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发布日期: Jul 17, 2019
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WRITER     
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Dopaminergic Pathways in Obesity-Associated Inflammation

Introduction.Humanity is on the fat track with the obesity epidemic worsening worldwide as recently demonstrated by the Global Burden of Disease study (GBD 2015 Obesity Collaborators 2017 ). Obesity is a complex disorder (Ghosh and Bouchard 2017 ). The acquisition of so-called modern Western lifestyle and its main negative features [excessive energy intake, decreasing physical activities, sedentary lifestyle (Church et al. 2011 ), stress and disruption of chronobiology (Laermans and Depoortere 2016 )] may directly impact the steady rise of obesity prevalence (Heymsfield and Wadden 2017 ). Obesity is associated with an increased risk of insulin resistance, type 2 diabetes (T2D), fatty liver disease, dyslipidemia, neurodegenerative disorders (Hotamisligil 2006 ), including dementia, depression (Lasselin and Capuron 2014 ; Kivipelto et al. 2018 ; Leite et al. 2018 ), certain types of cancers (Kolb et al. 2016 ) and with premature death (Greenberg 2013 ). Thus, it is expected that the increased prevalence of obesity justifies an intensified search for its causal factors (Ghosh and Bouchard 2017 ).During the last decades, research on pathways linking the pathogenesis of obesity with insulin resistance and diabetes has revealed a close relationship between nutrient excess and activation of the innate immune system in most organs related to energy homeostasis. A state of chronic low-grade inflammation is responsible for the metabolic dysfunction observed in obesity (Hotamisligil 2017a ).Dopamine (DA), a canonical central nervous system (CNS) neurotransmitter, is involved in the control of cognition, motivation, movement and reward (Feldman et al. 1997 ), Indeed, the mesolimbic dopamine system has been a primary focus of study concerning the relationship between food intake and brain reward systems and, as well, eating behaviors leading to obesity. Dopaminergic pathways not only have a major role in the regulation of appetite and feeding behaviors (Timper and Brüning 2017 ) but also as immunoregulators in inflammation (Pinoli et al. 2017 ); thus, dopaminergic regulation is suggested to impact in obesity-associated inflammation (Leite et al. 2016 ). Immune cells, neurons and adipocytes share common signaling pathways mediated by catecholamines (CA), and DA seems to have a prominent but underestimated role in this tripartite crosstalk (Flierl et al. 2008 ; Borcherding et al. 2011 ; Pinoli et al. 2017 ). DA, existing in peripheral tissues (Matt and Gaskill 2019 ) has effects on blood pressure, sodium balance and adrenal and renal functions (Tayebati et al. 2011 ; Jose et al. 2003 ), as well as glucose homeostasis and body weight (Rubí and Maechler 2010 ). DA is also a critical transmitter in the neuroimmune network, where, besides its contribution to the crosstalk between the nervous and immune systems, is a mediator of communication among immune cells (Cosentino et al. 2003 ; Cosentino et al. 2012 ; Cosentino and Marino 2013 ; Marino and Cosentino 2016 ; Pinoli et al. 2017 ). Importantly, human adipocytes express functional dopaminergic receptors (DR) involved in cytokine/adipokine release and are transcriptionally regulated during early adipogenesis (Borcherding et al. 2011 ).The role of dopaminergic pathways in immune-mediated diseases has been intensively investigated such as in multiple sclerosis (Cosentino and Marino 2013 ; Marino and Cosentino 2016 ), Parkinson’s disease (González et al. 2013 ; Kustrimovic et al. 2016 ) and rheumatoid arthritis (Capellino et al. 2014 ; Nakano et al. 2011 ). Comparatively, dopaminergic immunomodulation in obesity-associated inflammation is largely unknown.The present review will integrate the actual knowledge about dopaminergic pathways involved in obesity-associated inflammation with special focus on immune innate key cell players (monocytes/macrophages). We will propose a model that integrate central and peripheral dopaminergic circuits in the relationship between neuroimmune and metabolic systems in obesity- associated inflammation. A perspective on the potential role of dopaminergic drugs in the context of obesity will be given.Obesity and Inflammation: a Macrophage Point of View.A state of low chronic systemic inflammation associated to metabolic dysfunction disrupts the homeostasis in multiple organs such as adipose tissue (AT), liver, pancreas and brain contributing to disability and premature