Harnessing the melanocortin system in the control of food intake and glucose homeostasis.

The central and peripheral melanocortin system, comprising of five receptors and their endogenous ligands, is responsible for a wide array of physiological functions such as skin pigmentation, sexual function and development, and inflammation. A growing body of both clinical and pre-clinical research is demonstrating the relevance of this system in metabolic health. Disruption of hypothalamic melanocortin signalling is the most common cause of monogenic obesity in humans. Setmelanotide, an FDA-approved analogue of alpha-melanocyte stimulating hormone (α-MSH) that functions by restoring central melanocortin signalling, has proven to be a potent pharmacological tool in the treatment of syndromic obesity. As the first effective therapy targeting the melanocortin system to treat metabolic disorders, its approval has sparked research to further harness the links between these melanocortin receptors and metabolic processes. Here, we outline the structure of the central and peripheral melanocortin system, discuss its critical role in the regulation of food intake, and review promising targets that may hold potential to treat metabolic disorders in humans.

Synergism Between Hypothalamic Astrocytes and Neurons in Metabolic Control.

Astrocytes are no longer considered as passive support cells. In the hypothalamus, these glial cells actively participate in the control of appetite, energy expenditure, and the processes leading to obesity and its secondary complications. Here we briefly review studies supporting this conclusion and the advances made in understanding the underlying mechanisms.

The effects of urban thermal heterogeneity and feather coloration on oxidative stress and metabolism of pigeons (Columba livia).

Urbanization stands out as a significant anthropogenic factor, exerting selective pressures on ecosystems and biotic components. A notable outcome of urbanization is thermal heterogeneity where the emergence of Urban Heat Islands is characterized by elevated air and surface temperatures compared to adjacent rural areas. Investigating the influence of thermal heterogeneity on urban animals could offer insights into how temperature variations can lead to phenotypic shifts. Urban pigeons (Columba livia) serve as an excellent model for studying urban thermal effects, given the melanism variations, which are associated with the pleiotropy of the melanocortin system. To examine the development of physiological plasticity in response to urban thermal variations, we conducted a study on pigeons in Santiago, Chile, during the rainy season. We assessed the influence of habitat on physiological traits related to metabolism and antioxidant capacities, which are theoretically affected by feather coloration. Our findings reveal that variations in melanism significantly impact pigeon physiology, affecting both antioxidant capacities and the mitochondrial activity of red blood cells. It was found that higher urban temperatures, from both the current sampling month and the prior sampling month (from CRU TS dataset), were negatively and strongly associated with lower antioxidant and metabolic activities. This suggests that elevated urban temperatures likely benefit the energetic budgets of pigeon populations and mitigate the negative effects of oxidative metabolism, with differential effects depending on feather colorations.

Effects of the Combination of the C1473G Mutation in the Tph2 Gene and Lethal Yellow Mutations in the Raly-Agouti Locus on Behavior, Brain 5-HT and Melanocortin Systems in Mice.

Tryptophan hydroxylase 2 (TPH2) is the key and rate-limited enzyme of serotonin (5-HT) synthesis in the brain. The C1473G mutation in the Tph2 gene results in a two-fold decrease in enzyme activity in the mouse brain. The lethal yellow (AY) mutation in the Raly-Agouti locus results in the overexpression of the Agouti gene in the brain and causes obesity and depressive-like behavior in mice. Herein, the possible influences of these mutations and their combination on body mass, behavior, brain 5-HT and melanocortin systems in mice of the B6-1473CC/aa. B6-1473CC/AYa, B6-1473GG/aa are investigated. B6-1473GG/AYa genotypes were studied. The 1473G and AY alleles increase the activity of TPH2 and the expression of the Agouti gene, respectively, but they do not alter 5-HT and 5-HIAA levels or the expression of the genes Tph2, Maoa, Slc6a4, Htr1a, Htr2a, Mc3r and Mc4r in the brain. The 1473G allele attenuates weight gain and depressive-like immobility in the forced swim test, while the AY allele increases body weight gain and depressive-like immobility. The combination of these alleles results in hind limb dystonia in the B6-1473GG/AYa mice. This is the first evidence for the interaction between the C1473G and AY mutations.

