The Expression Pattern of Genes Related to Melanogenesis and Endogenous Opioids in Psoriasis

The melanocortin system is a major regulator of stress responses in the skin and is responsible for the induction of melanin synthesis through activation of melanogenesis enzymes. The expression of both melanocortin system genes and melanogenesis enzyme genes is altered in psoriasis, and the focus here was on twelve genes related to the signal transduction between them. Additionally, five endogenous opioid system genes that are involved in cutaneous inflammation were examined. Quantitative real-time-PCR was utilized to measure mRNA expression in punch biopsies from lesional and non-lesional skin of psoriasis patients and from the skin of healthy control subjects. Most of the genes related to melanogenesis were down-regulated in patients (CREB1, MITF, LEF1, USF1, MAPK14, ICAM1, PIK3CB, RPS6KB1, KIT, and ATRN). Conversely, an up-regulation occurred in the case of opioids (PENK, PDYN, and PNOC). The suppression of genes related to melanogenesis is in agreement with the reported reduction in pigmentation signaling in psoriatic skin and potentially results from the pro-inflammatory environment. The increase in endogenous opioids can be associated with their involvement in inflammatory dysregulation in psoriasis.

The Role of Melanocortin Plasticity in Pain-Related Outcomes After Alcohol Exposure

The global COVID-19 pandemic has shone a light on the rates and dangers of alcohol misuse in adults and adolescents in the US and globally. Alcohol exposure during adolescence causes persistent molecular, cellular, and behavioral changes that increase the risk of alcohol use disorder (AUD) into adulthood. It is established that alcohol abuse in adulthood increases the likelihood of pain hypersensitivity and the genesis of chronic pain, and humans report drinking alcohol to relieve pain symptoms. However, the longitudinal effects of alcohol exposure on pain and the underlying CNS signaling that mediates it are understudied. Specific brain regions mediate pain effects, alcohol effects, and pain-alcohol interactions, and neural signaling in those brain regions is modulated by neuropeptides. The CNS melanocortin system is sensitive to alcohol and modulates pain sensitivity, but this system is understudied in the context of pain-alcohol interactions. In this review, we focus on the role of melanocortin signaling in brain regions sensitive to alcohol and pain, in particular the amygdala. We also discuss interactions of melanocortins with other peptide systems, including the opioid system, as potential mediators of pain-alcohol interactions. Therapeutic strategies that target the melanocortin system may mitigate the negative consequences of alcohol misuse during adolescence and/or adulthood, including effects on pain-related outcomes.

Pharmacological modulation of the cAMP signaling of two isoforms of melanocortin-3 receptor by melanocortin receptor accessory proteins in the tetrapod Xenopus laevis

As a member of the seven-transmembrane rhodopsin-like G protein-coupled receptor superfamily, the melanocortin-3 receptor is vital for the regulation of energy homeostasis and rhythms synchronizing in mammals and its pharmacological effect could be directly influenced by the presence of melanocortin accessory proteins, MRAP1 and MRAP2. The tetrapod amphibian Xenopus laevis (xl) retains higher duplicated genome than extant teleosts and serves as an ideal model system for embryonic development and physiological studies. However, the melanocortin system of the Xenopus laevis has not been thoroughly evaluated yet. In this work, we performed sequence alignment, phylogenetic and synteny analysis of two xlMC3Rs. Co-immunoprecipitation and immunofluorescence assay further confirmed the co-localization and in vitro interaction of xlMC3Rs with xlMRAPs on the plasma membrane. Our results demonstrated that xlMRAP2.L/S could improve α-MSH stimulated xlMC3Rs signaling and suppress their surface expression. Moreover, xlMC3R.L showed a similar profile on the ligands and surface expression in the presence of xlMRAP1.L. Overall, the distinct pharmacological modulation of xlMC3R.L and xlMC3R.S by dual MRAP2 proteins elucidated the functional consistency of melanocortin system during genomic duplication of tetrapod vertebrates.