death (Hotamisligil 2017a ). The physiological communication between different tissues and organs has been considered crucial for the systemic involvement of obesity in disease manifestation (Lee et al. 2009 ) and the inflammatory pathways have been shown to be of most importance in the network of inter-tissue crosstalk (Samdani et al. 2015 ).The association between obesity and chronic low-grade inflammation emerged when macrophages were reported to accumulate in white AT (WAT) with the development of diet induced or genetic obesity in mice (Weisberg et al. 2003 ; Xu et al. 2003 ) and in humans with obesity (Cinti et al. 2005 ; Curat et al. 2006 ; Harman-Boehm et al. 2007 ; Cancello et al. 2005 ).The link between chronic inflammation and metabolic disease has been extensively described in elegant reviews (Hotamisligil 2017a , b ; Lee et al. 2018 ). The systemic chronic metabolic inflammation or “metaflammation” (Hotamisligil 2006 ) is implicated in metabolic disease namely in insulin resistance (Eguchi and Nagai 2017 ). The main characteristics of metabolic inflammation are altered circulating cytokine profiles, immune cell infiltration into tissues and activation of inflammatory pathways within tissue parenchyma (Chan et al. 2019 ). In humans with obesity, circulating pro-inflammatory cytokines becomes elevated including monocyte chemoattractant protein- 1 (MCP- 1/CCL2), interleukin- (IL-) 1β, IL-6, IL-8, IL-10, IL-12, IL-18, IFNδ, and tumor necrosis factor- (TNF-) α and C-reactive protein (CRP) (Chan et al. 2019 ). Other proinflammatory mediators are also involved in the development of obesity-associated insulin resistance such as lipopolysaccharide (LPS) from the membrane of gram-negative bacteria residing in gut microbiota (Yamashita et al. 2018 ) which has been considered as a major trigger factor linking excessive fat intake and the development of obesity-associated inflammation (Cani et al. 2007 ). In obesity induced by high fat diet (HFD), the expansion of visceral AT (VAT) has detrimental effects in intestinal barrier integrity favoring metabolic dysfunction and, although controversial, (Boutagy et al. 2016 ) metabolic endotoxemia (Kallio et al. 2015 ; Lassenius et al. 2011 ; Monte et al. 2012 ).In obese patients, not only was observed an increase in total macrophages in the AT (Weisberg et al. 2003 ; Xu et al. 2003 ), but subsequent studies established that T cells, B cells, eosinophils, mast cells, dendritic cells, natural killer cells, and neutrophils also infiltrate AT in human and rodent models of obesity (Hotamisligil 2017b ).AT inflammation is, also, an adaptative response which enables appropriate homeostasis with AT remodeling and expansion in response to caloric excess and contributes to a visceral depot barrier that filters gut-derived endotoxin (Wernstedt Asterholm et al. 2014 ).VAT increased macrophage accumulation is a key pathologic feature of obesity (Weisberg et al. 2003 ) and its comorbidities mentioned before. Mature adipocytes represent 20%–40% of the cellular content of AT and in addition to a matrix of extracellular proteins, adipocytes are surrounded by immune cells, endothelium, fibroblasts, preadipocytes, and stem cells (Kanneganti and Dixit 2012 ).Increased AT lipolysis was shown to induce adipose tissue macrophages (ATM) accumulation in mice (Kosteli et al. 2010 ) and generates a lipidic environment once exceeded the circulating fatty acids (FA) concentrations. Saturated FA can induce inflammatory responses in macrophages through Toll-like receptors (TLR) 2 and 4 signaling pathways (Shi et al. 2006 ; Huang et al. 2012 ) or activating directly the NLRP3 inflammasome with subsequent IL-1β release ((L'homme et al. 2013 ; Li et al. 2013 ).ATM suffer “polarization shift”, from resident/ “M2-like” cells, to proinflammatory, “classically activated/M1” macrophages, proposed to promote AT inflammation in obese mice (Lumeng et al. 2007a , b ; Nguyen et al. 2007 ), and confirmed in humans (Zeyda et al. 2007 ; Aron-Wisnewsky et al. 2009 ). In murine experimental models, free fatty acid (FFA) exposure, via TLR2 and TLR4 and c-jun N-terminal kinase (JNK)-dependent pathways, promotes ATM M1 polarization expressing cytokines like TNF-α, IL-6, and IL-1β in response to LPS and interferon δ (IFN-δ), with the capacity of blocking insulin action (Lumeng et al. 2007a , b ; Nguyen et al. 2005 , 2007 ; Hevener et al. 2007 ). On the other phenotype pole of the spectrum M2 macrophages have a role in tissue remodeling with secretion of anti-inflammatory cytokines such as IL-10 and IL-1 receptor antagonist. In mice, adipocyte class II major histocompatibility