Fast neurotransmitter identity of MCH neurons: Do contents depend on context?

Hypothalamic melanin-concentrating hormone (MCH) neurons participate in many fundamental neuroendocrine processes. While some of their effects can be attributed to MCH itself, others appear to depend on co-released neurotransmitters. Historically, the subject of fast neurotransmitter co-release from MCH neurons has been contentious, with data to support MCH neurons releasing GABA, glutamate, both, and neither. Rather than assuming a position in that debate, this review considers the evidence for all sides and presents an alternative explanation: neurochemical identity, including classical neurotransmitter content, is subject to change. With an emphasis on the variability of experimental details, we posit that MCH neurons may release GABA and/or glutamate at different points according to environmental and contextual factors. Through the lens of the MCH system, we offer evidence that the field of neuroendocrinology would benefit from a more nuanced and dynamic interpretation of neurotransmitter identity.

Melanocytes in regenerative medicine applications and disease modeling.

Melanocytes are dendritic cells localized in skin, eyes, hair follicles, ears, heart and central nervous system. They are characterized by the presence of melanosomes enriched in melanin which are responsible for skin, eye and hair pigmentation. They also have different functions in photoprotection, immunity and sound perception. Melanocyte dysfunction can cause pigmentary disorders, hearing and vision impairments or increased cancer susceptibility. This review focuses on the role of melanocytes in homeostasis and disease, before discussing their potential in regenerative medicine applications, such as for disease modeling, drug testing or therapy development using stem cell technologies, tissue engineering and extracellular vesicles.

Differential diagnosis and management of hyperpigmentation.

There is an increasing recognition of ethnic dermatology to reflect the increase in skin of colour (SOC) populations in the UK. Hyperpigmentary disorder is one of the commonest skin concerns in SOC but there has been limited training available in this field of dermatology. Variations in skin colour are genetically determined by the amount of melanin content, the eumelanin/pheomelanin ratio and the size of melanosomes, but is also influenced by other factors such as hormones and extrinsic factors such as ultraviolet radiation. Hyperpigmentation is a broad term to describe increased pigmentation in the skin, and making a correct diagnosis is an important first step in the successful management of hyperpigmentary disorders. A systematic approach based on the disease pathogenesis (e.g. reactive vs. nonreactive, increased melanin vs. increased number of cells or epidermal vs. dermal pigmentation) aided by a detailed history and clinical examination is the best way to diagnose a hyperpigmentary disorder. Based on its pathogenesis, management can be planned. For epidermal hyperpigmentation caused by increased melanin, topical skin-lightening agents targeting inhibition of tyrosinase or melanosome transfer and promotion of keratinocyte turnover can be used. Hydroquinone-containing cream is the gold-standard treatment for epidermal hyperpigmentation. Alternative treatments include laser toning or chemical peels. However, increased dermal pigmentation is more challenging to target with topical treatments. If hyperpigmentation is due to increased numbers of melanocytes or keratinocytes, high-fluence laser is the most appropriate treatment method.

Neural Contributions of the Hypothalamus to Parental Behaviour.

Parental behaviour is a comprehensive set of neural responses to social cues. The neural circuits that govern parental behaviour reside in several putative nuclei in the brain. Melanin concentrating hormone (MCH), a neuromodulator that integrates physiological functions, has been confirmed to be involved in parental behaviour, particularly in crouching behaviour during nursing. Abolishing MCH neurons in innate MCH knockout males promotes infanticide in virgin male mice. To understand the mechanism and function of neural networks underlying parental care and aggression against pups, it is essential to understand the basic organisation and function of the involved nuclei. This review presents newly discovered aspects of neural circuits within the hypothalamus that regulate parental behaviours.

The puzzling construction of the conidial outer layer of Aspergillus fumigatus.

If the mycelium of Aspergillus fumigatus is very short-lived in the laboratory, conidia can survive for years. This survival capacity and extreme resistance to environmental insults is a major biological characteristic of this fungal species. Moreover, conidia, which easily reach the host alveola, are the infective propagules. Earlier studies have shown the role of some molecules of the outer conidial layer in protecting the fungus against the host defense. The outer layer of the conidial cell wall, directly in contact with the host cells, consists of α-(1,3)-glucan, melanin, and proteinaceous rodlets. This study is focused on the global importance of this outer layer. Single and multiple mutants without one to three major components of the outer layer were constructed and studied. The results showed that the absence of the target molecules resulting from multiple gene deletions led to unexpected phenotypes without any logical additivity. Unexpected compensatory cell wall surface modifications were indeed observed, such as the synthesis of the mycelial virulence factor galactosaminogalactan, the increase in chitin and glycoprotein concentration or particular changes in permeability. However, sensitivity of the multiple mutants to killing by phagocytic host cells confirmed the major importance of melanin in protecting conidia.

