Pregnancy-specific Adaptations in Leptin and Melanocortin Neuropeptides in Early Human Gestation.

INTRODUCTION: Pregnancy is characterized by increased appetitive drive beginning early in gestation, yet the central mechanisms underlying this adaptation are poorly understood in humans. To elucidate central mechanisms underlying appetite regulation in early pregnancy, we examine plasma and cerebrospinal fluid (CSF) leptin and Agouti-related peptide (AgRP) as well as CSF proopiomelanocortin (POMC) as surrogates for brain melanocortin activity. METHODS: Plasma leptin, soluble leptin receptor, AgRP, and CSF leptin, POMC, and AgRP were collected from pregnant women before cerclage placement (16.6 ±â€…1.1 weeks; N = 24), scheduled cesarean section (39.2 ±â€…0.2 weeks; N = 24), and from nonpregnant controls (N = 24), matched for age and body mass index. RESULTS: Plasma leptin was 1.5 times higher in pregnancy vs controls (P = 0.01), but CSF leptin did not differ. CSF/plasma leptin percentage was lower in early pregnancy vs controls (0.8 ±â€…0.1 vs 1.7 ±â€…0.2; P < 0.0001) and remained unchanged at term (0.9 ±â€…0.1), supporting a decrease in leptin transport into CSF in pregnancy. Plasma AgRP, a peripheral biomarker of the orexigenic hypothalamic neuropeptide, was higher in early pregnancy vs controls (95.0 ±â€…7.8 vs 67.5 ±â€…5.3; P = 0.005). In early gestation, CSF AgRP did not differ from controls, but CSF POMC was 25% lower (P = 0.006). In contrast, at term, CSF AgRP was 42% higher vs controls (P = 0.0001), but CSF POMC no longer differed. Overall, the CSF AgRP/POMC ratio was 1.5-fold higher in early pregnancy vs controls, reflecting a decrease in melanocortin tone favoring appetitive drive. CONCLUSIONS: Pregnancy-specific adaptions in the central regulation of energy balance occur early in human gestation and are consistent with decreased leptin transport into brain and resistance to the effects of leptin on target melanocortin neuropeptides.

Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3.

The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC3, MC4, and MC5 receptors. In a model of inflammatory arthritis, fenoprofen afforded potent inhibition while ibuprofen was nearly inactive. Fenoprofen presented anti-arthritic actions on cartilage integrity and synovitis, effects markedly attenuated in Mc3r-/- mice. Fenoprofen displayed pro-resolving properties promoting macrophage phagocytosis and efferocytosis, independently of cyclooxygenase inhibition. In conclusion, combining repositioning with advances in G-protein coupled receptor biology (allosterism) may lead to potential new therapeutics. In addition, MC3 PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases.

Niveles de 25-hidroxivitamina D en pacientes con melanoma y factores asociados con su insuficiencia / 25-hydroxyvitamin D in patients with melanoma and factors associated with inadequate levels

INTRODUCCIÓN Y OBJETIVOS: Los pacientes con melanoma parecen llevar al extremo las medidas de protección, lo que puede influir en los niveles de 25-hidroxivitamina D-25(OH)D-. El objetivo del estudio fue evaluar los niveles de 25(OH)D en pacientes con melanoma cutáneo e identificar factores relacionados con niveles inadecuados. MATERIAL Y MÉTODOS: Se midieron prospectivamente los niveles séricos de 25(OH)D en pacientes diagnosticados de melanoma cutáneo durante un periodo de seguimiento de un año. Se evaluaron qué factores ambientales, fenotípicos y genotípicos se relacionaban con niveles insuficientes y deficientes mediante regresión logística. RESULTADOS: De un total de 215 pacientes solo un 24,7% tenían valores normales de 25(OH)D y un 8,8% tenían valores deficientes (< 10 ng/ml). La obesidad (OR: 4,2; IC 95% OR: 1,3-13,3) y la extracción de sangre realizada en otoño/invierno (OR: 2,1; IC 95% OR: 1,1-4) se asociaron a niveles insuficientes (< 30 ng/ml). Los niveles deficitarios (< 10 ng/m) se asociaron a la obesidad (OR: 7,1; IC 95% OR: 1,1-46,9), la extracción de sangre realizada en otoño/invierno (OR: 9,0; IC 95% OR: 1,7-47,0), la ausencia de efélides (OR: 5,4; IC 95% OR: 1,2-23,4) y, marginalmente, a la presencia de tener < 2 polimorfismos no sinónimos en el receptor 1 de la melanocortina (MC1R) (OR: 5,0; IC 95% OR: 0,9-28,9). Limitaciones: No se han incluido en el análisis algunos factores, como la alimentación, relacionados con los niveles de 25(OH)D. CONCLUSIONES: Se deberían monitorizar los niveles de 25(OH)D en los pacientes con melanoma y valorar dar suplementos orales en los casos que lo precisen

