Trade-offs, Pleiotropy, and Shared Molecular Pathways: A Unified View of Constraints on Adaptation.

The concept of trade-offs permeates our thinking about adaptive evolution because they are exhibited at every level of biological organization, from molecular and cellular processes to organismal and ecological functions. Trade-offs inevitably arise because different traits do not occur in isolation, but instead are imbedded within complex, integrated systems that make up whole organisms. The genetic and mechanistic underpinning of trade-offs can be found in the pleiotropic nodes that occur in the biological pathways shared between traits. Yet, often trade-offs are only understood as statistical correlations, limiting the ability to evaluate the interplay between how selection and constraint interact during adaptive evolution. Here, we first review the classic paradigms in which physiologists and evolutionary biologists have studied trade-offs and highlight the ways in which network and molecular pathway approaches unify these paradigms. We discuss how these approaches allow researchers to evaluate why trade-offs arise and how selection can act to overcome trait correlations and evolutionary constraints. We argue that understanding how the conserved molecular pathways are shared between different traits and functions provides a conceptual framework for evolutionary biologists, physiologists, and molecular biologists to meaningfully work together toward the goal of understanding why correlations and trade-offs occur between traits. We briefly highlight the melanocortin system and the hormonal control of osmoregulation as two case studies where an understanding of shared molecular pathways reveals why trade-offs occur between seemingly unrelated traits. While we recognize that applying such approaches poses challenges and limitations particularly in the context of natural populations, we advocate for the view that focusing on the biological pathways responsible for trade-offs provides a unified conceptual context accessible to a broad range of integrative biologists.

The melanocortin system as a potential target for treating alcohol use disorders: A review of pre-clinical data.

The melanocortin (MC) system consists of neuropeptides that are cleaved from the polypeptide precursor proopiomelanocortin (POMC). In the brain, MC neuropeptides signal primarily through the MC-3 and MC-4 receptors, which are widely expressed throughout the brain. While the MC system has been largely studied for its role in food intake and body weight regulation, converging evidence has emerged over approximately the last 20-years showing that alcohol (ethanol), and other drugs of abuse influence the central MC system, and that manipulating MC receptor signalling modulates ethanol intake. Although there is divergent evidence, the wealth of data appears to suggest that activating MC signalling, primarily through the MC-4 receptor, is protective against excessive ethanol consumption. In the present review, we first describe the MC system and then detail how ethanol exposure and consumption alters central MC and MC-receptor expression and levels. This is followed by a review of the data, from pharmacological and genetic studies, which show that manipulations of MC receptor activity alter ethanol intake. We then briefly highlight studies implicating a role for the MC system in modulating neurobiological responses and intake of other drugs of abuse, including amphetamine, cocaine and opioids. Finally, we introduce relatively new observations that the drug, bupropion (BUP), a drug that activates central MC activity, significantly reduces ethanol intake in rodent models when administered alone and in combination with the non-selective opioid receptor antagonist, naltrexone. Phase II clinical trials are currently underway to assess the efficacy of BUP as a treatment for alcohol use disorders.

Melanocortin overexpression limits diet-induced inflammation and atherosclerosis in LDLR-/- mice.