Pharmacotherapy for Weight Reduction: Bupropion/Naltrexone Drugs for Obesity

Background: There is no valid and accurate documentation on the combination therapy of bupropion along with naltrexone. The experimentations on these actions of combination drugs have resulted in rare success. Methods: A complex interaction occurs in the central and peripheral nervous system for reducing weight loss. It is difficult to find out the major mechanism of action of these drugs on weight reduction. Naltrexone and bupropion is the experimental combination for reducing the weight. For obesity, the combination of naltrexone/bupropion therapy’s mechanism working is still unknown. Results: The attempts for weight loss rarely have a long-term effect. It is an outcome of more likely some complex interaction between various peripheral and Central Nervous systems, and an overwhelming lack of real obesity treatment may be explained. Based on the evidence that obesity involves a change in the hypothalamic melanocortin system in addition to a brain reward system, which causes food craving and mood swings, this investigational combination therapy of NB was developed. Naltrexone and bupropion work in an interesting way. Conclusion: It affects the parts of the brain that influences food craving, food intake, eating behaviors, and loss of body weight. We will have a review on the working of naltrexone, and bupropion separately, and Vivo, current in vitro, and clinical evidence will be provided, describing how NB affects food intake and food craving. Keywords: CNS, obesity, medicine, weight lose, NB, therapy.

Role of the Melanocortin System in the Central Regulation of Cardiovascular Functions

Increasing evidence indicates that the melanocortin system is not only a central player in energy homeostasis, food intake and glucose level regulation, but also in the modulation of cardiovascular functions, such as blood pressure and heart rate. The melanocortins, and in particular α- and γ-MSH, have been shown to exert their cardiovascular activity both at the central nervous system level and in the periphery (e.g., in the adrenal gland), binding their receptors MC3R and MC4R and influencing the activity of the sympathetic nervous system. In addition, some studies have shown that the activation of MC3R and MC4R by their endogenous ligands is able to improve the outcome of cardiovascular diseases, such as myocardial and cerebral ischemia. In this brief review, we will discuss the current knowledge of how the melanocortin system influences essential cardiovascular functions, such as blood pressure and heart rate, and its protective role in ischemic events, with a particular focus on the central regulation of such mechanisms.

Depletion of Alpha-Melanocyte-Stimulating Hormone Induces Insatiable Appetite and Gains in Energy Reserves and Body Weight in Zebrafish

The functions of anorexigenic neurons secreting proopiomelanocortin (POMC)/alpha-melanocyte-stimulating hormone (α-MSH) of the melanocortin system in the hypothalamus in vertebrates are energy homeostasis, food intake, and body weight regulation. However, the mechanisms remain elusive. This article reports on zebrafish that have been genetically engineered to produce α-MSH mutants, α-MSH−7aa and α-MSH−8aa, selectively lacking 7 and 8 amino acids within the α-MSH region, but retaining most of the other normal melanocortin-signaling (Pomc-derived) peptides. The α-MSH mutants exhibited hyperphagic phenotypes leading to body weight gain, as observed in human patients and mammalian models. The actions of several genes regulating appetite in zebrafish are similar to those in mammals when analyzed using gene expression analysis. These include four selected orexigenic genes: Promelanin-concentrating hormone (pmch), agouti-related protein 2 (agrp2), neuropeptide Y (npy), and hypothalamic hypocretin/orexin (hcrt). We also study five selected anorexigenic genes: Brain-derived neurotrophic factor (bdnf), single-minded homolog 1-a (sim1a), corticotropin-releasing hormone b (crhb), thyrotropin-releasing hormone (trh), and prohormone convertase 2 (pcsk2). The orexigenic actions of α-MSH mutants are rescued completely after hindbrain ventricle injection with a synthetic analog of α-MSH and a melanocortin receptor agonist, Melanotan II. We evaluate the adverse effects of MSH depletion on energy balance using the Alamar Blue metabolic rate assay. Our results show that α-MSH is a key regulator of POMC signaling in appetite regulation and energy expenditure, suggesting that it might be a potential therapeutic target for treating human obesity.

