Biomedical subjects

Jan Born

Publications and source records attributed to Jan Born.

At least 19 recordsLinked to original sources

PubMed2006

Elevated sleep spindle density after learning or after retrieval in rats.

Non-rapid eye movement sleep has been strongly implicated in consolidation of both declarative and procedural memory in humans. Elevated sleep-spindle density in slow-wave sleep after learning has been shown recently in humans. It has been proposed that sleep spindles, 12-15 Hz oscillations superimposed on slow waves (<1 Hz), in concert with high-frequency hippocampal sharp waves/ripples, promote neural plasticity underlying remote memory formation. The present study reports the first indication of learning-associated increase in spindle density in the rat, providing an animal model to study the role of brain oscillations in memory consolidation during sleep. An odor-reward association task, analogous in many respects to human paired-associate learning, is rapidly learned and leads to robust memory in rats. Rats learned the task over 10 massed trials within a single session, and EEG was monitored for 3 h after learning. Learning-induced increase in spindle density is reliably reproduced in rats in two different learning situations, differing primarily in the behavioral component of the task. This increase in spindle density is also present after reactivation of remote memory and in situations when memory update is required; it is not observed after noncontingent exposure to reward and training context. The latter results substantially extend findings in humans. The magnitude of increase (approximately 25%) and the time window of maximal effect (approximately 1 h after sleep onset) were remarkably similar to human data, making this a valid rodent model to study network interactions through the use of simultaneous unit recordings and local field potentials during postlearning sleep.

Action Potentials↗

PubMed2006

Boosting slow oscillations during sleep potentiates memory.

There is compelling evidence that sleep contributes to the long-term consolidation of new memories. This function of sleep has been linked to slow (<1 Hz) potential oscillations, which predominantly arise from the prefrontal neocortex and characterize slow wave sleep. However, oscillations in brain potentials are commonly considered to be mere epiphenomena that reflect synchronized activity arising from neuronal networks, which links the membrane and synaptic processes of these neurons in time. Whether brain potentials and their extracellular equivalent have any physiological meaning per se is unclear, but can easily be investigated by inducing the extracellular oscillating potential fields of interest. Here we show that inducing slow oscillation-like potential fields by transcranial application of oscillating potentials (0.75 Hz) during early nocturnal non-rapid-eye-movement sleep, that is, a period of emerging slow wave sleep, enhances the retention of hippocampus-dependent declarative memories in healthy humans. The slowly oscillating potential stimulation induced an immediate increase in slow wave sleep, endogenous cortical slow oscillations and slow spindle activity in the frontal cortex. Brain stimulation with oscillations at 5 Hz--another frequency band that normally predominates during rapid-eye-movement sleep--decreased slow oscillations and left declarative memory unchanged. Our findings indicate that endogenous slow potential oscillations have a causal role in the sleep-associated consolidation of memory, and that this role is enhanced by field effects in cortical extracellular space.

Adult↗

PubMed2006

Shift of monocyte function toward cellular immunity during sleep.

BACKGROUND: Sleep is considered to strengthen immune defense. We hypothesized that sleep achieves this effect by shifting the balance between types 1 and 2 cytokine activity toward increased type 1 activity, thereby supporting adaptive cellular immune responses. METHODS: We analyzed monocyte-derived type 1 (interleukin 12 [IL-12]) and type 2 (IL-10) cytokines by means of multiparametric flow cytometry in healthy human subjects (n = 11) during a regular sleep-wake cycle and 24 hours of wakefulness. RESULTS: Sleep increased the number of IL-12-producing monocytes and concurrently decreased the number of IL-10-producing monocytes, thereby inducing clear rhythms in these cells, with maximum numbers at 2:20 and 11:30 am, respectively. The rhythms were completely absent during continuous wakefulness. Correlation analyses and supplementary in vitro studies suggest that high prolactin and low cortisol levels are factors contributing to the shift in the IL-12/IL-10 ratio toward increased IL-12 activity during sleep. CONCLUSIONS: Monocyte-derived IL-12 and IL-10 play a critical role for tuning the synapse between antigen-presenting cells and lymphocytes. By preferentially supporting type 1 IL-12 activity, sleep induces a 24-hour oscillation between predominant types 1 and 2 cytokines and, in this way, acts to globally increase the efficacy of adaptive immune responses. Improving sleep could represent a therapeutic option to enhance the success of vaccinations and success in the treatment of diseases (eg, atopic dermatitis and human immunodeficiency virus infection) that are characterized by type 2 cytokine overactivity.

