 0.675, p < 0.001). The acute effect of the bicycle ergometer test and the 12-week training intervention showed no significant changes in circulating leptin levels.
Conclusion: Leptin levels were not altered in patients with major depression compared to healthy controls and exercise, both the acute response and after 12 weeks of endurance training, had no effect on the change in leptin levels.
Leptin is an adipokine synthesized mainly by the white adipose tissue, with a key role in the regulation of food intake and energy balance. In humans, leptin deficiency is observed in cases of lipodystrophy, functional hypothalamic amenorrhea, and congenital leptin deficiency (CLD) due to mutations in the leptin gene. To date, 34 cases of CLD have been described in the literature, with eight different mutations in the leptin gene been identified so far. For these patients, leptin replacement therapy with metreleptin (a recombinant leptin analog) is the only available therapy, which has been offered to most of these patients. The analysis of the effects of leptin replacement therapy in patients with CLD has shown that leptin has diverse effects, not only by leading to substantial weight loss due to decreases in food intake, but also to endocrine, metabolic, immune, and both structural and functional changes in the brain. A better understanding of the physiological roles of leptin may lead to the development of leptin-based therapies for more prevalent disorders such as fatty liver disease and neurocognitive diseases.
Leptin has key roles in the regulation of energy balance, body weight, metabolism, and endocrine function. Leptin levels are undetectable or very low in patients with lipodystrophy, hypothalamic amenorrhea, and congenital leptin deficiency (CLD) due to mutations in the leptin gene. For these patients, leptin replacement therapy with metreleptin (a recombinant leptin analogue) has improved or normalized most of their phenotypes, including normalization of endocrine axes, decrease in insulin resistance, and improvement of lipid profile and hepatic steatosis. Remarkable weight loss has been observed in patients with CLD. Due to its effects, leptin therapy has also been evaluated in conditions where leptin levels are normal or high, such as common obesity, diabetes (types 1 and 2), and Rabson-Mendenhall syndrome. A better understanding of the physiological roles of leptin may lead to the development of leptin-based therapies for other prevalent disorders such as obesity-associated nonalcoholic fatty liver disease, depression and dementia.