Lethal Yellow Mutation Causes Anxiety, Obsessive-compulsive Behavior and Affects the Brain Melanocortin System in Males and Females of Mice.

BACKGROUND: The brain melanocortin system regulates numerous physiological functions and kinds of behavior. The agouti protein inhibits melanocortin receptors in melanocytes. The lethal yellow (AY) mutation puts the Agouti gene under the control of the Raly gene promotor and causes the agouti protein expression in the brain. In the present article, we investigated the effects of the AY mutation on brain mRNA levels of Agouti, Raly, and melanocortin-related genes such as Agrp, Pomc, Mc3r, Mc4r, and their relationship to behavior. METHODS: The experiment was performed on 6-month-old males and females of AY/a and a/a (control) mice. Anxiety and obsessive-compulsive behavior were studied in elevated plus-maze and marble- burying tests. The mRNA levels were quantified by qPCR. RESULTS: AY mutation caused anxiety in males and obsessive-compulsive behavior in females. Positive correlation between Agouti and Raly genes mRNA levels were shown in the hypothalamus, hippocampus, and frontal cortex in AY/a mice. Reduced RNA concentrations of Mc3r and Mc4r genes were found respectively in the hypothalamus and frontal cortex in AY/a males. The Raly gene expression positively correlates with mRNA concentrations of the Mc3r gene in the hypothalamus and the Mc4r gene in the hypothalamus and frontal cortex. CONCLUSION: Possible association of obsessive-compulsive behavior with reduced Raly, Mc3r, or Mc4r gene expression is suggested.

Investigating the role of the central melanocortin system in stress and stress-related disorders.

The melanocortinergic neural circuit, known for its influence on energy expenditure and feeding behavior, also plays a role in stress and stress-induced psychiatric disorders, including anxiety and depression. The major contribution is given by the melanocortin-4 receptor (MC4R) subtype, highly expressed in brain regions involved in the control of stress responses. Furthermore, the MC4R appears to profoundly affect the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and it has been also highlighted a functional and anatomical interaction with the corticotropin-releasing factor (CRF), an important mediator of stress and stress-related behaviors. The MC4R agonists seem to exacerbate stress-inducing anxiety- and depressive-like behavior, while MC4R antagonists have been demonstrated to mitigate such disorders, as shown in several preclinical behavioral tests. The evidence collected in the present review suggests that the melanocortin system, through the MC4R, could possibly modulate behavioral responses to stress, suggesting the use of MC4R antagonists as a possible novel treatment for anxiety and depression induced by stress.

TRPV1-Mediated Sensing of Sodium and Osmotic Pressure in POMC Neurons in the Arcuate Nucleus of the Hypothalamus.

The central melanocortin system conducted by anorexigenic pro-opiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARC) not only regulates feeding behavior but also blood pressure. Excessive salt intake raises the Na+ concentration ([Na+]) in the cerebrospinal fluid (CSF) and worsens hypertension. The blood-brain barrier is immature in the ARC. Therefore, both AgRP and POMC neurons in the ARC have easy access to the electrolytes in the blood and can sense changes in their concentrations. However, the sensitivity of AgRP and POMC neurons to Na+ remains unclear. This study aimed to explore how the changes in the extracellular Na+ concentration ([Na+]) influence these neurons by measuring the cytosolic Ca2+ concentration ([Ca2+]i) in the single neurons isolated from the ARC that were subsequently immunocytochemically identified as AgRP or POMC neurons. Both AgRP and POMC neurons responded to increases in both [Na+] and osmolarity in C57BL/6 mice. In contrast, in transient receptor potential vanilloid 1 (TRPV1) knockout (KO) mice, POMC neurons failed to respond to increases in both [Na+] and osmolarity, while they responded to high glucose and angiotensin II levels with increases in [Ca2+]i. Moreover, in KO mice fed a high-salt diet, the expression of POMC was lower than that in wild-type mice. These results demonstrate that changes in [Na+] and osmolarity are sensed by the ARC POMC neurons via the TRPV1-dependent mechanism.