A quantitative cross-sectional analysis of the melanin index in the skin of preterm newborns and its association with gestational age at birth.

BACKGROUND: Estimation of gestational age (GA) is important to make timely decisions and provide appropriate neonatal care. Clinical maturity scales to estimate GA have used skin texture and color to assess maturity at birth facing situations of the uncertainty of pregnancy dating. The size and darkness of the areola around the nipple to grade skin characteristics are based on visual appearance. The melanin index (M-Index) is an optical skin parameter related to the melanin content in the tissue. This study is aimed to associate the M-Index of the skin with the GA. METHODS: A cross-sectional study evaluated 80 newborns at birth. A photometer device quantified the skin pigmentation on the areolae, forearms, and soles. Paired average differences of M-Index were compared among the three body sites. The skin M-Indexes were compared between subgroups of newborns until 34 weeks or with 34 and more. RESULTS: The skin over the areola had the highest values of M-Index compared with the forearm or sole areas (P < .001 for both). Infants with a GA between 34 and <37 weeks had higher M-Index values over the areola than the group with a GA with 24 to <34 weeks: 41.7 (8.9) and 38.3 (10.5) median (IQR), P = .005. CONCLUSIONS: The measurable M-Index values have the potential to improve physical evaluation in assessing GA at birth.

Locus Coeruleus Activity Strengthens Prioritized Memories Under Arousal.

Recent models posit that bursts of locus ceruleus (LC) activity amplify neural gain such that limited attention and encoding resources focus even more on prioritized mental representations under arousal. Here, we tested this hypothesis in human males and females using fMRI, neuromelanin MRI, and pupil dilation, a biomarker of arousal and LC activity. During scanning, participants performed a monetary incentive encoding task in which threat of punishment motivated them to prioritize encoding of scene images over superimposed objects. Threat of punishment elicited arousal and selectively enhanced memory for goal-relevant scenes. Furthermore, trial-level pupil dilations predicted better scene memory under threat, but were not related to object memory outcomes. fMRI analyses revealed that greater threat-evoked pupil dilations were positively associated with greater scene encoding activity in LC and parahippocampal cortex, a region specialized to process scene information. Across participants, this pattern of LC engagement for goal-relevant encoding was correlated with neuromelanin signal intensity, providing the first evidence that LC structure relates to its activation pattern during cognitive processing. Threat also reduced dynamic functional connectivity between high-priority (parahippocampal place area) and lower-priority (lateral occipital cortex) category-selective visual cortex in ways that predicted increased memory selectivity. Together, these findings support the idea that, under arousal, LC activity selectively strengthens prioritized memory representations by modulating local and functional network-level patterns of information processing.SIGNIFICANCE STATEMENT Adaptive behavior relies on the ability to select and store important information amid distraction. Prioritizing encoding of task-relevant inputs is especially critical in threatening or arousing situations, when forming these memories is essential for avoiding danger in the future. However, little is known about the arousal mechanisms that support such memory selectivity. Using fMRI, neuromelanin MRI, and pupil measures, we demonstrate that locus ceruleus (LC) activity amplifies neural gain such that limited encoding resources focus even more on prioritized mental representations under arousal. For the first time, we also show that LC structure relates to its involvement in threat-related encoding processes. These results shed new light on the brain mechanisms by which we process important information when it is most needed.

Sleep Deprivation Distinctly Alters Glutamate Transporter 1 Apposition and Excitatory Transmission to Orexin and MCH Neurons.

