Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome.

Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, ß-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is ß-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.

Interleukin-2 improves insulin sensitivity through hypothalamic sympathetic activation in obese mice.

BACKGROUND: IL-2 regulates T cell differentiation: low-dose IL-2 induces immunoregulatory Treg differentiation, while high-dose IL-2 acts as a potent activator of cytotoxic T cells and NK cells. Therefore, high-dose IL-2 has been studied for use in cancer immunotherapy. We aimed to utilize low-dose IL-2 to treat inflammatory diseases such as obesity and insulin resistance, which involve low-grade chronic inflammation. MAIN BODY: Systemic administration of low-dose IL-2 increased Treg cells and decreased inflammation in gonadal white adipose tissue (gWAT), leading to improved insulin sensitivity in high-fat diet-fed obese mice. Additionally, central administration of IL-2 significantly enhanced insulin sensitivity through the activation of the sympathetic nervous system. The sympathetic signaling induced by central IL-2 administration not only decreased interferon γ (IFNγ) + Th1 cells and the expression of pro-inflammatory cytokines, including Il-1ß, Il-6, and Il-8, but also increased CD4 + CD25 + FoxP3 + Treg cells and Tgfß expression in the gWAT of obese mice. These phenomena were accompanied by hypothalamic microgliosis and activation of pro-opiomelanocortin neurons. Furthermore, sympathetic denervation in gWAT reversed the enhanced insulin sensitivity and immune cell polarization induced by central IL-2 administration. CONCLUSION: Overall, we demonstrated that IL-2 improves insulin sensitivity through two mechanisms: direct action on CD4 + T cells and via the neuro-immune axis triggered by hypothalamic microgliosis.

The Mechanism of Leptin Resistance in Obesity and Therapeutic Perspective.

Leptin resistance is induced via leptin signaling blockade by chronic overstimulation of the leptin receptor and intracellular signaling defect or increased hypothalamic inflammation and suppressor of cytokine signaling (SOCS)-3 expression. High-fat diet triggers leptin resistance induced by at least two independent causes: first, the limited ability of peripheral leptin to activate hypothalamic signaling transducers and activators of transcription (STAT) signaling and secondly a signaling defect in leptin-responsive hypothalamic neurons. Central leptin resistance is dependent on decreased leptin transport efficiency across the blood brain barrier (BBB) rather than hypothalamic leptin insensitivity. Since the hypothalamic phosphorylated STAT3 (pSTAT3) represents a sensitive and specific readout of leptin receptor-B signaling, the assessment of pSTAT3 levels is the gold standard. Hypertriglyceridemia is one of important factors to inhibit the transport of leptin across BBB in obesity. Mismatch between high leptin and the amount of leptin receptor expression in obesity triggers brain leptin resistance via increasing hypothalamic inflammation and SOCS-3 expression. Therapeutic strategies that regulate the passage of leptin to the brain include the development of modifications in the structure of leptin analogues as well as the synthesis of new leptin receptor agonists with increased BBB permeability. In the hyperleptinemic state, polyethylene glycol (PEG)-modified leptin is unable to pass through the BBB. Peripheral histone deacetylase (HDAC) 6 inhibitor, tubastatin, and metformin increase central leptin sensitization. While add-on therapy with anagliptin, metformin and miglitol reduce leptin concentrations, the use of long-acting leptin analogs, and exendin-4 lead to the recovery of leptin sensitivity. Contouring surgery with fat removal, and bariatric surgery independently of the type of surgery performed provide significant improvement in leptin concentrations. Although approaches to correcting leptin resistance have shown some success, no clinically effective application has been developed to date. Due to the impairment of central and peripheral leptin signaling, as well as the extensive integration of leptin-sensitive metabolic pathways with other neurons, the effectiveness of methods used to eliminate leptin resistance is extremely limited.

Transcriptomic analysis reveals the effects of maternal exposure to bisphenol AF on hypothalamic development in male neonatal mice.