CX3CL1 Action on Microglia Protects from Diet-Induced Obesity by Restoring POMC Neuronal Excitability and Melanocortin System Activity Impaired by High-Fat Diet Feeding.

Both hypothalamic microglial inflammation and melanocortin pathway dysfunction contribute to diet-induced obesity (DIO) pathogenesis. Previous studies involving models of altered microglial signaling demonstrate altered DIO susceptibility with corresponding POMC neuron cytological changes, suggesting a link between microglia and the melanocortin system. We addressed this hypothesis using the specific microglial silencing molecule, CX3CL1 (fractalkine), to determine whether reducing hypothalamic microglial activation can restore POMC/melanocortin signaling to protect against DIO. We performed metabolic analyses in high fat diet (HFD)-fed mice with targeted viral overexpression of CX3CL1 in the hypothalamus. Electrophysiologic recording in hypothalamic slices from POMC-MAPT-GFP mice was used to determine the effects of HFD feeding and microglial silencing via minocycline or CX3CL1 on GFP-labeled POMC neurons. Finally, mice with hypothalamic overexpression of CX3CL1 received central treatment with the melanocortin receptor antagonist SHU9119 to determine whether melanocortin signaling is required for the metabolic benefits of CX3CL1. Hypothalamic overexpression of CX3CL1 increased leptin sensitivity and POMC gene expression, while reducing weight gain in animals fed an HFD. In electrophysiological recordings from hypothalamic slice preparations, HFD feeding was associated with reduced POMC neuron excitability and increased amplitude of inhibitory postsynaptic currents. Microglial silencing using minocycline or CX3CL1 treatment reversed these HFD-induced changes in POMC neuron electrophysiologic properties. Correspondingly, blockade of melanocortin receptor signaling in vivo prevented both the acute and chronic reduction in food intake and body weight mediated by CX3CL1. Our results show that suppressing microglial activation during HFD feeding reduces DIO susceptibility via a mechanism involving increased POMC neuron excitability and melanocortin signaling.

Regulation of the central melanocortin system on energy balance in mammals and birds.

Agouti-related protein/neuropeptide Y (AgRP/NPY) neurons promote feeding, while proopiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/CART) neurons and melanocortin receptor neurons inhibit feeding; these three types of neurons play vital roles in regulating feeding. The central melanocortin system composed of these neurons is critical for the regulation of food intake and energy metabolism. It regulates energy intake and consumption by activating or inhibiting the activities of AgRP/NPY neurons and POMC/CART neurons and then affects the feeding behaviour of animals to maintain the energy balance. Meanwhile, organisms can also positively or negatively regulate energy homeostasis through the negative feedback of the neuron system. With further studies, understanding of the process and factors involved in the energy balance regulation of mammals and birds can be improved, which will provide a favourable scientific basis to reduce costs and improve meat production in production and breeding.

Development of "Hunger Neurons" and the Unanticipated Relationship Between Energy Metabolism and Mother-Infant Interactions.

Over the course of a lifetime, the perinatal period plays an outsized role in the function of physiological systems. Here, we discuss how neurons that regulate energy metabolism contribute to the infant's relationship with the mother. We focus our discussion on Agrp neurons, which are located in the arcuate nucleus of the hypothalamus. These neurons heavily regulate energy metabolism. Because offspring transition from a period of dependence on the caregiver to independence, we discuss the importance of the caregiver-offspring relationship for the function of Agrp neurons. We present evidence that in the adult, Agrp neurons motivate the animal to eat, while in the neonate, they motivate the offspring to seek the proximity of the caregiver. We specifically highlight the peculiarities in the development of Agrp neurons and how they relate to the regulation of metabolism and behavior over the course of a lifetime. In sum, this review considers the unique insights that ontogenetic studies can offer toward our understanding of complex biological systems, such as the regulation of energy metabolism and mother-infant attachment.

Melanocortin receptor agonists suppress experimental autoimmune uveitis.