Adult↗

PubMed2006

Intranasal insulin improves memory in humans: superiority of insulin aspart.

There is compelling evidence that intranasal administration of regular human insulin (RH-I) improves memory in humans. Owing to the reduced tendency of its molecules to form hexamers, the rapid-acting insulin analog insulin aspart (ASP-I) is more rapidly absorbed than RH-I after subcutaneous administration. Since after intranasal insulin administration, ASP-I may also be expected to access the brain, we examined whether intranasal ASP-I has stronger beneficial effects on declarative memory than RH-I in humans. Acute (40 IU) and long-term (4 x 40 IU/day over 8 weeks) effects of intranasally administered ASP-I, RH-I, and placebo on declarative memory (word lists) were assessed in 36 healthy men in a between-subject design. Plasma insulin and glucose levels were not affected. After 8 weeks of treatment, however, word list recall was improved compared to placebo in both the ASP-I (p<0.01) and the RH-I groups (p<0.05). ASP-I-treated subjects performed even better than those of the RH-I-treated group (p<0.05). Our results indicate that insulin-induced memory improvement can be enhanced by using ASP-I. This finding may be especially relevant for a potential clinical administration of intranasal insulin in the treatment of memory disorders like Alzheimer's disease.

Administration, Intranasal↗

PubMed2006

Sleep enhances IL-6 trans-signaling in humans.

Sleep is commonly considered to support immune defense. The underlying sleep-immune interaction appears to rely critically on cytokines, like interleukin-6 (IL-6), that combine effects on immune and neuronal functions. The IL-6 signal is conveyed in two ways: it stimulates a restricted group of (mostly immune) cells via membrane-bound IL-6 receptors (mIL-6R) by forming a complex with soluble IL-6R (sIL-6R), and it stimulates (via membrane-bound gp130) a great variety of other cell types--a process termed trans-signaling. Focusing on the receptor side of IL-6 signaling, we examined the effect of sleep on sIL-6R plasma concentrations, mIL-6R expression, plasma sgp130, and numbers of IL-6-producing monocytes in healthy humans who were tested during a regular sleep-wake cycle and 24 h of wakefulness while blood was sampled repeatedly. Sleep strongly enhanced concentrations of sIL-6R, exceeding wake levels by 70% at the end of sleep. This rise was due to an increase in the PC (proteolytic cleavage) rather than the DS (differentially spliced) variant of sIL-6R. Sleep did not affect IL-6-producing monocytes, mIL-6R density, or sgp130 concentrations. The selective increase in sIL-6R implicates an enhanced trans-signaling capacity whereby sleep distinctly widens the profile of IL-6 actions, enabling an integrated influence on brain and peripheral organs.

Adult↗

PubMed2006

Impaired declarative memory consolidation during sleep in patients with primary insomnia: Influence of sleep architecture and nocturnal cortisol release.

BACKGROUND: A central cognitive function of sleep is to consolidate newly acquired memories for long-term storage. Here, we investigated whether the overnight consolidation of declarative memory in patients with chronic sleep disturbances is impaired, owing to less slow wave sleep (SWS) and an increased cortisol release. METHODS: Polysomnographic recordings, serum cortisol concentrations, and overnight memory consolidation in 16 patients with primary insomnia were compared with those of 13 healthy control subjects. RESULTS: Patients displayed distinctly less overnight consolidation of declarative memory (p < .05), which was significantly correlated with SWS in the control subjects (r = .69) but with rapid eye movement (REM) sleep in the patients (r = .56), who had a diminished amount of SWS (p < .05). Increased cortisol levels in the middle of the night were associated with impaired retrieval of declarative memory after sleep for both control subjects (r = -.52) and patients (r = -.46). CONCLUSIONS: Primary insomnia is associated with a diminished sleep-related consolidation of declarative memory. Efficient overnight consolidation of declarative memory is associated with high amounts of SWS and low serum cortisol levels during the early part of the night. Where SWS is decreased, REM sleep might play a partly compensatory role in the consolidation of declarative memory.

Adult↗

PubMed2006

A 3-day estrogen treatment improves prefrontal cortex-dependent cognitive function in postmenopausal women.