Fragmented data suggest that bisphenol AF (BPAF), a chemical widely used in a variety of products, might have potential impacts on the hypothalamus. Here, we employed male neonatal mice following maternal exposure to explore the effects of low-dose BPAF on hypothalamic development by RNA-sequencing. We found that maternal exposure to approximately 50 µg/(kg·day) BPAF from postanal day (PND) 0 to PND 15 altered the hypothalamic transcriptome, primarily involving the pathways and genes associated with extracellular matrix (ECM) and intercellular adhesion, neuroendocrine regulation, and neurological processes. Further RNA analysis confirmed the changes in the expression levels of concerned genes. Importantly, we further revealed that low-dose BPAF posed a stimulatory impact on pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus and induced the browning of inguinal white adipose tissue. All findings indicate that developmental exposure to low-dose BPAF could interfere with hypothalamic development and thereby lead to alterations in the metabolism. Interestingly, 5000 µg/(kg·day) BPAF caused slighter, non-significant or even inverse alterations than the low dose of 50 µg/(kg·day), displaying a dose-independent effect. Further observations suggest that the the dose-independent effects of BPAF might be associated with oxidative stress and inflammatory responses caused by the high dose. Overall, our study highlights a risk of low-dose BPAF to human neuroendocrine regulation and metabolism.

Influence of Nutritional Status and Leptin Action on Agrp and Pomc Co-Expression in Hypothalamic Melanocortin System Neurons.

OBJECTIVES: The control of energy balance relies on the counterbalancing release of neuropeptides encoded by the pro-opiomelanocortin (Pomc) and agouti-related protein (Agrp) genes, expressed by 2 distinct neuronal populations of the arcuate (ARC) nucleus of the hypothalamus. Although largely segregated, single-cell resolution techniques demonstrate some degree of co-expression. We studied whether challenges to the control of energy balance influence the degree of Agrp and Pomc co-expression in ARC melanocortin neurons. METHODS: We used fluorescence-activated cell sorting followed by quantitative polymerase chain reaction and fluorescent in situ hybridization to measure Pomc and Agrp gene co-expression in POMC or AGRP neurons in response to (1) acute or chronic calorie restriction, or (2) obesity due to loss of leptin receptor expression or chronic high-fat diet feeding in male mice. RESULTS: Melanocortin ARC neurons of fed mice exhibited low, yet detectable, levels of Pomc and Agrp gene co-expression. Calorie restriction significantly increased and decreased total Agrp and Pomc expression, respectively, and reduced the expression of Pomc relative to Agrp in AGRP neurons. Leptin-deficient db/db mice showed increased total Agrp levels and decreased Pomc expression, as well as significantly increased Agrp expression relative to Pomc in POMC neurons. Expression or co-expression levels did not differ between diet-induced obese mice and lean controls. CONCLUSIONS: Changes in Agrp and Pomc co-expression within POMC and AGRP neurons following chronic calorie restriction or in db/db mice suggest an additional mechanism to further suppress the melanocortin signaling during conditions of severely reduced leptin action.

Two ACTH analogs exert differential effects on monocytes/macrophages function regulation in ayu (Plecoglossus altivelis).

Adrenocorticotropic hormone (ACTH), a bioactive peptide of the family of melanocortins, is generated from pro-opiomelanocortin (POMC). So far, the research on the specific functions of ACTH in the immune system of teleosts is limited. We determined two complementary DNA (cDNA) sequences of POMC in ayu (Plecoglossus altivelis), termed PaPOMC-A and PaPOMC-B. PaPOMCs transcripts occurred in all examined tissues, and their expression in immune tissues changed following experimental infection with Vibrio anguillarum. PaACTH-B, but not PaACTH-A, suppressed the phagocytosis of monocytes/macrophages (MO/MФ). Two isoforms of PaACTH increased the bactericidal capacity of MO/MФ. PaACTH-A increased anti-inflammatory cytokine expression, while PaACTH-B decreased pro-inflammatory cytokine expression in MO/MФ. Compared with PaACTH-B treatment, the PaACTH-A treatment improved survival rate and reduced the bacterial load in V. anguillarum-infected ayu through interleukin (IL)-10. Our results indicate that the two PaACTH isoforms exert different effects in the host defense against bacterial infection.

The role of pro-opiomelanocortin in the ACTH-cortisol dissociation of sepsis.