The melanocortin system plays an essential role in the regulation of immune activity. The anti-inflammatory microenvironment of the eye is dependent on the expression of the melanocortin-neuropeptide alpha-melanocyte stimulating hormone (α-MSH). In addition, the melanocortin system may have a role in retinal development and retinal cell survival under conditions of retinal degeneration. We have found that treating experimental autoimmune uveitis (EAU) with α-MSH suppresses retinal inflammation. Also, this augmentation of the melanocortin system promotes immune tolerance and protection of the retinal structure. The benefit of α-MSH-therapy appears to be dependent on different melanocortin receptors. Therefore, we treated EAU mice with α-MSH-analogs with different melanocortin-receptor targets. This approach demonstrated which melanocortin-receptors suppress inflammation, preserve retinal structure, and induce immune tolerance in uveitis. At the chronic stage of EAU the mice were injected twice 1 day apart with 50 µg of α-MSH or an α-MSH-analog. The α-MSH-analogs were a pan-agonist PL8331, PL8177 (potent MC1r-only agonist), PL5000 (a pan-agonist with no MC5r functional activity), MT-II (same as PL5000) and PG901 (MC5r agonist, but also an antagonist to MC3r, and MC4r). Clinical EAU scores were measured until resolution in the α-MSH-treated mice, when the eyes were collected for histology, and spleen cells collected for retinal-antigen-stimulated cytokine production. Significant suppression of EAU was seen with α-MSH or PL8331 treatment. This was accompanied with significant preservation of retinal structure. A similar effect was seen in EAU-mice that were treated with PL8177, except the suppression of EAU was temporary. In EAU mice treated with PL5000, MTII, or PG901, there was no suppression of EAU with a significant loss in whole retina and outer-nuclear layer thickness. There was significant suppression of IL-17 with induction of IL-10 by retinal-antigen stimulated spleen T cells from EAU mice treated with α-MSH, PL8331, PL8177, or PL5000, but not from EAU mice treated with MT-II, or PG901. Our previous studies show the melanocortin system's importance in maintaining ocular immune privilege and that α-MSH-treatment accelerates recovery and induces retinal-antigen-specific regulatory immunity in EAU. Our current results show that this activity is centered around MC1r and MC5r. In addition, the results suggest that a therapeutic potential to target MC1r and MC5r together to suppress uveitis induces regulatory immunity with potentially maintaining a normal retinal structure.

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.

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.

Rolling out physical exercise and energy homeostasis: Focus on hypothalamic circuitries.

Energy balance is the fine regulation of energy expenditure and energy intake. Negative energy balance causes body weight loss, while positive energy balance promotes weight gain. Modern societies offer a maladapted way of life, where easy access to palatable foods and the lack of opportunities to perform physical activity are considered the roots of the obesity pandemic. Physical exercise increases energy expenditure and, consequently, is supposed to promote weight loss. Paradoxically, physical exercise acutely drives anorexigenic-like effects, but the mechanisms are still poorly understood. Using an evolutionary background, this review aims to highlight the potential involvement of the melanocortin system and other hypothalamic neural circuitries regulating energy balance during and after physical exercise. The physiological significance of these changes will be explored, and possible signalling agents will be addressed. The knowledge discussed here might be important for clarifying obesity aetiology as well as new therapeutic approaches for body weight loss.

Changes in daily energy expenditure and movement behavior in unilateral vestibular hypofunction: Relationships with neuro-otological parameters.