Estrogen secretion in young women follows a cyclic pattern characterized by a pronounced surge in estrogen around ovulation. The way in which this estrogen peak affects cognitive functioning is unclear. Short-term estrogen treatment for a few days mimicking normal pre-menopausal estrogen dynamics substantially enhanced cognitive functions in ovariectomized animals. Here, we provide evidence that inducing a single estrogen peak in postmenopausal women improves their cognitive abilities. Healthy women (51-64 yrs, n=14) received either 100 microg estrogen transdermally for 3 days or placebo in a double-blind within-subject design. The treatment caused a temporary rise in serum estrogen levels roughly comparable to the mid-cyclic changes in estrogen in young women. At the end of the treatment, the women completed two types of tests involving primarily hippocampus-dependent functions of memory retention or prefrontal cortex-dependent functions. Results revealed a clear beneficial effect of estrogen on tasks mainly involving the prefrontal cortex: performance on a digit-ordering task (p<0.05) and on a task requiring short-term memory of event sequences in an unfamiliar story (p<0.01) were improved, and susceptibility to interference in the Stroop test (p<0.05) was diminished after estrogen. On the other hand, estrogen did not affect hippocampus-dependent retention of a story, with delayed recall tested after 30 min or 1 week, although immediate recall was improved by estrogen. We conclude that in postmenopausal women, a transient increase in plasma estrogen concentration acutely improves prefrontal cortex-dependent cognitive functions, whereas hippocampus-dependent memory retention is less affected. Our results encourage future studies to investigate whether repeated induction of short-lasting estrogen peaks could enhance cognitive efficacy of hormonal replacement therapy.

Administration, Cutaneous↗

PubMed2006

Brief sleep after learning keeps emotional memories alive for years.

BACKGROUND: Sleep after learning supports memory consolidation. However, long-lasting memory effects of sleep have not yet been investigated. Postlearning sleep may be particularly involved in the long-term retention of emotional memories and could thereby contribute to the development of posttraumatic stress disorder (PTSD), a disease thought to result from overconsolidation of traumatic memories. METHODS: Subjects (healthy men) who had learned neutral and emotional texts immediately before sleeping or remaining awake for the subsequent 3 hours were recontacted after 4 years for long-term memory assessment (forced-choice recognition test). RESULTS: Sleep following learning compared with wakefulness enhanced memory for emotional texts after 4 years (p = .001). No such enhancement was observed for neutral texts (p = .571). CONCLUSIONS: Brief periods of sleep immediately following learning cause preservation of emotional memories over several years. Sleep deprivation in the immediate aftermath of traumatic events could be a promising therapeutic measure to prevent PTSD.

Chi-Square Distribution↗

PubMed2006

Sleep-dependent surges in growth hormone do not contribute to sleep-dependent memory consolidation.

In the search for the mechanisms that mediate the effects of sleep on the consolidation of memories, growth hormone (GH) recently became of interest, because in humans it is released mainly during slow-wave sleep (SWS), a period of enhanced declarative memory consolidation. In addition, recent studies showed that GH is involved in proper memory function in GH deficient and elderly humans and this effect has been linked to regulatory influences of GH on hippocampal NMDA receptors. Here, we blocked GH secretion by intravenous infusion of somatostatin in healthy young subjects during the first 3 h of sleep, which contain mainly SWS. Declarative and procedural memory consolidation was tested across this period, using a word pair association task and a mirror tracing task, respectively. Although GH was effectively suppressed, memory performance as well as sleep were entirely unaffected by this suppression. Whereas GH may in the long run generally support brain systems required for maintaining proper memory function, our data exclude a necessary contribution of the nocturnal surge in pituitary GH secretion to the acute processing and formation of specific memories during sleep.

Adult↗

PubMed2006

Hippocampal sharp wave-ripples linked to slow oscillations in rat slow-wave sleep.