Glutamate transporter 1 (GLT1) is the main astrocytic transporter that shapes glutamatergic transmission in the brain. However, whether this transporter modulates sleep-wake regulatory neurons is unknown. Using quantitative immunohistochemical analysis, we assessed perisomatic GLT1 apposition with sleep-wake neurons in the male rat following 6 h sleep deprivation (SD) or following 6 h undisturbed conditions when animals were mostly asleep (Rest). We found that SD decreased perisomatic GLT1 apposition with wake-promoting orexin neurons in the lateral hypothalamus compared with Rest. Reduced GLT1 apposition was associated with tonic presynaptic inhibition of excitatory transmission to these neurons due to the activation of Group III metabotropic glutamate receptors, an effect mimicked by a GLT1 inhibitor in the Rest condition. In contrast, SD resulted in increased GLT1 apposition with sleep-promoting melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus. Functionally, this decreased the postsynaptic response of MCH neurons to high-frequency synaptic activation without changing presynaptic glutamate release. The changes in GLT1 apposition with orexin and MCH neurons were reversed after 3 h of sleep opportunity following 6 h SD. These SD effects were specific to orexin and MCH neurons, as no change in GLT1 apposition was seen in basal forebrain cholinergic or parvalbumin-positive GABA neurons. Thus, within a single hypothalamic area, GLT1 differentially regulates excitatory transmission to wake- and sleep-promoting neurons depending on sleep history. These processes may constitute novel astrocyte-mediated homeostatic mechanisms controlling sleep-wake behavior.SIGNIFICANCE STATEMENT Sleep-wake cycles are regulated by the alternate activation of sleep- and wake-promoting neurons. Whether and how astrocytes can regulate this reciprocal neuronal activity are unclear. Here we report that, within the lateral hypothalamus, where functionally opposite wake-promoting orexin neurons and sleep-promoting melanin-concentrating hormone neurons codistribute, the glutamate transporter GLT1, mainly present on astrocytes, distinctly modulates excitatory transmission in a cell-type-specific manner and according to sleep history. Specifically, GLT1 is reduced around the somata of orexin neurons while increased around melanin-concentrating hormone neurons following sleep deprivation, resulting in different forms of synaptic plasticity. Thus, astrocytes can fine-tune the excitability of functionally discrete neurons via glutamate transport, which may represent novel regulatory mechanisms for sleep.

Immune-related molecular and physiological differences between black-shelled and white-shelled Pacific oysters Crassostrea gigas.

The black-and-white traits on shells and mantle edges of the Pacific oyster, Crassostrea gigas, are inheritable and correlated, and black shells (melanin pigmentation) are usually found in the Pacific oysters. Based on differentially expressed genes from RNA-Seq and physiological characteristics, in this study, Black-shelled Pacific oysters (BSO) and White-shelled Pacific oysters (WSO) were selected to determine the molecular differences between oysters with obviously different melanin content. The differences in the process of immune recognition and modulation indicated that BSO may be more sensitive to the immune substances. There might have different modulation mode of apoptosis and phagocytosis between BSO and WSO, and caspase-3 might have played a key role in the apoptotic process of BSO. Different oxidation-related pathways were enriched in both BSO and WSO, suggesting the different response strategies of BSO and WSO to oxidative stress. The physiological evidences showed that, compared with WSO, in BSO, the tyrosinase content, the caspase-3 activity and the suppression of hydroxyl radical increased, and the reactive oxygen species concentration decreased. Therefore, immune-related molecular and physiological differences were found between BSO and WSO.

A CreER mouse to study melanin concentrating hormone signaling in the developing brain.

The neuropeptide, melanin concentrating hormone (MCH), and its G protein-coupled receptor, melanin concentrating hormone receptor 1 (Mchr1), are expressed centrally in adult rodents. MCH signaling has been implicated in diverse behaviors such as feeding, sleep, anxiety, as well as addiction and reward. While a model utilizing the Mchr1 promoter to drive constitutive expression of Cre recombinase (Mchr1-Cre) exists, there is a need for an inducible Mchr1-Cre to determine the roles for this signaling pathway in neural development and adult neuronal function. Here, we generated a BAC transgenic mouse where the Mchr1 promotor drives expression of tamoxifen inducible CreER recombinase. Many aspects of the Mchr1-Cre expression pattern are recapitulated by the Mchr1-CreER model, though there are also notable differences. Most strikingly, compared to the constitutive model, the new Mchr1-CreER model shows strong expression in adult animals in hypothalamic brain regions involved in feeding behavior but diminished expression in regions involved in reward, such as the nucleus accumbens. The inducible Mchr1-CreER allele will help reveal the potential for Mchr1 signaling to impact neural development and subsequent behavioral phenotypes, as well as contribute to the understanding of the MCH signaling pathway in terminally differentiated adult neurons and the diverse behaviors that it influences.

Melanin-based coloration and host-parasite interactions under global change.