Cardiac phenotype and tissue sodium content in adolescents with defects in the melanocortin system

CONTEXT Pro-opiomelanocortin (POMC) and the melanocortin-4 receptor (MC4R) play a pivotal role in the leptin-melanocortin pathway. Mutations in these genes lead to monogenic types of obesity due to severe hyperphagia. In addition to dietary-induced obesity, a cardiac phenotype without hypertrophy has been identified in MC4R knockout mice. OBJECTIVE We aimed to characterize cardiac morphology and function as well as tissue Na + content in humans with mutations in POMC and MC4R genes. PARTICIPANTS A cohort of 42 patients (5 patients with bi-allelic POMC mutations, 6 heterozygous MC4R mutation carriers, 19 obese controls without known monogenic cause and 12 normal-weight controls) underwent cardiac magnetic resonance (CMR) imaging and 23Na-MRI. RESULTS Monogenic obese patients with POMC or MC4R mutation respectively had a significantly lower left ventricular mass/body surface area (BSA) compared to non-monogenic obese patients. Left ventricular end-diastolic volume/BSA was significantly lower in POMC- and MC4R-deficient patients than in non-monogenic obese patients. Subcutaneous fat and skin Na + content was significantly higher in POMC- and MC4R-deficient patients compared to non-monogenic obese patients. In these compartments, the water content was significantly higher in patients with POMC and MC4R mutation than in control-groups. CONCLUSIONS Patients with POMC or MC4R mutations carriers had a lack of transition to hypertrophy, significantly lower cardiac muscle mass/BSA and stored more Na + within the subcutaneous fat tissue compared to non-monogenic obese patients. The results point towards the role of the melanocortin pathway for cardiac function, tissue Na + storage and the importance of including cardiologic assessments into the diagnostic work-up of these patients.

Sirtuin 1 Regulates Synapsin 1 in POMC-Producing N43-5 Neurons via FOXO1

The nutrient-sensor protein Sirtuin 1 (Sirt1; silent mating type information regulation 2 homolog 1) has been shown to have significant and opposing effects on insulin resistance, leptin resistance, and body weight in the periphery and the brain. In the hypothalamic arcuate nucleus (ARC) of the brain, Sirt1 increases in the obese state and acts to promote weight gain as well as insulin and leptin resistance by increasing the orexigenic neuropeptides Agouti-related protein (AgRP) and neuropeptide Y (NPY), and in a distinct set of ARC neurons, by decreasing POMC and thus its anorexigenic derivative alpha-melanocyte stimulating hormone (alpha-MSH) (1). Sirt1’s actions on these neuropeptides are mediated at least in part by the deacetylation of the transcription factor forkhead box O1 (FOXO1). Another mechanism by which Sirt1 regulates body weight appears to be through mediating changes in the synapses of these neuropeptide-producing ARC neurons. For example, a previous study demonstrated that Sirt1 inhibition with the specific Sirt1 inhibitor, Ex-527, decreased AgRP-NPY inhibitory synaptic input on POMC neurons, which suggests that the obesity-induced increase in ARC Sirt1 would increase AgRP-NPY inhibition of POMC neurons thus promoting weight gain (2). The present study investigated how Sirt1 regulates synapses specifically in POMC-producing N43-5 neurons. Results reveal that inhibition of Sirt1 with Ex-527 significantly increased the presynaptic marker Synapsin 1 (Syn1) in N43-5 neurons. Furthermore, we investigated whether the Sirt1 target, FOXO1, mediates these synaptic changes. FOXO1 overexpression significantly decreased Syn1 and transfection of mutant FOXO1 significantly increased Syn1. Overall, our results suggest that Sirt1 regulates synapses of POMC neurons and does so in a manner that differs from Sirt1’s regulation of AgRP-NPY neuronal synapses. Future work will elucidate the mechanisms and consequences of Sirt1 and FOXO1 regulation of POMC neuron synapses under different nutritional conditions in vitro and in vivo. (1) Cyr, N. E., Steger, J. S., Toorie, A. M., Yang, J. Z., Stuart, R., Nillni, E. A. (2014). Central Sirt1 Regulates Body Weight and Energy Expenditure Along With the POMC-Derived Peptide α-MSH and the Processing Enzyme CPE Production in Diet-Induced Obese Male Rats, Endocrinology, 155(7), 2423–2435. (2) Dietrich, M. O., Antunes, C., Geliang, G., Liu, Z., Borok, E., Nie, Y., . . . Horvath, T. L. (2010). Agrp neurons mediate Sirt1’s action on the melanocortin system and energy balance: Roles for Sirt1 in neuronal firing and synaptic plasticity. The Journal of Neuroscience, 30(35), 11815–11825.