BACKGROUND: Sepsis is typically hallmarked by high plasma (free) cortisol and suppressed cortisol breakdown, while plasma adrenocorticotropic hormone (ACTH) is not increased, referred to as 'ACTH-cortisol dissociation.' We hypothesized that sepsis acutely activates the hypothalamus to generate, via corticotropin-releasing hormone (CRH) and vasopressin (AVP), ACTH-induced hypercortisolemia. Thereafter, via increased availability of free cortisol, of which breakdown is reduced, feedback inhibition at the pituitary level interferes with normal processing of pro-opiomelanocortin (POMC) into ACTH, explaining the ACTH-cortisol dissociation. We further hypothesized that, in this constellation, POMC leaches into the circulation and can contribute to adrenocortical steroidogenesis. METHODS: In two human studies of acute (ICU admission to day 7, N = 71) and prolonged (from ICU day 7 until recovery; N = 65) sepsis-induced critical illness, POMC plasma concentrations were quantified in relation to plasma ACTH and cortisol. In a mouse study of acute (1 day), subacute (3 and 5 days) and prolonged (7 days) fluid-resuscitated, antibiotic-treated sepsis (N = 123), we further documented alterations in hypothalamic CRH and AVP, plasma and pituitary POMC and its glucocorticoid-receptor-regulated processing into ACTH, as well as adrenal cortex integrity and steroidogenesis markers. RESULTS: The two human studies revealed several-fold elevated plasma concentrations of the ACTH precursor POMC from the acute to the prolonged phase of sepsis and upon recovery (all p < 0.0001), coinciding with the known ACTH-cortisol dissociation. Elevated plasma POMC and ACTH-corticosterone dissociation were confirmed in the mouse model. In mice, sepsis acutely increased hypothalamic mRNA of CRH (p = 0.04) and AVP (p = 0.03) which subsequently normalized. From 3 days onward, pituitary expression of CRH receptor and AVP receptor was increased. From acute throughout prolonged sepsis, pituitary POMC mRNA was always elevated (all p < 0.05). In contrast, markers of POMC processing into ACTH and of ACTH secretion, negatively regulated by glucocorticoid receptor ligand binding, were suppressed at all time points (all p ≤ 0.05). Distorted adrenocortical structure (p < 0.05) and lipid depletion (p < 0.05) were present, while most markers of adrenocortical steroidogenic activity were increased at all time points (all p < 0.05). CONCLUSION: Together, these findings suggest that increased circulating POMC, through CRH/AVP-driven POMC expression and impaired processing into ACTH, could represent a new piece in the puzzling ACTH-cortisol dissociation.

Orexin A Enhances Pro-Opiomelanocortin Transcription Regulated by BMP-4 in Mouse Corticotrope AtT20 Cells.

Orexin is expressed mainly in the hypothalamus and is known to activate the hypothalamic-pituitary-adrenal (HPA) axis that is involved in various stress responses and its resilience. However, the effects of orexin on the endocrine function of pituitary corticotrope cells remain unclear. In this study, we investigated the roles of orexin A in pro-opiomelanocortin (POMC) transcription using mouse corticotrope AtT20 cells, focusing on the bone morphogenetic protein (BMP) system expressed in the pituitary. Regarding the receptors for orexin, type 2 (OXR2) rather than type 1 (OX1R) receptor mRNA was predominantly expressed in AtT20 cells. It was found that orexin A treatment enhanced POMC expression, induced by corticotropin-releasing hormone (CRH) stimulation through upregulation of CRH receptor type-1 (CRHR1). Orexin A had no direct effect on the POMC transcription suppressed by BMP-4 treatment, whereas it suppressed Smad1/5/9 phosphorylation and Id-1 mRNA expression induced by BMP-4. It was further revealed that orexin A had no significant effect on the expression levels of type I and II BMP receptors but upregulated inhibitory Smad6/7 mRNA and protein levels in AtT20 cells. The results demonstrated that orexin A upregulated CRHR signaling and downregulated BMP-Smad signaling, leading to an enhancement of POMC transcription by corticotrope cells.

Adrenal function/dysfunction in critically ill patients: a concise narrative review of recent novel insights.