Slow oscillations originating in the prefrontal neocortex during slow-wave sleep (SWS) group neuronal network activity and thereby presumably support the consolidation of memories. Here, we investigated whether the grouping influence of slow oscillations extends to hippocampal sharp wave-ripple (SPW) activity thought to underlie memory replay processes during SWS. The prefrontal surface EEG and multiunit activity (MUA), along with hippocampal local field potentials (LFP) from CA1, were recorded in rats during sleep. Average spindle and ripple activity and event correlation histograms of SPWs were calculated, time-locked to half-waves of slow oscillations. Results confirm decreased prefrontal MUA and spindle activity during EEG slow oscillation negativity and increases in this activity during subsequent positivity. A remarkably close temporal link was revealed between slow oscillations and hippocampal activity, with ripple activity and SPWs being also distinctly decreased during negative half-waves and increased during slow oscillation positivity. Fine-grained analyses of temporal dynamics revealed for the slow oscillation a phase delay of approximately 90 ms with reference to up and down states of prefrontal MUA, and of only approximately 60 ms with reference to changes in SPWs, indicating that up and down states in prefrontal MUA precede corresponding changes in hippocampal SPWs by approximately 30 ms. Results support the notion that the depolarizing surface-positive phase of the slow oscillation and the associated up state of prefrontal excitation promotes hippocampal SPWs via efferent pathways. The preceding disfacilitation of hippocampal events temporally coupled to the negative slow oscillation half-wave appears to serve a synchronizing role in this neocorticohippocampal interplay.

Action Potentials↗

PubMed2006

Hormonal, subjective, and neurocognitive responses to brief hypoglycemia in postmenopausal women and age-matched men with type 2 diabetes mellitus.

Sexual dimorphisms in hypoglycemic counterregulation are well documented in young healthy and type 1 diabetic subjects. Here, we questioned whether sex differences in counterregulation are present also in type 2 diabetic patients who are in a postmenopausal state. In an attempt to answer this question, we examined hormonal responses to a single-step hypoglycemic clamp (50 mg/dL) in 15 postmenopausal women and 15 age-matched men. Patients were also matched for body mass index, HbA(1c), diabetes duration, and diabetes therapy. In addition to hormonal counterregulation, perception of symptoms as well as aspects of neurocognitive function (short-term memory of words and reaction time on an auditory vigilance task) was assessed at baseline and during the hypoglycemic clamp. Hypoglycemia induced a profound rise in almost all counterregulatory hormones, that is, epinephrine, norepinephrine, corticotropin, cortisol, and growth hormone (all P < .007), except for glucagon, which slightly decreased (P = .014). However, none of the responses differed between sexes (all P > .256). In addition, perceived symptoms (P < .001) as well as reaction time on the vigilance task (P < .001) increased, and short-term memory performance tended to deteriorate (P = .091) during hypoglycemia. Again these changes did not differ between the sexes (all P > .370). In sum, data suggest that, in contrast to previous observations in young, healthy, and type 1 diabetic subjects, sex does not represent an important determinant of hormonal, subjective, and neurocognitive responses to hypoglycemia in postmenopausal type 2 diabetic patients. However, the women in our study were all postmenopausal and not receiving hormone replacement therapy. Therefore, our results cannot be generalized to female patients with type 2 diabetes who are premenopausal or on hormone replacement therapy, that is, conditions characterized by increased blood estrogen levels.

Adrenocorticotropic Hormone↗

PubMed2006

Persistent suppression of resting energy expenditure after acute hypoxia.

Resting energy expenditure (REE) is known to be influenced by various ambient conditions such as oxygen supply. Investigations in healthy subjects during acute hypoxia revealed a drop in REE, but persistent effects after hypoxia had ended have not been examined so far. Although indirect calorimetry is a well-established method to measure REE, it may lead to false conclusions when hyperventilation, rise in lactate or catecholamines, and decrease of food intake accompany hypoxia. Therefore, we determined REE in healthy men after hypoxia had ended and under conditions of controlled energy supply during a glucose clamp. In a double-blind crossover study design, we induced hypoxia for 30 minutes by decreasing oxygen saturation to 75% (vs 96% in a control session) in 13 healthy men. Indirect calorimetry was performed at baseline and 150 minutes after hypoxia had ended. Plasma glucose was held stable between 4.5 and 5.5 mmol/L, and lactate as well as catecholamine concentrations were monitored. In parallel, we measured alterations in hormones of the hypothalamic-pituitary-thyroid axis, which is one known factor mediating changes in REE. Resting energy expenditure was decreased after hypoxia (from 1656+/-80 to 1564+/-97 kcal/d) as compared with the normoxic control condition (1700+/-82 to 1749+/-79 kcal/d, P=.037), whereas the respiratory quotient remained stable (P=.79). Plasma lactate, catecholamine levels, and the pituitary thyroid secretory activity were unchanged after hypoxia (P>.2). Our data demonstrate that the REE decrease persists 150 minutes after acute hypoxia, indicating an adaptation of energy metabolism. This should be valued as an additive pathogenic factor in diseases with disturbed energy metabolism.