Atherosclerosis is a chronic inflammatory disease of the arteries. The disease is initiated by endothelial dysfunction that allows the transport of leukocytes and low-density lipoprotein into the vessel wall forming atherosclerotic plaques. The melanocortin system is an endogenous peptide system that regulates, for example, energy homeostasis and cardiovascular function. Melanocortin treatment with endogenous or synthetic melanocortin peptides reduces body weight, protects the endothelium and alleviates vascular inflammation, but the long-term effects of melanocortin system activation on atheroprogression remain largely unknown. In this study, we evaluated the effects of transgenic melanocortin overexpression in a mouse model of atherosclerosis. Low-density lipoprotein receptor-deficient mice overexpressing alpha- and gamma3-MSH (MSH-OE) and their wild-type littermates were fed either a regular chow or Western-style diet for 16 weeks. During this time, their metabolic parameters were monitored. The aortae were collected for functional analysis, and the plaques in the aortic root and arch were characterised by histological and immunohistochemical stainings. The aortic expression of inflammatory mediators was determined by quantitative PCR. We found that transgenic MSH-OE improved glucose tolerance and limited atherosclerotic plaque formation particularly in Western diet-fed mice. In terms of aortic vasoreactivity, MSH-OE blunted alpha1-adrenoceptor-mediated vasoconstriction and enhanced relaxation response to acetylcholine, indicating improved endothelial function. In addition, MSH-OE markedly attenuated Western diet-induced upregulation of proinflammatory cytokines (Ccl2, Ccl5 and Il6) that contribute to the pathogenesis of atherosclerosis. These results show that the activation of the melanocortin system improves glucose homeostasis and limits diet-induced vascular inflammation and atherosclerotic plaque formation.

Genetic and Syndromic Causes of Obesity and its Management.

The aim of this article is to provide an in depth review of the rare genetic and syndromic forms of childhood obesity. The authors demonstrate the complexity and inter-relationships of the leptin-melanocortin signaling pathway and its central nervous system and systemic effects. Authors highlight the clinical distinctive features of genetic/syndromic causes for childhood obesity, in particular, relative shorter height to their genetic potential, developmental challenges and in some instances, ophthalmological and retina changes. They outline specific genetic testing and treatment options available for these conditions.

The melanocortin signaling cAMP axis accelerates repair and reduces mutagenesis of platinum-induced DNA damage.

Using primary melanocytes and HEK293 cells, we found that cAMP signaling accelerates repair of bi- and mono-functional platinum-induced DNA damage. Elevating cAMP signaling either by the agonistic MC1R ligand melanocyte stimulating hormone (MSH) or by pharmacologic cAMP induction by forskolin enhanced clearance of intrastrand cisplatin-adducts in melanocytes or MC1R-transfected HEK293 cells. MC1R antagonists human beta-defensin 3 and agouti signaling protein blocked MSH- but not forskolin-mediated enhancement of platinum-induced DNA damage. cAMP-enhanced repair of cisplatin-induced DNA damage was dependent on PKA-mediated phosphorylation of ATR on S435 which promoted ATR's interaction with the key NER factor xeroderma pigmentosum A (XPA) and facilitated recruitment of an XPA-ATR-pS435 complex to sites of cisplatin DNA damage. Moreover, we developed an oligonucleotide retrieval immunoprecipitation (ORiP) assay using a novel platinated-DNA substrate to establish kinetics of ATR-pS435 and XPA's associations with cisplatin-damaged DNA. Expression of a non-phosphorylatable ATR-S435A construct or deletion of A kinase-anchoring protein 12 (AKAP12) impeded platinum adduct clearance and prevented cAMP-mediated enhancement of ATR and XPA's associations with cisplatin-damaged DNA, indicating that ATR phosphorylation at S435 is necessary for cAMP-enhanced repair of platinum-induced damage and protection against cisplatin-induced mutagenesis. These data implicate cAMP signaling as a critical regulator of genomic stability against platinum-induced mutagenesis.

Fish pigmentation and the melanocortin system.

The melanocortin system is a complex neuroendocrine signaling mechanism involved in numerous physiological processes in vertebrates, including pigmentation, steroidogenesis and metabolic control. This review focuses at one of its most fascinating function in fish, its regulatory role in the control of pigmentation, in which the melanocortin 1 receptor (Mc1r), its agonist α-melanocyte stimulating hormone (α-Msh), and the endogenous antagonist agouti signaling protein (Asip1) are the main players. Functional control of Mc1r, which is highly expressed in fish skin and whose activation stimulates melanin production and melanosome dispersion in fish melanophores, is considered a key mechanism for vertebrate pigment phenotypes. The α-Msh peptide, the most documented Mc1r agonist involved in pigmentation, is produced in the pituitary gland, activating melanin synthesis by binding to Mc1r in fish melanophores. Finally, Asip1 is the putative factor for establishing the evolutionarily conserved dorso-ventral pigment pattern found across vertebrates. However, we are just starting to understand how other melanocortin system components are acting in this complex regulatory network.