The "fight or flight" response to critical illness relies on increased cortisol availability, traditionally attributed to several-fold-increased cortisol production via hypothalamus-pituitary-adrenal-axis activation. Recent studies provided evidence against this concept with clinical implications. First, high cortisol availability during critical illness is driven by suppressed cortisol binding and reduced cortisol breakdown rather than increased cortisol production. This implies reduction of hydrocortisone doses when prescribed in ICU. Second, plasma ACTH is low, explained by feedback inhibition by peripherally driven high free cortisol and/or other central glucocorticoid-receptor ligands. Third, ICU patients have elevated plasma concentrations of the ACTH-precursor hormone, pro-opiomelanocortin, because of impaired pituitary processing into ACTH, and pro-opiomelanocortin could drive some adrenocortical cortisol production in face of low ACTH. Fourth, in prolonged critically ill patients, endogenously suppressed ACTH, aggravated by exogenous corticosteroids, associates with poor outcome. In long-stay ICU patients, central adrenal insufficiency may occur due to lack of trophic ACTH signaling. Finally, the Cosyntropin test is not suitable to assess adrenocortical reserve in ICU patients as the test is confounded by increased cortisol distribution volume. These insights necessitate further research focusing on the need, if any, of treating ICU patients with corticosteroids, and timing thereof, outside indications for pharmacological anti-inflammatory drugs.

C-terminal tails mimicking bioactive intermediates cause different plasma degradation patterns and kinetics in neuropeptides γ-MSH, α-MSH, and neurotensin.

Peptides are attractive drugs because of their specificity and minimal off-target effects. Short half-lives are within their major drawbacks, limiting actual use in clinics. The golden standard in therapeutic peptide development implies identification of a minimal core sequence, then modified to increase stability through several strategies, including the introduction of nonnatural amino acids, cyclization, and lipidation. Here, we investigated plasma degradations of hormone sequences all composed of a minimal active core peptide and a C-terminal extension. We first investigated pro-opimelanocortin (POMC) γ2/γ3-MSH hormone behavior and extended our analysis to POMC-derived α-melanocyte stimulating hormone/adrenocorticotropic hormone signaling neuropeptides and neurotensin. We demonstrated that in all the three cases analyzed in this study, few additional residues mimicking the natural sequence alter both peptide stability and the mechanism(s) of degradation of the minimal conserved functional pattern. Our results suggest that the impact of extensions on the bioactivity of a peptide drug has to be carefully evaluated throughout the optimization process.

Regulation of pro-opiomelanocortin (POMC) gene transcription by interleukin-31 via early growth response 1 (EGR-1) in HaCaT keratinocytes.

Pro-opiomelanocortin (POMC) is a large precursor protein of and ß-endorphin. POMC expressed in keratinocytes regulates various pathophysiological responses, such as pruritus in atopic dermatitis. Interleukin (IL)-31 is a T helper 2 (Th2)-derived cytokine that functions as a pruritogen, stimulating the sensory neurons in the skin. However, the regulatory mechanism underlying IL-31-induced POMC expression in keratinocytes remains largely unknown. Herein, using a 5'-serial deletion and site-specific mutation constructs of the regulatory region of POMC, we demonstrated that a putative EGR1-binding sequence (EBS) motif in POMC is required for its upregulation by IL-31 in HaCaT keratinocytes. Notably, EGR-1 directly interacted with the EBS motif in POMC. The ectopic expression of EGR-1 stimulated the POMC promoter activity, whereas the knockdown of EGR-1 expression by RNA interference reduced IL-31-induced POMC expression. Furthermore, we observed that three major mitogen-activated protein kinases, ERK, JNK, and p38 kinase, mediated IL-31-induced EGR-1 expression. In summary, our results suggest that EGR-1 trans-activates POMC in response to IL-31 stimulation in HaCaT keratinocytes.