The role of parasites in shaping melanin-based colour polymorphism, and the consequences of colour polymorphism for disease resistance, remain debated. Here we review recent evidence of the links between melanin-based coloration and the behavioural and immunological defences of vertebrates against their parasites. First we propose that (1) differences between colour morphs can result in variable exposure to parasites, either directly (certain colours might be more or less attractive to parasites) or indirectly (variations in behaviour and encounter probability). Once infected, we propose that (2) immune variation between differently coloured individuals might result in different abilities to cope with parasite infection. We then discuss (3) how these different abilities could translate into variable sexual and natural selection in environments varying in parasite pressure. Finally, we address (4) the potential role of parasites in the maintenance of melanin-based colour polymorphism, especially in the context of global change and multiple stressors in human-altered environments. Because global change will probably affect both coloration and the spread of parasitic diseases in the decades to come, future studies should take into account melanin-based coloration to better predict the evolutionary responses of animals to changing disease risk in human-altered environments.

Hypothalamic kappa opioid receptor mediates both diet-induced and melanin concentrating hormone-induced liver damage through inflammation and endoplasmic reticulum stress.

UNLABELLED: The opioid system is widely known to modulate the brain reward system and thus affect the behavior of humans and other animals, including feeding. We hypothesized that the hypothalamic opioid system might also control energy metabolism in peripheral tissues. Mice lacking the kappa opioid receptor (κOR) and adenoviral vectors overexpressing or silencing κOR were stereotaxically delivered in the lateral hypothalamic area (LHA) of rats. Vagal denervation was performed to assess its effect on liver metabolism. Endoplasmic reticulum (ER) stress was inhibited by pharmacological (tauroursodeoxycholic acid) and genetic (overexpression of the chaperone glucose-regulated protein 78 kDa) approaches. The peripheral effects on lipid metabolism were assessed by histological techniques and western blot. We show that in the LHA κOR directly controls hepatic lipid metabolism through the parasympathetic nervous system, independent of changes in food intake and body weight. κOR colocalizes with melanin concentrating hormone receptor 1 (MCH-R1) in the LHA, and genetic disruption of κOR reduced melanin concentrating hormone-induced liver steatosis. The functional relevance of these findings was given by the fact that silencing of κOR in the LHA attenuated both methionine choline-deficient, diet-induced and choline-deficient, high-fat diet-induced ER stress, inflammation, steatohepatitis, and fibrosis, whereas overexpression of κOR in this area promoted liver steatosis. Overexpression of glucose-regulated protein 78 kDa in the liver abolished hypothalamic κOR-induced steatosis by reducing hepatic ER stress. CONCLUSIONS: This study reveals a novel hypothalamic-parasympathetic circuit modulating hepatic function through inflammation and ER stress independent of changes in food intake or body weight; these findings might have implications for the clinical use of opioid receptor antagonists. (Hepatology 2016;64:1086-1104).

Activation of Aedes aegypti prophenoloxidase-3 and its role in the immune response against entomopathogenic fungi.

Serine protease cascade-mediated melanization is an important innate immune response in insects and crustaceans, which involves the proteolytic activation of prophenoloxidase (PPO). In this study, we investigated the role of Aedes aegypti PPO3 in antifungal immune defence. We expressed and purified recombinant PPO3 (rPPO3) in Escherichia coli and demonstrated that rPPO3 was activated by ethanol and, to a lesser extent, by cetylpyridinium chloride. In the presence of Cu2+ , rPPO3 exhibited enzyme activity. Immunoblot results revealed that the rPPO3 was cleaved by the haemolymph from immune-challenged mosquitoes or purified Ostrinia furnacalis serine protease 105 in vitro. The cleaved rPPO3 converted dopamine to toxic intermediates that killed fungal conidia of Beauveria bassiana in vitro. In mosquitoes challenged with Be. bassiana, cleavage of rPPO3 produced a 50 kDa phenoloxidase (PO) fragment. Further analysis revealed that the survival rate of mosquitoes with fungal infection increased significantly following injection of rPPO3 into the haemocoel. Taken together, our results suggest that proteolytic cleavage of the mosquito PPO3 plays an important role in the antifungal immune response. This has led to a better understanding of the mechanism of PPO activation in the mosquito and the role of melanization in the antifungal immune response.

Does melanin matter in the dark?