The melanocortin system regulates body pigmentation and social behaviour in a colour polymorphic cichlid fish.

The melanocortin system is a neuroendocrine system that regulates a range of physiological and behavioural processes. We examined the extent to which the melanocortin system simultaneously regulates colour and behaviour in the cichlid fish Astatotilapia burtoni We found that yellow males are more aggressive than blue males, in line with previous studies. We then found that exogenous α-melanocyte-stimulating hormone (α-MSH) increases yellowness of the body and dispersal of xanthophore pigments in both morphs. However, α-MSH had a morph-specific effect on aggression, with only blue males showing an increase in the rate of aggression. Exogenous agouti signalling peptide (ASIP), a melanocortin antagonist, did not affect coloration but reduced the rate of aggression in both colour morphs. Blue males had higher cortisol levels than yellow males. Neural gene expression of melanocortin receptors (mcr) and ligands was not differentially regulated between colour morphs. In the skin, however, mc1r and pro-opiomelanocortin (pomc) ß were upregulated in blue males, while asip 1 was upregulated in yellow males. The effects of α-MSH on behaviour and body coloration, combined with morph-specific regulation of the stress response and the melanocortin system, suggest that the melanocortin system contributes to the polymorphism in behaviour and coloration in A. burtoni.

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances.

Obesity is increasing in prevalence across all sectors of society, and with it a constellation of associated ailments including hypertension, type 2 diabetes, and eating disorders. The melanocortin system is a critical neural system underlying the control of body weight and other functions. Deficits in the melanocortin system may promote or exacerbate the comorbidities of obesity. This system has therefore generated great interest as a potential target for treatment of obesity. However, drugs targeting melanocortin receptors are plagued by problematic side effects, including undesirable increases in sympathetic nervous system activity, heart rate, and blood pressure. Circumnavigating this roadblock will require a clearer picture of the precise neural circuits that mediate the functions of melanocortins. Recent, novel experimental approaches have significantly advanced our understanding of these pathways. We here review the latest advances in our understanding of the role of melanocortins in food intake, reward pathways, blood pressure, glucose control, and energy expenditure. The evidence suggests that downstream melanocortin-responsive circuits responsible for different physiological actions do diverge. Ultimately, a more complete understanding of melanocortin pathways and their myriad roles should allow treatments tailored to the mix of metabolic disorders in the individual patient.

Innate Obesity, Revealed by Selection Markers, Confers Significant Imprint of Hypothalamic Genes Controlling Energy Expenditure.

The incidence of obesity is rapidly escalating and has reached epidemic proportions. In all species, including rodents, humans, and sheep, there is large variation in the degree of weight gain across individuals in response to an obesogenic environment. This individual variation is, at least in part, determined by innate differences in energy expenditure, of which adaptive thermogenesis is a key component. The hypothalamus is essential to the control of body weight and adiposity. Appetite-regulating peptides within the hypothalamus exert reciprocal effects on food intake and energy expenditure, such that neuropeptides that stimulate food intake inhibit thermogenesis and vice versa. This review discusses the role of the hypothalamic neuropeptides in determining innate predisposition to obesity in 3 animal models being obesity-prone and obesity-resistant rodents, genetically lean and obese sheep, and animals selected for high/low cortisol responsiveness. In rodents, leptin resistance is a primary feature of the propensity to become obese. This contrasts that of larger mammals, such as sheep, where altered susceptibility to obesity manifests within the melanocortin and/or orexin pathways. This review highlights fundamental species differences within the hypothalamus that lead to altered susceptibility to weight gain and increased propensity to become obese.

The sympathetic nervous system alterations in human hypertension.