INTRODUCTION AND OBJECTIVES: Patients with melanoma appear to take extreme sun-protection measures, which could influence 25-hydroxyvitamin D [25(OH)D] levels. The aim of this study was to measure 25(OH)D levels in patients with cutaneous melanoma and identify factors associated with inadequate levels. MATERIAL AND METHODS: Over a period of 1 year, we prospectively measured serum 25(OH)D in patients with cutaneous melanoma and used logistic regression analysis to identify environmental, phenotypic, and genotypic factors that were associated with insufficient and deficient levels. RESULTS: Of 215 patients analyzed, 8.8% had deficient 25(OH)D levels (< 10 ng/mL) and just 24.7% had normal levels. Insufficient levels (< 30 ng/mL) were associated with obesity (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.3-13.3) and blood sampling in autumn/winter (OR, 2.1; 95% CI, 1.1-4). Deficient levels (< 10 ng/mL) were associated with obesity (OR, 7.1; 95% CI, 1.1-46.9), blood sampling in autumn/winter (OR, 9.0; 95% CI, 1.7-47.0), absence of freckles (OR, 5.4; 95% CI, 1.2-23.4), and, with marginal significance, the presence of fewer than 2 nonsynonymous melanocortin-1 receptor (MC1R) polymorphisms (OR, 5.0; 95% CI, 0.9-28.9). Limitations: Some factors related to 25(OH)D levels, such as food, were not included in the analyses. CONCLUSIONS: 25(OH)D levels should be monitored in patients with melanoma and the need for oral supplements should be contemplated where appropriate

Obesidad monogénica humana: papel del sistema leptina-melanocortina en la regulación de la ingesta de alimentos y el peso corporal en humanos / Monogenic human obesity: role of the leptin-melanocortin system in the regulation of food intake and body weight in humans

La obesidad humana es un trastorno de origen multifactorial en el que intervienen factores tanto genéticos como ambientales. La existencia de alteraciones genéticas que dan origen a obesidades monogénicas resulta muy interesante para el estudio de los mecanismos que contribuyen a un aumento de la ingesta de energía y la acumulación de grasa en el cuerpo. La mayoría de los genes implicados en obesidad monogénica se relacionan con el sistema de la leptina-melanocortinas, de ahí la importancia de su estudio a través de mutaciones naturales en ratones. Así, se han descrito mutaciones relacionadas con obesidad humana de tipo monogénica en la leptina y su receptor, propio melanocortina y prohormona convertasa 1. El objetivo de este trabajo ha sido ofrecer una revisión actualizada acerca de las principales características y funcionamiento del sistema leptina-melanocortinas, así como de sus implicaciones y potencialidades en el proceso de regulación de la ingesta alimentaria y control del peso corporal(AU)

Human obesity is a disorder of multifactorial origin in which genetic and environmental factors are involved. To understand the mechanisms regulating energy intake and fat accumulation in the body, it is important to study the genetic alterations causing monogenic obesity. Most of the genes involved in monogenic obesity are associated with the leptin-melanocortin system; hence the importance of studying this system by analyzing natural mutations in mice. Previous studies have described mutations in leptin and its receptor, proopiomelanocortin and prohormone convertase 1 associated with human obesity of monogenic origin. The aim of this study is to provide an updated review of the main characteristics and functioning of the leptin-melanocortin system, and its implications and potentialities in regulating food intake and body weight(AU)

Proopiomelanocortin (POMC), the ACTH/melanocortin precursor, is secreted by human epidermal keratinocytes and melanocytes and stimulates melanogenesis.

Proopiomelanocortin (POMC) can be processed to ACTH and melanocortin peptides. However, processing is incomplete in some tissues, leading to POMC precursor release from cells. This study examined POMC processing in human skin and the effect of POMC on the melanocortin-1 receptor (MC-1R) and melanocyte regulation. POMC was secreted by both human epidermal keratinocytes (from 5 healthy donors) and matched epidermal melanocytes in culture. Much lower levels of alpha-MSH were secreted and only by the keratinocytes. Neither cell type released ACTH. Cell extracts contained significantly more ACTH than POMC, and alpha-MSH was detected only in keratinocytes. Nevertheless, the POMC processing components, prohormone convertases 1, 2 and regulatory protein 7B2, were detected in melanocytes and keratinocytes. In contrast, hair follicle melanocytes secreted both POMC and alpha-MSH, and this was enhanced in response to corticotrophin-releasing hormone (CRH) acting primarily through the CRH receptor 1. In cells stably transfected with the MC-1R, POMC stimulated cAMP, albeit with a lower potency than ACTH, alpha-MSH, and beta-MSH. POMC also increased melanogenesis and dendricity in human pigment cells. This release of POMC from skin cells and its functional activity at the MC-1R highlight the importance of POMC processing as a key regulatory event in the skin.