In living cells, melanin pigment is formed within melanosomes, which not only protect the cells from autodestruction, but also serve as second messenger organelles regulating important skin functions, with melanocytes acting as primary sensory and regulatory cells of the epidermis. Yet, one can argue that skin melanin, which may negatively affect cellular homeostasis in melanoma, really exerts protective functions. Consequently, the actual functions of melanin and the melanogenic pathway in skin biology remains enigmatic. Yet, the solution of this riddle seems simple - to check the actual influence of natural melanin on skin cells in the dark. Since many interesting hypotheses and theories put forward in this respect did not survive confrontation with the experiment, a leading pigment research group from Naples was brave to "jump off the cliff" by confronting theory with experimental reality. They showed that, in the dark, human hair-derived melanin promotes inflammatory responses in keratinocytes, lowers their viability, promotes oxidative stress, and that pheomelanin does so more strongly than eumelanin. Thus, pheomelanin hardly protects red-haired individuals, even when avoiding the sun. Black hairs do not do much better either, unless they undergo graying.

A guide to the field of palaeo colour: Melanin and other pigments can fossilise: Reconstructing colour patterns from ancient organisms can give new insights to ecology and behaviour.

Melanin, and other pigments have recently been shown to preserve over geologic time scales, and are found in several different organisms. This opens up the possibility of inferring colours and colour patterns ranging from invertebrates to feathered dinosaurs and mammals. An emerging discipline is palaeo colour: colour plays an important role in display and camouflage as well as in integumental strengthening and protection, which makes possible the hitherto difficult task of doing inferences about past ecologies, behaviours, and organismal appearance. Several studies and techniques have been presented in the last couple of years that have described ways to characterize pigment patterns. Here, I will review the available methods and the likely applications to understand past ecologies. A golden age of colourized dinosaurs and other animals is now dawning upon us, which may elucidate the nature of ancient predator prey interactions and display structures.

Melanin granules melanophages and a fully-melanized epidermis are common traits of odontocete and mysticete cetaceans.

BACKGROUND: The cellular mechanisms used to counteract or limit damage caused by exposure of marine vertebrates to solar ultraviolet (UV) radiation are poorly understood. Cetaceans are vulnerable because they lack protective skin appendages and are obliged to surface continuously to breathe, thus being exposed repeatedly to UV light. Although molecular mechanisms of photoprotection of cetaceans have been studied, there is limited knowledge about their epidermal structure and photoprotective effectors. OBJECTIVE: To describe and compare the epidermis of mysticete and odontocete cetaceans and identify potentially photoprotective traits. ANIMALS: Twenty eight free-living individuals belonging to six cetacean species were sampled in the Mexican Central Pacific and Gulf of California. Species sampled were the bottlenose dolphin, pantropical spotted dolphin, spinner dolphin, Bryde's whale, fin whale and humpback whale. METHODS: Histological and cytological evaluation of skin biopsy tissue collected in the field between 2014 and 2016. RESULTS: All cetaceans had only three epidermal layers, lacking both the stratum granulosum and stratum lucidum. A relatively thick stratum corneum with a parakeratosis-like morphology was noted. Melanin was observed within keratinocytes in all epidermal layers, including the stratum corneum and apical melanin granules obscured the keratinocyte nucleus. Keratinocytes had a perinuclear halo. Keratinocyte diameter differed between cetacean suborders and amongst species. Melanophage clusters were common in most cetacean species. CONCLUSIONS: The widespread presence of melanin and the unexpectedly high number of melanophages may constitute a unique photoprotective trait of cetaceans and could reflect primitive adaptations to their environment and to their obligate marine-bound life.

Journey From Black To Pink Gums: Management Of Melanin Induced Physiological Gingival Hyper Pigmentation.

Smile is an expression of happiness, self-confidence, kindness and beauty. Along with teeth and lips, gingiva is also a vital component of smile. Melanin induced gingival hyper pigmentation may appear un-aesthetic especially when it is associated with high smile line, upper anterior labial segment and is uneven in appearance. It affects individuals from all races. Generally, it is believed that melanin induced gingival hyper pigmentation is confined to individuals from dark races. But studies have shown that Iranian, Indian, Italian, Arabian, Greek. German, French, Japanese, Chinese, Jewish, Thai, Malaysian and other ethnic groups also display clinical gingival pigmentation.1 Gingival hyper pigmentation may result in psychological distress especially when the appearance is of utmost importance for the individuals. This article aims to focus on the physiology, clinical appearance and treatment options available for the melanin induced gingival hyper pigmentation along with the reported recurrence in the light of current literature.

Bioinspired Functionalized Melanin Nanovariants with a Range of Properties Provide Effective Color Matched Photoprotection in Skin.