Several articles have dealt with the importance and mechanisms of the sympathetic nervous system alterations in experimental animal models of hypertension. This review addresses the role of the sympathetic nervous system in the pathophysiology and therapy of human hypertension. We first discuss the strengths and limitations of various techniques for assessing the sympathetic nervous system in humans, with a focus on heart rate, plasma norepinephrine, microneurographic recording of sympathetic nerve traffic, and measurements of radiolabeled norepinephrine spillover. We then examine the evidence supporting the importance of neuroadrenergic factors as promoters and amplifiers of human hypertension. We expand on the role of the sympathetic nervous system in 2 increasingly common forms of secondary hypertension, namely hypertension associated with obesity and with renal disease. With this background, we examine interventions of sympathetic deactivation as a mode of antihypertensive treatment. Particular emphasis is given to the background and results of recent therapeutic approaches based on carotid baroreceptor stimulation and radiofrequency ablation of the renal nerves.

Network of hypothalamic neurons that control appetite.

The central nervous system (CNS) controls food intake and energy expenditure via tight coordinations between multiple neuronal populations. Specifically, two distinct neuronal populations exist in the arcuate nucleus of hypothalamus (ARH): the anorexigenic (appetite-suppressing) pro-opiomelanocortin (POMC) neurons and the orexigenic (appetite-increasing) neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. The coordinated regulation of neuronal circuit involving these neurons is essential in properly maintaining energy balance, and any disturbance therein may result in hyperphagia/obesity or hypophagia/starvation. Thus, adequate knowledge of the POMC and NPY/AgRP neuron physiology is mandatory to understand the pathophysiology of obesity and related metabolic diseases. This review will discuss the history and recent updates on the POMC and NPY/AgRP neuronal circuits, as well as the general anorexigenic and orexigenic circuits in the CNS.

[FUNCTIONAL ACTIVITY OF THE BRAIN INSULIN SIGNALING SYS TEM IN NORM AND IN TYPE 2 DIABETES MELLITUS].

The insulin signaling system of the brain has a key role in the regulation of fundamental cell processes in neurons and controls metabolic processes in the CNS and periphery. In hypothalamic neurons insulin signaling system interacts closely with the other signaling systems regulated by leptin, melanocortin peptides, dopamine, serotonin, and is the key component of the hypothalamic signaling network, which integrates and transforms the central and peripheral signals. The disturbances in the brain insulin system lead to central insulin resistance, which is one of the primary causes of type 2 diabetes mellitus (DM), metabolic syndrome and Alzheimer's disease. The early restoration of the functions of this system provides an effective approach to prevent and treat type 2 DM and neurodegenerative diseases associated to it. In this review the literature data and own results on structural functional organization of the brain insulin signaling system, causes and functional consequences of central insulin resistance, abnormalities of insulin signaling in the CNS and approaches to its restoration in type 2 DM are analyzed and discussed.

Fuel homeostasis and locomotor behavior: role of leptin and melanocortin pathways.

BACKGROUND: While it is now accepted that genes and their products affect food intake, the concept that locomotor behavior or the propensity for physical activity is controlled by neuro hum oral regulators is frequently underappreciated. In mammals, complex interactions have developed to allow the cross-talk between fuel homeostasis and physical activity. AIM: The aim of this review is to provide a synopsis of the influence of the leptin-melanocortin pathway, a well-studied pivotal player in body weight regulation, on locomotor behaviors. CONCLUSIONS: In rodents, reductions in leptin levels that physiologically occur following acute food deprivation or a reduction of the fat mass consequent to prolonged caloric restrictions are associated with a decrease in total locomotor activity and simultaneous increase in food-anticipatory activity, a locomotor behavior which reflects a foraging attitude. These actions can be prevented by leptin administration and are at least partially mediated by the neurons of the melanocortin pathway. In humans, twin studies have attributed to genetic factors approximately 50% of the variance of physical activity. An elevated number of the genes or loci which may affect physical activity are involved in body weight homeostasis. Polymorphisms of the melanocortin-4 and leptin receptors have repeatedly been associated with the level of physical activity. Unraveling the complexity of the regulation of locomotor behavior and the interconnections with the pathways involved in energy homeostasis may help explain the substantial individual variability in physical activities in humans and disentangle the harmful effects of sedentary lifestyle, which may be distinct from the detrimental effects of obesity.