complex (MHCII) increased within 2 weeks on HFD preceding ATM accumulation and proinflammatory M1 polarization (Deng et al. 2013 ). Moreover, murine adipocytes may act as antigen-presenting cells (APCs) stimulating IFN-γ-expressing CD4+ T cells, interacting with both macrophages and T cells (Xiao et al. 2016 ). Human adipocytes have been shown to induce inflammation and activate CD4+ cells independent of macrophages (Meijer et al. 2011 ). Free FA (FFA) promotes adipocytes hypertrophy and expression of MHCII-associated genes (Xiao et al. 2016 ).M1 and M2 macrophages is suggested to be the two extremes in a more complex in vivo cell population continuum (Xue et al. 2014 ; Wynn et al. 2013 ). The origin of tissue macrophage accumulation is due during obesity development, at least partially, to either monocyte transmigration from peripheral blood (Weisberg et al. 2006 ; Oh et al. 2012 ; Kanda et al. 2006 ; Nagareddy et al. 2014 ), proliferative expansion of local ATM (Amano et al. 2014 ; Haase et al. 2014 ; Zheng et al. 2016 ; Braune et al. 2017 ) (in mice and humans), or to differentiation of hematopoietic progenitors resident in AT (Poglio et al. 2012 ). The increased accumulation of macrophages is associated with AT dysfunction and related insulin resistance in mouse models (Weisberg et al. 2003 ; Kanda et al. 2006 ) and in humans with obesity comorbidities (Cinti et al. 2005 ; Harman-Boehm et al. 2007 ). However, insulin resistance may precede ATM accumulation and inflammation in AT as it is suggested by the work of Shimobayashi et al. (2018 ) since in mice and in human VAT insulin resistance in adipocytes results in production of the MCP-1, which recruits monocytes and activates proinflammatory macrophages. Moreover, it has been proposed by Kratz et al. (2014 ) a specific phenotype for ATM, “metabolically activated macrophages” distinct from classical activation.M2 macrophages can promote browning of white AT. In a BALB/cJ mice background, cold exposure was found to polarize macrophages toward the alternatively activated form in an IL-4-dependent manner, leading to the formation and secretion of catecholamines (CA) (Nguyen et al. 2011 ). Importantly, alternatively activated macrophages produce and secrete noradrenaline (Flierl et al. 2007 ) allowing these cells to coordinate the thermogenic response in animals suffering cold stress insult. In addition to noradrenaline and adrenaline, it has been shown in murine brown adipocytes that DA increases thermogenesis mediated by direct effect on D1-like receptor (Kohlie et al. 2017 ).In addition to peripheral inflammation, obesity triggers inflammatory pathways in the central nervous system (CNS), with special focus on the hypothalamus given its role in regulating appetite and feeding behavior (Schwartz et al. 2000 ). High saturated fat diets trigger hypothalamic inflammation, leading to central leptin and insulin resistance, and as result increased food intake and weight gain (Milanski et al. 2009 ). As a consequence of these findings, further investigation into the involvement of central immune cells in metabolic dysfunction has evolved.There is a crosstalk between macrophages and neurons at both central and peripheral levels. Brain macrophages, the microglia, establish a bidirectional communication with neurons in both physiological and pathological states (Schafer et al. 2012 ; Cardona et al. 2006 ; Wohleb 2016 ; Szepesi et al. 2018 ). A neuroimmune communication has been proposed in the sense that macrophages convey information to the nervous system to regulate behavior, metabolism and inflammation through direct access to CA produced by the sympathetic nerve (Camell et al. 2017 ). In this regard, it should be considered that monocytes/macrophages themselves, like many other different immune cells, produce CA (Pinoli et al. 2017 ; Cosentino and Marino 2013 ; Cosentino et al. 2014 ; Marino and Cosentino 2013 ). CA, and in particular, DA are likely key signaling molecules connecting monocytes/macrophages, adipocytes and sympathetic nerve terminals thus regulating immune-metabolic disease clusters.HFD induces pro-inflammatory signals in the hypothalamus in rodents and humans (Thaler et al. 2012 ) and it has been suggested that, in both rats and mice, this inflammation occurs before weight gain (Thaler et al. 2012 ). Microglia sense directly saturated FA and orchestrate TLR4 downstream inflammatory response in the mediobasal hypothalamus (Valdearcos et al. 2014 ) and related neuronal dysfunction (e.g. anorexigenic leptin action) with a critical role for nuclear factor-kB (NF-kB) signaling (Valdearcos et al. 2017 ). However, is still