Adult↗

PubMed2006

Combined blockade of cholinergic receptors shifts the brain from stimulus encoding to memory consolidation.

High central nervous system levels of acetylcholine (ACh) are commonly regarded as crucial for learning and memory, and a decline in cholinergic neurotransmission is associated with Alzheimer's dementia. However, recent findings revealed exceptions to this rule: The low ACh tone characterizing slow wave sleep (SWS) has proven necessary for consolidation of hippocampus-dependent declarative memories during this sleep stage. Such observations, together with recent models of a hippocampal-neocortical dialogue underlying systems memory consolidation, suggest that high levels of ACh support memory encoding, whereas low levels facilitate consolidation. We tested this hypothesis in human subjects by blocking cholinergic neurotransmission during wakefulness, starting 30 min after learning. Subjects received the muscarinic antagonist scopolamine (4 microg/kg bodyweight intravenously) and the nicotinic antagonist mecamylamine (5 mg orally). Compared to placebo, combined muscarinic and nicotinic receptor blockade significantly improved consolidation of declarative memories tested 10 hr later, but simultaneously impaired acquisition of similar material. Consolidation of procedural memories, which are not dependent on hippocampal functioning, was unaffected. Neither scopolamine nor mecamylamine alone enhanced declarative memory consolidation. Our findings support the notion that ACh acts as a switch between modes of acquisition and consolidation. We propose that the natural shift in central nervous system cholinergic tone from high levels during wakefulness to minimal levels during SWS optimizes declarative memory consolidation during a period with no need for new memory encoding.

Adult↗

PubMed2006

Sleep to remember.

Recently, compelling evidence has accumulated that links sleep to learning and memory. Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory. Consolidation is an active process that is presumed to rely on the covert reactivation and reorganization of newly encoded representations. Hippocampus-dependent memories benefit primarily from slow-wave sleep (SWS), whereas memories not depending on the hippocampus show greater gains over periods containing high amounts of rapid eye movement sleep. One way sleep does this is by establishing different patterns of neurotransmitters and neurohormone secretion between sleep stages. Another central role for consolidating memories is played by the slow oscillation, that is, the oscillating field potential change dominating SWS. The emergence of slow oscillations in neocortical networks depends on the prior use of these networks for encoding of information. Via efferent pathways, they synchronize the occurrence of sharp wave ripples accompanying memory reactivations in the hippocampus with thalamocortical spindle activity. Thus, hippocampal memories are fed back into neocortical networks at a time when these networks are depolarized and, because of concurrent spindle activity, can most sensitively react to these inputs with plastic changes underlying the formation of long-term memory representations.

Animals↗

PubMed2006

Cortisol correlates with metabolic disturbances in a population study of type 2 diabetic patients.

OBJECTIVE: The prevalence of type 2 diabetes mellitus is increasing rapidly in industrialized countries, and adrenal glucocorticoids may intensify this disease. We sought to assess the relationship between diabetes-associated metabolic disturbances and cortisol concentrations in patients with type 2 diabetes. DESIGN: We investigated 190 type 2 diabetic patients who volunteered from a population study of 12,430 people in Luebeck and its suburbs. The target population comprised men and women born between 1939 and 1958 who initially received a postal questionnaire about their health status. We identified 346 subjects with confirmed diabetes mellitus and 216 patients participated in the study. Patients with type 1 diabetes were excluded. METHODS: Five salivary cortisol samples were collected before and after lunch, in the evening and then the next morning before and after standing. Clinical variables associated with diabetes were measured and correlated with cortisol concentrations. RESULTS: None of the cohort had salivary cortisol concentrations that exceeded the normally accepted range. Based on cortisol samples collected just prior to a standard lunch, the cohort was divided into tertiles. Cortisol was positively related to: fasting blood, urinary and postprandial glucose; glycosylated hemoglobin; and systolic and diastolic blood pressures (all P < 0.05). Cortisol concentrations also correlated with the relative abdominal mass (P < 0.05) when patients with marked glucosuria were excluded. CONCLUSIONS: The degree of severity of several clinical measures of type 2 diabetes correlates with cortisol concentrations. Moreover, the results provide evidence for a positive relationship between metabolic disturbances and cortisol concentrations that are within the accepted normal range.