Presence of aberrant adrenocorticotropic hormone precursors in two cases of McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is a rare disorder. MAS is classically defined by the occurrence of fibrous dysplasia, café-au-lait skin macules, and precocious puberty. In addition to precocious puberty, other hyperfunctioning endocrinopathies may occur. We evaluated hypothalamic-pituitary-adrenal function in two cases of typical MAS associated with fibrous dysplasia and growth hormone excess. Pituitary adenoma or hyperplasia was not detected by magnetic resonance imaging. Hormonal data showed normal or low cortisol levels, despite high ACTH levels in the blood. A high ratio of circulating ACTH to cortisol was found in the two cases. Insulin tolerance and CRH tests showed hyper-responses of ACTH and an insufficient increase in cortisol levels. No involvement of 11ß-HSD1 by GH excess was suggested because basal levels of ACTH and cortisol showed no changes, even after therapy for acromegaly by somatostatin analogues. Patients with Cushing's disease cases of pituitary macroadenoma can have high circulating ACTH precursor levels, and elevated ACTH precursors have been observed in ectopic ACTH syndrome. Autonomous cortisol excess was excluded by the level of midnight cortisol and the level of cortisol after a low-dose dexamethasone suppression test in the two cases. Finally, the gel filtration profiles of immunoreactive ACTH contents showed the presence of aberrant ACTH precursors. To the best of our knowledge, there have been no reports of MAS associated with aberrant ACTH precursors. Our findings in these cases emphasize that attention should be to secretion of inactive ACTH precursors in MAS.

Chronic treatment with tributyltin induces sexually dimorphic alterations in the hypothalamic POMC system of adult mice.

Tributyltin (TBT), an antifouling agent found in boat paints, is a common contaminant of marine and freshwater ecosystems. It is rapidly absorbed by organic materials and accumulated in many aquatic animals. Human exposure may depend on ingestion of contaminated food or by indirect exposure from household items containing organotin compounds. TBT is defined as an endocrine disruptor compound (EDC) because it binds to androgen receptors. Moreover, it is also included on the list of metabolic disruptors. The brain is a known target of TBT and this compound interferes with the orexigenic system, inducing a strong decrease in NPY expression in the hypothalamus. In the present experiment, we investigated the effect of a chronic treatment with TBT on the mouse anorexigenic system in both sexes, to look at the pro-opiomelanocortin (POMC) expression in the paraventricular (PVN), dorsomedial (DMN), ventromedial (VMN), and arcuate (ARC) hypothalamic nuclei. The results show a sexually dimorphic effect of TBT on both systems. TBT induced a significant decrease of POMC-positive structures only in female mice in DMN, ARC, and in PVN for both sexes. Apparently, these results show that TBT may interfere with the anorexigenic system in hypothalamic areas involved in the control of food intake, by inhibiting POMC in a sexually dimorphic way. In conclusion, in addition to having a direct effect on fat tissue, the effects of TBT as metabolic disruptor, may be due to gender-specific actions on both orexigenic and anorexigenic hypothalamic systems.

The Leptin, Dopamine and Serotonin Receptors in Hypothalamic POMC-Neurons of Normal and Obese Rodents.

The pro-opiomelanocortin (POMC)-expressing neurons of the hypothalamic arcuate nucleus (ARC) are involved in the control of food intake and metabolic processes. It is assumed that, in addition to leptin, the activity of these neurons is regulated by serotonin and dopamine, but only subtype 2C serotonin receptors (5-HT2CR) was identified earlier on the POMC-neurons. The aim of this work was a comparative study of the localization and number of leptin receptors (LepR), types 1 and 2 dopamine receptors (D1R, D2R), 5-HT1BR and 5-HT2CR on the POMC-neurons and the expression of the genes encoding them in the ARC of the normal and diet-induced obese (DIO) rodents and the agouti mice (A y /a) with the melanocortin obesity. As shown by immunohistochemistry (IHC), all the studied receptors were located on the POMC-immunopositive neurons, and their IHC-content was in agreement with the expression of their genes. In DIO rats the number of D1R and D2R in the POMC-neurons and their expression in the ARC were reduced. In DIO mice the number of D1R and D2R did not change, while the number of LepR and 5-HT2CR was increased, although to a small extent. In the POMC-neurons of agouti mice the number of LepR, D2R, 5-HT1BR and 5-HT2CR was increased, and the D1R number was reduced. Thus, our data demonstrates for the first time the localization of different types of the serotonin and dopamine receptors on the POMC-neurons and a specific pattern of the changes of their number and expression in the DIO and melanocortin obesity.