unknown whether microglia response is required for the neuronal inflammation and dysfunction and/or the obesogenic diet has a direct neuronal effect (Ávalos et al. 2018 ).At the periphery, in AT, there is a crosstalk between macrophages and neurons. This interaction is classically described as the result of AT innervation by the sympathetic nervous system (SNS) (Lafontan 2012 ). It has been shown anatomical and functional associations between sympathetic neurons and macrophages in white AT (WAT) (Camell et al. 2017 ; Pirzgalska et al. 2017 ) and brown AT (BAT) (Wolf et al. 2017 ). Sympathetic neuron associated macrophages (SAM), a unique macrophage population has been described to accumulate in AT as a sink of the excessive CA released by neuronal terminals, in an obesity model, and by this way controlling the lipolytic tone of WAT (Pirzgalska et al. 2017 ; Bartness et al. 2014 ). It was also established an association between reduced lipolysis in aged mice, with concomitant higher inflammation, and increased CA catabolism machinery in WAT macrophages due to upregulation of monoamine oxidase A (Mao A) and Comt (catechol-o-methyltransferase) genes in an inflammasome -dependent pathway (Camell et al. 2017 ).DA, through dopaminergic receptors (DR) present in human adipocytes (Borcherding et al. 2011 ) and in human monocytes/macrophages (McKenna et al. 2002 ; Pinoli et al. 2017 ), is a key molecule in the neuro-immune- metabolic crosstalk in AT. According to Borcherding et al. (2011 ) while DR D2 mediates the inhibitory effect of DA on adipocyte prolactin gene expression, D1-like DR are involved in the regulation of adipokine/cytokine release. Indeed, DA inhibited leptin release and moderately stimulated adiponectin and IL-6. DA can reach adipocytes from infiltrating or resident immune cells, namely monocytes/macrophages, through sympathetic neuronal terminals or via circulatory dopamine- sulfate (DA-S) that suffer de-conjugation by arylsulfatase becoming bioactive DA (Borcherding et al. 2011 ).Dopaminergic Pathways and Inflammation.DA has an important immunomodulatory role in both innate (Pinoli et al. 2017 ) and adaptative immunity (Basu and Dasgupta 2000 ; Sarkar et al. 2010 ; Levite 2012 , 2016 ). Immune cells themselves produce and release DA with autocrine and paracrine effects (Cosentino et al. 2002 , 2005 , 2007 ). The dopaminergic regulation of innate immunity has been recently reviewed (Cosentino and Marino 2013 ; Pinoli et al. 2017 ) and will not be covered here in detail. Notwithstanding it is worth stressing important concepts of dopaminergic pathways both at central and peripheral levels concerning feeding behaviors, homeostatic metabolic systems and immunomodulatory effects bringing the fundamentals for the support of a newly described dopaminergic signaling pathway in the obesity-associated inflammation. Since the cellular key players in metaflammation are monocytes/macrophages, we will focus on these immune innate cells although adaptative immune cells have been also implicated in inflammatory obesity in murine experimental models (Feuerer et al. 2009 ; Yang et al. 2010 ; Cipolletta et al. 2012 ; Bapat et al. 2015 ) and in humans (Winer et al. 2011 ; DeFuria et al. 2013 ). DA has been described as a possible transmitter in the crosstalk between innate and adaptative immunity (Nakano et al. 2009 ; Nakagome et al. 2011 ; Pinoli et al. 2017 ).The first and rate limiting step of DA biosynthesis is the hydroxylation of the L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) via tyrosine hydroxylase (TH) followed by the action of L-DOPA decarboxylase (DDC) and then can be converted to noradrenaline and adrenaline by, respective and subsequently, the action of the enzymes dopamine β-hydroxylase and phenylethanolamine N-methyltransferase (PNMT).The dopaminergic neurons are clustered in the i) midbrain substantia nigra giving rise to ascending fibers densely innervating the basal ganglia, with highest dopamine levels occurring in the caudate and putamen and in the ii) ventral tegmental area (VTA) projecting axons mainly into the nucleus accumbens (NAcc) and prefrontal cortex. DA acts on specific dopaminergic receptors (DR) belonging to the G protein-coupled receptor (GPCR) family of class A seven-transmembrane domain receptors, which are categorized in two main families: D1-like (D1 and D5 receptors) and D2-like (D2, D3, and D4 receptors). DR transmit signals toward two transducer-coupled systems: one using heterotrimeric G protein activation and the other using noncanonical G protein-independent, β-arrestin-dependent mechanisms. Indeed, DR signaling, apart from