Skip to main content



  • Access


      • Send article to Kindle

        To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

        Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

        Find out more about the Kindle Personal Document Service.

        Dopaminergic pathways in obesity-associated immuno-metabolic depression
        Available formats
        Send article to Dropbox

        To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

        Dopaminergic pathways in obesity-associated immuno-metabolic depression
        Available formats
        Send article to Google Drive

        To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

        Dopaminergic pathways in obesity-associated immuno-metabolic depression
        Available formats
Export citation

Immuno-metabolic diseases emerge in clusters since a state of chronic systemic inflammation associated to metabolic dysfunction disrupts homeostasis in multiple organs such as adipose tissue and brain (Hotamisligil, 2017). The association between obesity and depression is well established (Lasselin and Capuron, 2014), although the underlying pathophysiological mechanisms remain unrevealed. Lamers et al. (2018) found increased appetite as the core symptom driving the associations between depression and both metabolic and inflammatory markers highlighting a specific biological type of depression. The novelty of such findings resides in the mechanisms regulating appetite such as dopaminergic pathways being also involved in immunomodulation and inflammation. Systemic inflammation is a stronger contributor of obesity-related depressive symptoms than metabolic dysfunction per se (Delgado et al., 2018). Major depressive disorder patients, during a depressive episode, have a subclinical inflammation and reduced response to lipopolysaccharide in monocytes (Zhang et al., 2018). Moreover, higher leptin was associated with hyperphagia, independently from weight (Milaneschi et al., 2017). We found that plasma levels of leptin, very-low-density lipoprotein-cholesterol and CD14 expression in monocyte subsets are predictors of subclinical inflammatory obesity (Leite et al., 2017a), which can constitute an important tool for early therapeutic interventions in obesity-related comorbidities, namely depression.

Dopaminergic pathways have a major role in appetite regulation and as immunoregulators in inflammation. Immune cells, neurons and adipocytes share common signalling pathways mediated by catecholamines (CA), and dopamine (DA) plays a prominent and so far, possibly underestimated role (Flierl et al., 2008; Borcherding et al., 2011; Pinoli et al., 2017). DA regulates behaviour, reward, movement, endocrine, cardiovascular, renal and gastrointestinal functions, but it is also a crucial transmitter in the neuroimmune network, contributing to the nervous–immune systems interplay as well as in the communication among immune cells (Pinoli et al., 2017). We showed that central obesity is associated with a distinct pattern of CA receptors in circulating immune cells and that β 2-adrenoceptors (AR) and dopaminergic receptors (DR)D2 might be protective towards visceral obesity (Leite et al., 2016, 2017b). β 2-AR and DRD2 transcripts were associated with lower inflammatory pattern of monocytes and with a better metabolic profile, suggesting an immunomodulatory role for CA in obesity-associated inflammation.

DA exerts its effects through the interaction with five different DR (D1−5). Human monocytes express all DR and evidence suggests that DA inhibit monocyte NLRP3 inflammasome thus resulting in the reduction of the inflammatory processes (Pinoli et al., 2017).

Monocytes in peripheral blood are considered as classical (CD14++CD16), intermediate (CD14++CD16+) and non-classical monocytes (CD14+CD16++). Expansion of the intermediate monocyte subset has been described in chronic inflammatory diseases (Wong et al., 2012), while the contribution of non-classical monocyte subset in inflammation remains unclear.

We studied DR expression in human monocyte subsets and the effect of DA on phosphorylation of monocyte signal transducer and activator of transcription 3 (STAT3), a crucial step in the production of pro-inflammatory cytokines in obesity and interacts with the double-stranded RNA-sensing kinase PKR, a critical mediator of inflammasome activity and metabolic regulation (Hotamisligil, 2017). Our results show that all five DR are expressed by circulating monocytes, however DR+ cells are on average only 16–33% of classical and intermediate monocytes but about 89–96% of non-classical monocytes, and incubation of whole blood with DA reduced IL-6-induced phosphorylation of STAT3 in CD14+ monocytes (Fig. 1).

Fig. 1. Dopaminergic receptors are preferentially expressed on proinflammatory monocytes and dopamine downregulates STAT3 phosphorylation. (a) In peripheral blood, the majority of circulating monocytes is represented by classical (CD14++ CD16−) monocytes, while intermediate (CD14++ CD16+) and proinflammatory (CD14+ CD16++) monocytes are on average, respectively, 13% and 8% of total monocytes. (b) Both D1- and D2-like dopaminergic receptors (DR) are expressed by circulating monocytes; however, while on average only 16–33% of classical (empty) and intermediate (shaded) monocytes are DR+, with low expression levels, about 89–96% of proinflammatory monocytes (dashed) are DR+, with high expression levels. (c) Incubation of whole blood with dopamine 1 µm reduces IL-6 100 ng/mL-induced phosphorylation of STAT3 in CD14+monocytes (methodology in online Supplementary Information).

Preferential DR expression on non-classical monocytes in comparison with classical and intermediate monocyte subsets suggests that DA anti-inflammatory effects involve mainly non-classical monocytes. Our findings in human monocytes of reduction of IL-6-induced STAT3 phosphorylation by DA infers an immunomodulatory role for this CA given STAT3 function in the production of pro-inflammatory cytokines and its interaction with PKR mediating metabolic signals and inflammasome activity.