Anesthetic drugs modulate feeding behavior and hypothalamic expression of the POMC polypeptide precursor and the NPY neuropeptide.

BACKGROUND: Several hypnotic drugs have been previously identified as modulators of food intake, but exact mechanisms remain unknown. Feeding behavior implicates several neuronal populations in the hypothalamic arcuate nucleus including orexigenic neuropeptide Y and anorexigenic pro-opiomelanocortin producing neurons. The aim of this study was to investigate in mice the impact of different hypnotic drugs on food consumption and neuropeptide Y or pro-opiomelanocortine mRNA expression level in the hypothalamic arcuate nucleus. METHODS: Saline control, isoflurane, thiopental, midazolam or propofol were administered to C57Bl/6 mice. Feeding behavior was evaluated during 6 h. In situ hybridization of neuropeptide Y and pro-opiomelanocortine mRNAs in the hypothalamus brain region was also performed. Data were analyzed by Kruskal Wallis test and analysis of variance (p < 0.05). RESULTS: Midazolam, thiopental and propofol induced feeding behavior. Midazolam and thiopental increased neuropeptide Y mRNA level (respectively by 106 and 125%, p < 0.001) compared with control. Propofol and midazolam decreased pro-opiomelanocortine mRNA level by 31% (p < 0,01) compared with control. Isoflurane increased pro-opiomelanocortine mRNA level by 40% compared with control. CONCLUSION: In our murine model, most hypnotics induced food consumption. The hypnotic-induced regulation of neuropeptide Y and pro-opiomelanocortine hypothalamic peptides is associated with this finding. Our data suggest that administration of some hypnotic drugs may affect hypothalamic peptide precursor and neuropeptide expression and concomittantly modulate food intake. Thus, this questions the choice of anesthetics for better care management of patients undergoing major surgery or at risk of undernutrition.

Central administration of GLP-1 and GIP decreases feeding in mice.

Glucagon-like peptide-1 amide (GLP-1) and gastric inhibitory polypeptide (GIP) are incretin hormones regulating energy metabolism. GLP-1 and GIP combination is suggested as a promising therapeutic strategy for treatment of obesity and diabetes. However, the neuronal mechanisms are not yet investigated. In the present study, we investigated the role of central GLP-1 and GIP in regulation of body weight homeostasis. The effect of GLP-1 with GIP on food intake, body weight, locomotor activity were determined following intracerebroventricular (ICV) administration of GLP-1 and/or GIP in mice. ICV administration of low dose GLP-1 (0.3 nmol) and GIP (1 and 3 nmol) did not change food intake. However, ICV administration of higher doses GLP-1 (1 and 3 nmol) and GIP (6 nmol) significantly decreased food intake and body weight. To investigate the synergic effect of ICV GLP-1 and GIP, subeffective dose GLP-1 (0.3 nmol) and subeffective dose GIP (1 nmol) were chosen for further co-administration study. ICV co-administration of GLP-1 and GIP significantly decreased food intake, body weight and drinking. ICV co-administration of GLP-1 and GIP significantly increased neuronal activation and pro-opiomelanocortin (POMC) expression in hypothalamic arcuate nucleus. The neuronal activation and POMC expression were observed in two distinct neuronal populations. These results provide neuronal mechanisms supporting the development of GLP-1 and GIP combination therapeutics for treatment of obesity and diabetes.

Role of the brain melanocortins in blood pressure regulation.

Melanocortins play an important role in regulating blood pressure (BP) and sympathetic nervous system (SNS) activity as well as energy balance, glucose and other metabolic functions in humans and experimental animals. In experimental models of hypertension with high SNS activity, blockade of the melanocortin-4 receptor (MC4R) reduces BP despite causing marked hyperphagia and obesity. Activation of the central nervous system (CNS) pro-opiomelanocortin (POMC)-MC4R pathway appears to be an important link between obesity, SNS activation and hypertension. Despite having severe obesity, subjects with MC4R deficiency exhibit reductions in BP, heart rate, and urinary catecholamine excretion, as well as attenuated SNS responses to cold stimuli compared to obese subjects with normal MC4R function. In this review we discuss the importance of the brain POMC-MC4R system in regulating SNS activity and BP in obesity and other forms of hypertension. We also highlight potential mechanisms and brain circuitry by which the melanocortin system regulates cardiovascular function.