their canonical action on cAMP-mediated signaling, can regulate several cellular responses of dopamine-associated functions. DR signaling pathways may involve alternate G protein coupling or non-G protein mechanisms such as ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization (Beaulieu et al. 2015 ). DRs are functionally classified into the D1-like (D1 and D5 stimulatory receptors) located both pre- and post-synaptically and D2-like subtypes mainly post-synaptic (D2, D3 and D4 inhibitory receptors), based on their ability to stimulate the formation or inhibition of cyclic adenosine monophosphate (cAMP), respectively (Pinoli et al. 2017 ; Arreola et al. 2016 ). DR may form complexes of oligomers with other DR or with different receptors in neurons (Pinoli et al. 2017 ) which may impact therapeutic responses.The role of DA as immunoregulator depends on leukocyte subtype, state of cellular activation, DA concentration and time of exposure. DA regulates cell activation, cell adhesion, proliferation, chemotaxis, apoptosis, cytotoxicity, cytokine and antibody production and changes in phenotype and function of immune cells (Cosentino et al. 2003 , 2007 , 2012 ; Cosentino and Marino 2013 ; Arreola et al. 2016 ).DA regulates immune response via its effect on hematopoiesis (Cosentino et al. 2015 ) and on cells involved in the immune response (Cosentino et al. 2012 ; Pinoli et al. 2017 ). Bone marrow (BM) is innervated by sympathoadrenergic efferent nerve fibers (Kuntz and Richins 1945 ) in which the hematopoietic stem cell (HSC) niche microenvironment is crucial for HSC homeostasis (Schofield 1978 ). Hematopoiesis is regulated by CA, namely by DA (Cosentino et al. 2015 ) even in stress conditions (Dygai and Skurikhin 2011 ). In BM, DA and other CA may originate not only from nerve terminals but also from hematopoietic and immune cells (Maestroni et al. 1998 ) with a circadian release for DA and NA in a murine model, (Maestroni et al. 1998 ). Indeed, there is a circadian control of the immune system (Scheiermann et al. 2013 ). Spiegel et al. (2007 ) have demonstrated the expression of DR D3 and DR D5 in human HSC CD34+ cells with higher expression in the more immature CD34 + CD38lo cells in comparison with the more differentiated CD34 + CD38hi cells. This work also showed that DA is a chemoattractant enhancing the migration of immature CD34+ cells. In addition, transcriptome analysis demonstrated a relative expansion of the immature proinflammatory monocyte in peripheral blood mononuclear cells from people subject to chronic social stress and mice subject to repeated social defeat (Powell et al. 2013 ; Bergamini et al. 2018 ). After Powell et al. (2013 ) there is an increased risk of inflammation- related diseases associated with chronic stress events mediated by sympathoadrenergic induction of myelopoiesis. Human obesity-associated inflammation is characterized by sympathetic nervous system (SNS) activation (Lambert et al. 2010 ); although the mechanisms responsible for initiating catecholaminergic activation remain to be completely elucidated, stress and catecholaminergic receptor polymorphisms are implicated (Lambert et al. 2010 ). Importantly, obesity is associated with psychoneurological comorbidities, such as, chronic stress, anxiety and depression (Niccolai et al. 2019 ; Leite et al. 2018 ). It is well established that chronic stress increases proliferation of HSC, giving rise to higher levels of disease-promoting inflammatory leukocytes in mice and humans (Heidt et al. 2014 ). Chronic stress induced monocytosis and neutrophilia in humans via stress activation of upstream HSC (Heidt et al. 2014 ). Mice, under chronic variable stress, showed higher release of CA from sympathetic nerve fibers which signaled bone marrow niche cells to decrease CXCL12 levels and to increase HSC proliferation leading to higher output of neutrophils and inflammatory monocytes (Nagareddy et al. 2014 ; Cosentino et al. 2015 ).As stated before, an important milestone in obesity is that VAT becomes infiltrated by monocytes and inflammation has been shown to drive the recruitment of blood monocyte-derived macrophages. In murine models of obesity, monocytosis was associated with proliferation and expansion of BM myeloid progenitors (Nagareddy et al. 2014 ). Adipose S100A8/A9 induced ATM TLR4/MyD88 and NLRP3 inflammasome-dependent IL-1β production. The interaction of IL-1β with the respective IL-1 receptor on BM myeloid progenitors stimulate the production of monocytes in the BM remotely (Nagareddy et al. 2014 ). These data suggest an important role for the positive feedback loop between ATMs