Melanin and related polydopamine hold great promise; however, restricted fine-tunabilility limits their usefulness in biocompatible applications. In the present study, by taking a biomimetic approach, we synthesize peptide-derived melanin with a range of physicochemical properties. Characterization of these melanin polymers indicates that they exist as nanorange materials with distinct size distribution, shapes, and surface charges. These variants demonstrate similar absorption spectra but have different optical properties that correlate with particle size. Our approach enables incorporation of chemical groups to create functionalized polyvalent organic nanomaterials and enables customization of melanin. Further, we establish that these synthetic variants are efficiently taken up by the skin keratinocytes, display appreciable photoprotection with minimal cytotoxicity, and thereby function as effective color matched photoprotective agents. In effect we demonstrate that an array of functionalized melanins with distinct properties could be synthesized using bioinspired green chemistry, and these are of immense utility in generating customized melanin/polydopamine like materials.

Melanin-Concentrating Hormone and Its MCH-1 Receptor: Relationship Between Effects on Alcohol and Caloric Intake.

BACKGROUND: Reward and energy homeostasis are both regulated by a network of hypothalamic neuropeptide systems. The melanin-concentrating hormone (MCH) and its MCH-1 receptor (MCH1-R) modulate alcohol intake, but it remains unknown to what extent this reflects actions on energy balance or reward. Here, we evaluated the MCH1-R in regulation of caloric intake and motivation to consume alcohol in states of escalated consumption. METHODS: Rats had intermittent access (IA) to alcohol and were divided into high- and low-drinking groups. Food and alcohol consumption was assessed after administration of an MCH1-R antagonist, GW803430. Next, GW803430 was evaluated on alcohol self-administration in protracted abstinence induced by IA in high-drinking rats. Finally, the effect of GW803430 was assessed on alcohol self-administration in acute withdrawal in rats exposed to alcohol vapor. Gene expression of MCH and MCH1-R was measured in the hypothalamus and nucleus accumbens (NAc) in both acute and protracted abstinence. RESULTS: High-drinking IA rats consumed more calories from alcohol than chow and GW803430 decreased both chow and alcohol intake. In low-drinking rats, only food intake was affected. In protracted abstinence from IA, alcohol self-administration was significantly reduced by pretreatment with GW803430 and gene expression of both MCH and the MCH1-R were dysregulated in hypothalamus and NAc. In contrast, during acute withdrawal from vapor exposure, treatment with GW803430 did not affect alcohol self-administration, and no changes in MCH or MCH1-R gene expression were observed. CONCLUSIONS: Our data suggest a dual role of MCH and the MCH1-R in regulation of alcohol intake, possibly through mechanisms involving caloric intake and reward motivation. A selective suppression of alcohol self-administration during protracted abstinence by GW803430 was observed and accompanied by adaptations in gene expression of MCH and MCH1-R. Selective suppression of escalated consumption renders the MCH1-R an attractive target for treatment of alcohol use disorders.

Basis for the gain and subsequent dilution of epidermal pigmentation during human evolution: The barrier and metabolic conservation hypotheses revisited.

The evolution of human skin pigmentation must address both the initial evolution of intense epidermal pigmentation in hominins, and its subsequent dilution in modern humans. While many authorities believe that epidermal pigmentation evolved to protect against either ultraviolet B (UV-B) irradiation-induced mutagenesis or folic acid photolysis, we hypothesize that pigmentation augmented the epidermal barriers by shifting the UV-B dose-response curve from toxic to beneficial. Whereas erythemogenic UV-B doses produce apoptosis and cell death, suberythemogenic doses benefit permeability and antimicrobial function. Heavily melanized melanocytes acidify the outer epidermis and emit paracrine signals that augment barrier competence. Modern humans, residing in the cooler, wetter climes of south-central Europe and Asia, initially retained substantial pigmentation. While their outdoor lifestyles still permitted sufficient cutaneous vitamin D3 (VD3) synthesis, their marginal nutritional status, coupled with cold-induced caloric needs, selected for moderate pigment reductions that diverted limited nutritional resources towards more urgent priorities (=metabolic conservation). The further pigment-dilution that evolved as humans reached north-central Europe (i.e., northern France, Germany), likely facilitated cutaneous VD3 synthesis, while also supporting ongoing, nutritional requirements. But at still higher European latitudes where little UV-B breaches the atmosphere (i.e., present-day UK, Scandinavia, Baltic States), pigment dilution alone could not suffice. There, other nonpigment-related mutations evolved to facilitate VD3 production; for example, in the epidermal protein, filaggrin, resulting in reduced levels of its distal metabolite, trans-urocanic acid, a potent UV-B chromophore. Thus, changes in human pigmentation reflect a complex interplay between latitude, climate, diet, lifestyle, and shifting metabolic priorities.