Melatonin Receptor 1 Deficiency Affects Feeding Dynamics and Pro-Opiomelanocortin Expression in the Arcuate Nucleus and Pituitary of Mice.

BACKGROUND/METHODS: Melatonin, the neurohormone for darkness, mediates photoperiod-dependent changes in physiology and behavior by targeting specific membrane-bound receptors (MT1 and MT2). In the present study, we investigated the impact of MT1 receptor deficiency on feeding behavior, locomotor activity and mRNA expression levels encoding for the polypeptide pro-opiomelanocortin (Pomc) and neuropeptide Y (Npy) in the hypothalamic arcuate nucleus (ARC) and the adenohypophysis [pars distalis (PD) and pars intermedia (PI)] in a comparison between wild-type (WT) and MT1-deficient (MT1-/-) mice. RESULTS: The MT1-/- mice spent significantly more time feeding than the WT mice, while the general locomotor behavior, body weight and the total amount of food consumed did not differ between both genotypes. The nocturnal expression levels of Pomc in the ARC and PD were significantly higher in WT as compared to MT1-/- mice and exogenous melatonin administered during the light phase stimulated Pomc expression in WT mice only. No differences were found between WT and MT1-/- mice with regard to Pomc expression levels in the PI. CONCLUSION: Thus, the MT1-mediated signaling stimulates Pomc expression in a region-specific pattern. Since the MT1-mediated changes in Pomc expression do not elicit direct orexigenic or anorexigenic effects, such effects are obviously mediated by regulatory systems downstream of the Pomc mRNA (e.g. cleavage and release of POMC derivatives), which are independent of MT1 signaling.

Genetics of fat intake in the determination of body mass.

Body mass and fat intake are multifactorial traits that have genetic and environmental components. The gene with the greatest effect on body mass is FTO (fat mass and obesity-associated), but several studies have shown that the effect of FTO (and of other genes) on body mass can be modified by the intake of nutrients. The so-called gene-environment interactions may also be important for the effectiveness of weight-loss strategies. Food choices, and thus fat intake, depend to some extent on individual preferences. The most important biological component of food preference is taste, and the role of fat sensitivity in fat intake has recently been pointed out. Relatively few studies have analysed the genetic components of fat intake or fatty acid sensitivity in terms of their relation to obesity. It has been proposed that decreased oral fatty acid sensitivity leads to increased fat intake and thus increased body mass. One of the genes that affect fatty acid sensitivity is CD36 (cluster of differentiation 36). However, little is known so far about the genetic component of fat sensing. We performed a literature review to identify the state of knowledge regarding the genetics of fat intake and its relation to body-mass determination, and to identify the priorities for further investigations.

Diet-Induced Obesity and the Mechanism of Leptin Resistance.

Leptin signaling blockade by chronic overstimulation of the leptin receptor or hypothalamic pro-inflammatory responses due to elevated levels of saturated fatty acid can induce leptin resistance by activating negative feedback pathways. Although, long form leptin receptor (Ob-Rb) initiates leptin signaling through more than seven different signal transduction pathways, excessive suppressor of cytokine signaling-3 (SOCS-3) activity is a potential mechanism for the leptin resistance that characterizes human obesity. Because the leptin-responsive metabolic pathways broadly integrate with other neurons to control energy balance, the methods used to counteract the leptin resistance has extremely limited effect. In this chapter, besides the impairment of central and peripheral leptin signaling pathways, limited access of leptin to central nervous system (CNS) through blood-brain barrier, mismatch between high leptin and the amount of leptin receptor expression, contradictory effects of cellular and circulating molecules on leptin signaling, the connection between leptin signaling and endoplasmic reticulum (ER) stress and self-regulation of leptin signaling has been discussed in terms of leptin resistance.