Renal GLUT2 is Essential in Regulating Systemic Glucose Homeostasis by Glycosuria

Diabetes increases renal GLUT2 levels and consequently, worsens hyperglycemia by enhancing glucose reabsorption. We recently demonstrated that renal GLUT2 is a primary effector of the central melanocortin system in regulating glucose homeostasis. Therefore, we hypothesized that renal GLUT2 is essential for maintaining systemic glucose homeostasis by regulating glycosuria. To test the hypothesis, we generated kidney-specific inducible Glut2 knockout (KO) mice [Glut2LoxP/LoxP x KspCadCreERT2 (inducible by tamoxifen)]. These mice exhibited 90% reduction in Glut2 expression selectively in the kidneys, without affecting the expressions of other renal glucose transporters, such as Glut1, Sglt1, and Sglt2. To evaluate the physiological contribution of renal GLUT2 in systemic glucose homeostasis, we performed oral glucose tolerance tests (OGTT) in kidney-specific Glut2 KO mice and their control littermates (Ctrl). We observed that the kidney-specific GLUT2 deficient mice exhibited improved glucose tolerance compared to their Ctrls (AUC for OGTT, 41,950 ±2,014 vs. 52,165 ±1,686 mg/dL.min). To measure glycosuria in the kidney-specific Glut2 KO mice, we placed the mice in metabolic cages and collected 24h urine after acclimating the mice in the new cages. Indeed, the GLUT2 deficient mice had ~1,800-fold increase in urine glucose levels (53.5 ±11 vs. 0.03 ±0.005 mg/24h) and exhibited an increased urine volume (2.5 ±0.3 vs. 0.9 ±0.3 mL/24h) and water intake (7.6 ±0.7 vs. 4.9 ±0.7 mL/24h) compared to their Ctrl littermates. The improvement in glucose tolerance in the kidney-specific Glut2 KO mice was independent of the insulin signaling because we did not observe any changes in insulin tolerance tests (ITT) (AUC for ITT, 10,982 ±414 vs. 11,275 ±583 mg/dL.min) and serum insulin levels (1.07 ±0.14 vs. 1.05 ±0.13 ng/mL) between the groups. Importantly, the kidney-specific GLUT2 deficient mice had normal serum creatinine (0.42 ±0.02 vs. 0.41 ±0.03 mg/dL), free fatty acid (0.43 ±0.14 vs. 0.53±0.14 nmol/µL), β-hydroxybutyrate (0.29 ±0.01 vs. 0.27 ±0.02 mM) and glucagon (14 ±4 vs. 10 ±1 pg/mL) levels. Moreover, the kidney-specific Glut2 KO mice had normal glomerular area (4,190 ±119 vs. 4,219 ±186 µm2) as measured by kidney histology and normal glomerular filtration rate (153 ±9 vs. 173 ±10 [µL/min/b.w.]/100) compared with their Ctrl littermates, indicating the absence of any known renal injury. Altogether, we have developed a new mouse model in which we can knockout Glut2 selectively in the kidneys in adult mice. We show that loss-of-function of kidney-specific GLUT2 improves glucose tolerance due to elevated glycosuria without producing any known side effects. In conclusion, blocking kidney-specific GLUT2 has the potential to treat diabetes.