The vestibular system has been found to affect energy homeostasis and body composition, due to its extensive connections to the brainstem and melanocortin nuclei involved in regulating the metabolism and feeding behavior. The aim of this study was to evaluate - by means of a wrist-worn physical activity tracker and bioelectrical impedance analysis (BIA) - the energy expenditure (EE) in resting (REE) and free-living conditions and movement behavior in a group of chronic unilateral vestibular hypofunction (UVH) patients when compared with a control group (CG) of healthy participants. Forty-six chronic UVH and 60 CG participants underwent otoneurological (including video-Head Impulse Test [vHIT] for studying vestibulo-ocular reflex [VOR] and static posturography testing [SPT]), and EE and movement measurements and self-report (SRM) andperformance measures (PM). As well as significant (p < 0.001) changes in SPT variables (area and path length) and SRM/PM, UVH participants also demonstrated significantly (p < 0.001) lower values in REE, movement EE, hours/day spent upright, number of strides and distance covered and total daily EE (p = 0.007) compared to the CG. UVH patients consumed significantly lower Kcal/min in sweeping (p = 0.001) and walking upstairs and downstairs (p < 0.001) compared to the CG. Multiple correlations were found between free-living and resting EE and neuro-otological parameters in UVH participants. Since the melanocortin system could be affected along the central vestibular pathways as a consequence of chronic vestibular deafferentation, data collected by reliable wearables could reflect the phenomena that constitute an increased risk of falls and sedentary lifestyle for patients affected by UVH, and could improve rehabilitation stages.

Anti-Obesity Effect of Pine Needle Extract on High-Fat Diet-Induced Obese Mice.

BACKGROUND: Obesity due to an excessive intake of nutrient disturbs the hypothalamus-mediated energy metabolism subsequently develops metabolic disorders. In this study, we investigated the effect of pine needle extract (PNE) on the hypothalamic proopiomelanocortin (POMC) neurons involved in the regulation of energy balance via melanocortin system and fat tissue metabolism. METHODS: We performed electrophysiological and immunohistochemical analyses to determine the effect of PNE on POMC neurons. Mice were fed a normal or high-fat diet for 12 weeks, then received PNE for the last 2 weeks to measure the following physiological indices: Body weight, food intake, fat/lean mass, glucose metabolism, and plasma leptin levels. In addition, changes of thermogenic, lipolytic, and lipogenetic markers were evaluated in brown adipose tissue (BAT) and white adipose tissue (WAT) by western blotting, respectively. RESULTS: PNE increased hypothalamic POMC neuronal activity, and the effect was abolished by blockade of melanocortin 3/4 receptors (MC3/4Rs). PNE decreased body weight, fat mass, plasma leptin levels, and improved glucose metabolism after high-fat-induced obesity. However, PNE did not change the expression of thermogenic markers of the BAT in HFD fed groups, but decreased only the lipogenetic markers of WAT. This study suggests that PNE has a potent anti-obesity effect, inhibiting lipogenesis in WAT, even though HFD-induced leptin resistance-mediated disruption of POMC neuronal activity.

Changes in body composition in unilateral vestibular hypofunction: relationships between bioelectrical impedance analysis and neuro-otological parameters.

PURPOSE: Experimental works have indicated the potential of the vestibular system to affect body composition to be mediated by its extensive connections to brainstem nuclei involved in regulating metabolism and feeding behavior. The aim of this study was to evaluate-by means of bioelectrical impedance analysis (BIA)-the body composition in a group of chronic UVH normal-weighted patients when compared with an equally balanced group of healthy participants, serving as a control group (CG). METHODS: Forty-six chronic UVH and 60 CG participants underwent otoneurological (including video Head Impulse Test [vHIT] and static posturography testing [SPT]), BIA measurements and self-report (SRM) and performance measures (PM). RESULTS: Beyond significant (p < 0.001) changes in SPT variables (surface and length) and SRM/PM (including Dizziness Handicap Inventory, Dynamic Gait Index and Activity Balance Confidence scales), UVH participants demonstrated significant (p < 0.001) higher values of fat mass and visceral fat and lower values of muscle mass (p = 0.004), when compared to CG. Significant correlations were found in UVH participants between otoneurological and BIA measurements. CONCLUSION: These study findings represent the first clinical in-field attempt at depicting, with the use of BIA parameters, changes in body composition related to chronic UVH. Since such alterations in metabolic parameters could be considered both the consequences and/or the cause of vestibular-related quality of life deficit, BIA parameters could be considered as cheap, easy to use, noninvasive assessments in case of chronic UVH.

The Melanocortin System behind the Dysfunctional Eating Behaviors.