Abdominal Fat↗

PubMed2006

Implicit learning -- explicit knowing: a role for sleep in memory system interaction.

There is evidence that sleep supports the enhancement of implicit as well as explicit memories (i.e., two memory systems that during learning normally appear to act together). Here, employing a serial reaction time task (SRTT) paradigm, we examined the question whether sleep can provide explicit knowledge on an implicitly acquired skill. At learning, young healthy subjects (n = 20) were first trained on the SRTT. Then, implicit knowledge was assessed on two test blocks, in which grammatically incorrect target positions were occasionally interspersed by the difference in reaction times between grammatically correct and incorrect target positions. To assess explicit sequence knowledge, thereafter subjects performed on a generation task in which they were explicitly instructed to predict the sequential target positions. In half the subjects, learning took place before a 9-hour retention interval filled with nocturnal sleep (sleep group), in the other half, the retention interval covered a 9-hour period of daytime wakefulness (wake group). At subsequent retesting, both testing on the generation task and the SRTT test blocks was repeated. At learning before the retention interval, subjects displayed significant implicit sequence knowledge which was comparable for the sleep and wake groups. Moreover, both groups did not display any explicit sequence knowledge as indicated by a prediction performance not differing from chance on the generation task. However, at retesting, there was a distinct gain in explicit knowledge in the subjects who had slept in the retention interval, whereas generation task performance in the wake group remained at chance level. SRTT performance in the test blocks at retesting did not indicate any further gain in skill (i.e., unchanged reaction time differences between grammatically correct and incorrect target positions) independently of whether subjects had slept or remained awake after learning. Our results indicate a selective enhancement of explicit memory formation during sleep. Because before sleep subjects only had implicit knowledge on the sequence of target transitions, these data point to an interaction between implicit and explicit memory systems during sleep-dependent off-line learning.

Adolescent↗

PubMed2005

Motor memory consolidation in sleep shapes more effective neuronal representations.

Learning a motor skill involves a latent process of consolidation that develops after training to enhance the skill in the absence of any practice and crucially depends on sleep. Here, we show that this latent consolidation during sleep changes the brain representation of the motor skill by reducing overall the neocortical contributions to the representation. Functional magnetic resonance brain imaging was performed during initial training and 48 h later, at retesting, on a sequential finger movement task with training followed by either a night of regular sleep or sleep deprivation. An additional night of sleep for all subjects served to rule out unspecific effects of sleep loss at retrieval testing. Posttraining sleep, but not sleep deprivation, led to improved motor skill performance at retrieval. This sleep-dependent improvement was linked to greatly reduced brain activation in prefrontal, premotor, and primary motor cortical areas, along with a stronger involvement of left parietal cortical regions. Our findings indicate that storing a motor skill during sleep reorganizes its brain representation toward enhanced efficacy.

Adolescent↗

PubMed2005

Overweight humans are resistant to the weight-reducing effects of melanocortin4-10.

CONTEXT: By enhancing energy expenditure and suppressing appetite, melanocortin peptides derived from proopiomelanocortin play a primary role in the hypothalamic regulation of body weight. In a recent study in normal-weight adults, the 6-wk intranasal administration of the MSH/ACTH(4-10) core fragment of proopiomelanocortin resulted in a distinct reduction of body weight and body fat, accompanied by significant decreases in leptin and insulin plasma concentrations. OBJECTIVE: The present study aimed to generalize this finding to overweight patients. DESIGN, SUBJECTS, AND INTERVENTION: MSH/ACTH(4-10) (0.5 mg) and placebo were intranasally administered once in the morning and once in the evening over a period of 12 wk in 23 overweight men (body mass index, mean +/- sem: 29.72 +/- 0.43 kg/m(2)). RESULTS: MSH/ACTH(4-10) did not induce any significant reduction in body weight, body fat, and plasma levels of insulin and leptin as compared with the effects of placebo. Melanocortin treatment was accompanied by reduced cortisol concentrations. CONCLUSIONS: We conclude that contrasting with normal-weight humans, overweight subjects are not susceptible to the effects of melanocortin administration on hypothalamic weight regulatory systems. In overweight subjects, a decreased sensitivity to ACTH/MSH peptides may derive from alterations at the level of the melanocortin receptor or at subsequent steps in the processing of the body fat signal.

Administration, Intranasal↗