Protective effects of the melanocortin analog NDP-α-MSH in rats undergoing cardiac arrest.

We previously reported that melanocortins afford cardioprotection in conditions of experimental myocardial ischemia/reperfusion, with involvement of the janus kinases (JAK), extracellular signal-regulated kinases (ERK) and signal transducers and activators of transcription (STAT) signalings. We investigated the influence of the melanocortin analog [Nle(4), D-Phe(7)]α-melanocyte-stimulating hormone (NDP-α-MSH) on short-term detrimental responses to cardiac arrest (CA) induced in rats by intravenous (i.v.) administration of potassium chloride, followed by cardiopulmonary resuscitation (CPR) plus epinephrine treatment. In CA/CPR rats i.v. treated with epinephrine (0.1 mg/kg) and returned to spontaneous circulation (48%) we recorded low values of mean arterial pressure (MAP) and heart rate (HR), alteration of hemogasanalysis parameters, left ventricle low expression of the cardioprotective transcription factors pJAK2 and pTyr-STAT3 (JAK-dependent), increased oxidative stress, up-regulation of the inflammatory mediators tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and down-regulation of the anti-inflammatory cytokine IL-10, as assessed at 1h and 3h after CPR. On the other hand, i.v. treatment during CPR with epinephrine plus NDP-α-MSH (340 µg/kg) almost completely restored the basal conditions of MAP and HR, reversed metabolic acidosis, induced left ventricle up-regulation of pJAK2, pTyr-STAT3 and IL-10, attenuated oxidative stress, down-regulated TNF-α and IL-6 levels, and improved survival rate by 81%. CA/CPR plus epinephrine alone or in combination with NDP-α-MSH did not affect left ventricle pSer-STAT3 (ERK1/2-dependent) and pERK1/2 levels. These results indicate that melanocortins improve return to spontaneous circulation, reverse metabolic acidosis, and inhibit heart oxidative stress and inflammatory cascade triggered by CA/CPR, likely via activation of the JAK/STAT signaling pathway.

Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding.

We found that leptin receptors were expressed in hypothalamic astrocytes and that their conditional deletion led to altered glial morphology and synaptic inputs onto hypothalamic neurons involved in feeding control. Leptin-regulated feeding was diminished, whereas feeding after fasting or ghrelin administration was elevated in mice with astrocyte-specific leptin receptor deficiency. These data reveal an active role of glial cells in hypothalamic synaptic remodeling and control of feeding by leptin.

Bleomycin-induced fibrosis in MC1 signalling-deficient C57BL/6J-Mc1r(e/e) mice further supports a modulating role for melanocortins in collagen synthesis of the skin.

The melanocortin-1 receptor (MC1 ) binds α-melanocyte-stimulating hormone (α-MSH) with high affinity and has a physiological role in cutaneous melanin pigmentation. Previously, we reported that human dermal fibroblasts also express functional MC1 . α-MSH suppressed transforming growth factor-ß1 - and bleomycin (BLM)-induced collagen synthesis in vitro and in vivo. Using MC1 signalling-deficient C57BL/6J-Mc1r(e/e) mice, we tested as to whether MC1 has a regulatory role on dermal collagen synthesis in the BLM model of scleroderma. Notably, mice with a C57BL/6J genetic background were previously shown to be BLM-non-susceptible. Interestingly, treatment of C57BL/6J-Mc1r(e/e) but not of C57BL/6J-wild-type mice with BLM increased cutaneous collagen type I content at RNA and protein level along with development of skin fibrosis. Cutaneous levels of connective tissue growth factor and monocyte chemotactic protein-1 were also increased in BLM-treated C57BL/6J-Mc1r(e/e) mice. Primary dermal fibroblasts from C57BL/6J-wt mice further expressed MC1 , suggesting that these cells are directly targeted by melanocortins to affect collagen production of the skin. Our findings support the concept that MC1 has an endogenous regulatory function in collagen synthesis and controls the extent of fibrotic stress responses of the skin.