The dysfunction of melanocortin signaling has been associated with obesity, given the important role in the regulation of energy homeostasis, food intake, satiety and body weight. In the hypothalamus, the melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) contribute to the stability of these processes, but MC3R and MC4R are also localized in the mesolimbic dopamine system, the region that responds to the reinforcing properties of highly palatable food (HPF) and where these two receptors seem to affect food reward and motivation. Loss of function of the MC4R, resulting from genetic mutations, leads to overeating in humans, but to date, a clear understanding of the underlying mechanisms and behaviors that promote overconsumption of caloric foods remains unknown. Moreover, the MC4R demonstrated to be a crucial modulator of the stress response, factor that is known to be strictly related to binge eating behavior. In this review, we will explore the preclinical and clinical studies, and the controversies regarding the involvement of melanocortin system in altered eating patterns, especially binge eating behavior, food reward and motivation.

The Melanocortin System in Atlantic Salmon (Salmo salar L.) and Its Role in Appetite Control.

The melanocortin system is a key neuroendocrine network involved in the control of food intake and energy homeostasis in vertebrates. Within the hypothalamus, the system comprises two main distinct neuronal cell populations that express the neuropeptides proopiomelanocortin (POMC; anorexigenic) or agouti-related protein (AGRP; orexigenic). Both bind to the melanocortin-4 receptor (MC4R) in higher order neurons that control both food intake and energy expenditure. This system is relatively well-conserved among vertebrates. However, in Atlantic salmon (Salmo salar L.), the salmonid-specific fourth round whole-genome duplication led to the presence of several paralog genes which might result in divergent functions of the duplicated genes. In the current study, we report the first comprehensive comparative identification and characterization of Mc4r and extend the knowledge of Pomc and Agrp in appetite control in Atlantic salmon. In silico analysis revealed multiple paralogs for mc4r (a1, a2, b1, and b2) in the Atlantic salmon genome and confirmed the paralogs previously described for pomc (a1, a2, and b) and agrp (1 and 2). All Mc4r paralogs are relatively well-conserved with the human homolog, sharing at least 63% amino acid sequence identity. We analyzed the mRNA expression of mc4r, pomc, and agrp genes in eight brain regions of Atlantic salmon post-smolt under two feeding states: normally fed and fasted for 4 days. The mc4ra2 and b1 mRNAs were predominantly and equally abundant in the hypothalamus and telencephalon, the mc4rb2 in the hypothalamus, and a1 in the telencephalon. All pomc genes were highly expressed in the pituitary, followed by the hypothalamus and saccus vasculosus. The agrp genes showed a completely different expression pattern from each other, with prevalent expression of the agrp1 in the hypothalamus and agrp2 in the telencephalon. Fasting did not induce any significant changes in the mRNA level of mc4r, agrp, or pomc paralogs in the hypothalamus or in other highly expressed regions between fed and fasted states. The identification and wide distribution of multiple paralogs of mc4r, pomc, and agrp in Atlantic salmon brain provide new insights and give rise to new questions of the melanocortin system in the appetite regulation in Atlantic salmon.

The Resolution Approach to Cystic Fibrosis Inflammation.

Despite the high expectations associated with the recent introduction of CFTR modulators, airway inflammation still remains a relevant clinical issue in cystic fibrosis (CF). The classical anti-inflammatory drugs have shown very limited efficacy, when not being harmful, raising the question of whether alternative approaches should be undertaken. Thus, a better knowledge of the mechanisms underlying the aberrant inflammation observed in CF is pivotal to develop more efficacious pharmacology. In this respect, the observation that endogenous proresolving pathways are defective in CF and that proresolving mediators, physiologically generated during an acute inflammatory reaction, do not completely suppress inflammation, but promote resolution, tissue healing and microbial clearance, without compromising immune host defense mechanisms, opens interesting therapeutic scenarios for CF. In this mini-review, we present the current knowledge and perspectives of proresolving pharmacology in CF, focusing on the specialized proresolving lipid mediators and selected peptides.