DA and dopaminergic agonists interfere with tumour necrosis factor-α and nitric oxide production in mouse monocytes and DA modulate the expression of surface markers, such as the Fc-γ receptor, important for host defence (Pinoli et al., 2017). This suggests that dopaminergic pathways in human monocytes may counteract the effects of proinflammatory stimuli, acting on the non-classical subset and to a minor extent in the intermediate subset, the main responding subset of monocytes to standardized low-grade inflammation (Thaler et al., 2016).

Macrophages convey information to the nervous system regulating behaviour, metabolism and inflammation through direct access to CA produced by the sympathetic nerve (Camell et al., 2017). However, monocytes/macrophages themselves produce CA (Marino and Cosentino, 2013; Pinoli et al., 2017). CA, particularly DA, are key signalling molecules connecting monocytes/macrophages, adipocytes and sympathetic nerve terminals thus regulating immuno-metabolic disease clusters including depression. Dopaminergic pathways might thus allow simultaneously targeting adiposity, inflammation and the immuno-metabolic depression.

Supplementary material

The supplementary material for this article can be found at

Author contributions

FL, MC and FM analysed the data, conceived and wrote the manuscript with the contribution of ER, MG, AL and LR. ER and MG-produced the experiments. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. All authors agree to be accountable for all aspects of the work in ensuring that the questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved and declare to have confidence in the integrity of the contributions of their co-authors.


Borcherding, DC, Hugo, ER, Idelman, G, De Silva, A, Richtand, NW, Loftus, J and Ben-Jonathan, N (2011) Dopamine receptors in human adipocytes: expression and functions. PLoS ONE 6, e25537.
Camell, CD, Sander, J, Spadaro, O, Lee, A, Nguyen, KY, Wing, A, Goldberg, EL, Youm, YH, Brown, CW, Elsworth, J, Rodeheffer, MS, Schultze, JL and Dixit, VD (2017) Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 550, 119123.
Delgado, I, Huet, L, Dexpert, S, Beau, C, Forestier, D, Ledaguenel, P, Aubert, A, Sauvant, J, Aouizerate, B, Magne, E and Capuron, L (2018) Depressive symptoms in obesity: relative contribution of low-grade inflammation and metabolic health. Psychoneuroendocrinology 91, 5561.
Flierl, MA, Rittirsch, D, Huber-Lang, M, Sarma, JV and Ward, PA (2008) Catecholamines – crafty weapons in the inflammatory arsenal of immune/inflammatory cells or opening Pandora's box? Molecular Medicine 14, 195204.
Hotamisligil, GS (2017) Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177185.
Lamers, F, Milaneschi, Y, de Jonge, P, Giltay, EJ and Penninx, BWJH (2018) Metabolic and inflammatory markers: associations with individual depressive symptoms. Psychological Medicine 48, 11021110.
Lasselin, J and Capuron, L (2014) Chronic low-grade inflammation in metabolic disorders: relevance for behavioral symptoms. Neuroimmunomodulation 21, 95101.
Leite, F, Leite, Â, Santos, A, Lima, M, Barbosa, J, Cosentino, M and Ribeiro, L (2017 a) Predictors of subclinical inflammatory obesity: plasma levels of leptin, very low-density lipoprotein cholesterol and CD14 expression of CD16+ monocytes. Obesity Facts 10, 308322.
Leite, F, Lima, M, Marino, F, Cosentino, M and Ribeiro, L (2016) Dopaminergic receptors and tyrosine hydroxylase expression in peripheral blood mononuclear cells: a distinct pattern in central obesity. PLoS ONE 11, e0147483.
Leite, F, Lima, M, Marino, F, Cosentino, M and Ribeiro, L (2017 b) Β2 adrenoceptors are under expressed in peripheral blood mononuclear cells and associated with a better metabolic profile in central obesity. International Journal of Medical Sciences 14, 853861.
Marino, F and Cosentino, M (2013) Adrenergic modulation of immune cells: an update. Amino Acids 45, 5571.
Milaneschi, Y, Lamers, F, Peyrot, WJ, Baune, BT, Breen, G, Dehghan, A, Forstner, AJ, Grabe, HJ, Homuth, G, Kan, C, Lewis, C, Mullins, N, Nauck, M, Pistis, G, Preisig, M, Rivera, M, Rietschel, M, Streit, F, Strohmaier, J, Teumer, A, Van der Auwera, S, Wray, NR, Boomsma, DI, Penninx, BWJH and CHARGE Inflammation Working Group and the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (2017) Genetic association of major depression with atypical features and obesity-related immunometabolic dysregulations. JAMA Psychiatry 74, 12141225.
Pinoli, M, Marino, F and Cosentino, M (2017) Dopaminergic regulation of innate immunity: a review. Journal of Neuroimmune Pharmacology 12, 602623.
Thaler, B, Hohensinner, PJ, Krychtiuk, KA, Matzneller, P, Koller, L, Brekalo, M, Maurer, G, Huber, K, Zeitlinger, M, Jilma, B, Wojta, J and Speidl, WS (2016) Differential in vivo activation of monocyte subsets during low-grade inflammation through experimental endotoxemia in humans. Scientific Reports 6, 30162.
Wong, KL, Yeap, WH, Tai, JJ, Ong, SM, Dang, TM and Wong, SC (2012) The three human monocyte subsets: implications for health and disease. Immunologic Research 53, 4157.
Zhang, HX, Xu, YQ, Li, YY, Lu, MF, Shi, SX, Ji, JL and Wang, LW (2018) Difference in proinflammatory cytokines produced by monocytes between patients with major depressive disorder and healthy controls. Journal of Affective Disorders 234, 305310.