Molecular and cellular regulation of hypothalamic melanocortin neurons controlling food intake and energy metabolism.

The brain receives and integrates environmental and metabolic information, transforms these signals into adequate neuronal circuit activities, and generates physiological behaviors to promote energy homeostasis. The responsible neuronal circuitries show lifetime plasticity and guaranty metabolic health and survival. However, this highly evolved organization has become challenged nowadays by chronic overload with nutrients and reduced physical activity, which results in an ever-increasing number of obese individuals worldwide. Research within the last two decades has aimed to decipher the responsible molecular and cellular mechanisms for regulation of the hypothalamic melanocortin neurons, which have a key role in the control of food intake and energy metabolism. This review maps the central connections of the melanocortin system and highlights its global position and divergent character in physiological and pathological metabolic events. Moreover, recently uncovered molecular and cellular processes in hypothalamic neurons and glial cells that drive plastic morphological and physiological changes in these cells, and account for regulation of food intake and energy metabolism, are brought into focus. Finally, potential functional interactions between metabolic disorders and psychiatric diseases are discussed.

Neural circuitry underlying the central hypertensive action of nesfatin-1: melanocortins, corticotropin-releasing hormone, and oxytocin.

Nesfatin-1 is produced in the periphery and in the brain where it has been demonstrated to regulate appetite, stress hormone secretion, and cardiovascular function. The anorexigenic action of central nesfatin-1 requires recruitment of neurons producing the melanocortins and centrally projecting oxytocin (OT) and corticotropin-releasing hormone (CRH) neurons. We previously have shown that two components of this pathway, the central melanocortin and oxytocin systems, contribute to the hypertensive action of nesfatin-1 as well. We hypothesized that the cardiovascular effect of nesfatin-1 also was dependent on activation of neurons expressing CRH receptors, and that the order of activation of the melanocortin-CRH-oxytocin circuit was preserved for both the anorexigenic and hypertensive actions of the peptide. Pretreatment of male rats with the CRH-2 receptor antagonist astressin2B abrogated nesfatin-1-induced increases in mean arterial pressure (MAP). Furthermore, the hypertensive action of CRH was blocked by pretreatment with an oxytocin receptor antagonist ornithine vasotocin (OVT), indicating that the hypertensive effect of nesfatin-1 may require activation of oxytocinergic (OTergic) neurons in addition to recruitment of CRH neurons. Interestingly, we found that the hypertensive effect of α-melanocyte stimulating hormone (α-MSH) itself was not blocked by either astressin2B or OVT. These data suggest that while α-MSH-producing neurons are part of a core melanocortin-CRH-oxytocin circuit regulating food intake, and a subpopulation of melanocortin neurons activated by nesfatin-1 do mediate the hypertensive action of the peptide, α-MSH can signal independently from this circuit to increase MAP.

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

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 analysing 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.

Synaptic plasticity in neuronal circuits regulating energy balance.

Maintaining energy balance is of paramount importance for metabolic health and survival. It is achieved through the coordinated regulation of neuronal circuits that control a wide range of physiological processes affecting energy intake and expenditure, such as feeding, metabolic rate, locomotor activity, arousal, growth and reproduction. Neuronal populations distributed throughout the CNS but highly enriched in the mediobasal hypothalamus, sense hormonal, nutrient and neuronal signals of systemic energy status and relay this information to secondary neurons that integrate the information and regulate distinct physiological parameters in a manner that promotes energy homeostasis. To achieve this, it is critical that neuronal circuits provide information about short-term changes in nutrient availability in the larger context of long-term energy status. For example, the same signals lead to different cellular and physiological responses if delivered under fasted versus fed conditions. Thus, there is a clear need to have mechanisms that rapidly and reversibly adjust responsiveness of hypothalamic circuits to acute changes in nutrient availability.