and BM myeloid progenitors for obesity- associated inflammation.Human monocytes express all DR and DA might inhibit monocyte NLRP3 inflammasome thus resulting in reduction of inflammation (reviewed in Pinoli et al. 2017 ). Due to their heterogeneity, human monocytes are divided in subsets based on the different stages of differentiation, size and activation, characterized according to the expression of CD14, the LPS co-receptor, and by the FCγIII receptor CD16 that binds IgG complexed with modified low-density lipoprotein cholesterol. Monocytes in peripheral blood are usually considered as classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical monocytes (CD14 + CD16++) (Wong et al. 2012 ). The two CD16 positive subsets are commonly named proinflammatory monocytes. Alterations of monocyte subsets has been described in chronic inflammatory diseases, namely in human obesity (Rogacev et al. 2010 ), usually with expansion of the intermediate subset (Wong et al. 2012 ).In circulating human monocytes DR expression depends upon monocyte subsets: DR+ cells represent 16–33% of classical and intermediate monocytes and 89–96% of non-classical monocytes (Leite et al. 2018 ). DA reduced IL-6-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in CD14+ monocytes (Leite et al. 2018 ). The noticed higher expression of DR on non-classical CD14+ cells in comparison to classical and intermediate monocyte subsets suggests that the non-classical monocytes may be the main CD14+ cells subset implicated in the anti-inflammatory effects of DA (Leite et al. 2018 ). Zawada et al. showed a link to inflammation in human intermediate monocytes (CD14++CD16+) but not in the non-classical subset with genome-wide miRNA profiling data and Gene Ontology enrichment analysis approach (Zawada et al. 2011 ; Zawada et al. 2017 ). Accordingly, functional studies identified the non-classical monocytes as main targets for reduction of inflammation (Mukherjee et al. 2015 ). Indeed, the finding of significantly higher DR expression on this monocyte subset in comparison to classical and intermediate CD14+ cells is in agreement with the action of DA on DR in LPS-stimulated bone marrow-derived macrophages mitigating the inflammatory process through the inhibition of the NLRP3 inflammasome (Yan et al. 2015 ). This effect suggests that DR on non-classical monocytes mediate a potential antiinflammatory action of endogenous DA.In a previous work, we found a reduction of the expression of DR D2, D4 and D5 and lower levels of TH mRNA in PBMCs from individuals with central obesity (CO) in comparison to the non-obese group; DR D2 and D5 expression in these cells strongly correlated with a lower inflammatory pattern of peripheral monocytes (Leite et al. 2016 ).Decreased expression of DR D2 in PBMCs has been associated with other inflammatory immune mediated diseases (Magro et al. 2006 ; Jafari et al. 2013 ). In fact, DR D2 agonists reduced disease activity in patients with rheumatoid arthritis (McMurray 2001 ; Mobini et al. 2011 ) and decreased serum immunoglobulin and anti-DNA antibody levels in SLE patients (McMurray 2001 ). Single-nucleotide polymorphisms of DR D2 were found associated to DR D2 lower expression and function and consequent increased inflammation in human renal proximal tubule cells (Jiang et al. 2014 ).The role of the inflammasome in metabolic disease is well established (reviewed in Hotamisligil 2017a ) due to its function in AT macrophages gene upregulation related to CA inactivation and the downstream lipolysis dysfunction (Camell et al. 2017 ). In line with these works, human monocytes reduction of IL-6-induced STAT3 phosphorylation by DA (Leite et al. 2018 ) suggests an immunomodulatory role for this CA given STAT3 role in the production of pro-inflammatory cytokines and its connection with PKR mediating metabolic signals and inflammasome activity.Interestingly, LPS-stimulated monocytic cell lines increase DA levels and DA at high concentrations increased the apoptosis and decreased their proliferation. DA and dopaminergic agonists are capable to interfere with the production of TNF-α and nitric oxide in mouse monocytes and DA can also modulate the expression of surface markers, such as the Fc-gamma receptor, with a key role in host defense (Pinoli et al. 2017 ). It might be therefore suggested that dopaminergic pathways in human monocytes counteract the effects of proinflammatory stimuli, possibly acting preferentially on the non-classical subset, but only to a minor extent in the intermediate subset, which has been recently proposed as the main responding subset of monocytes to standardized low-grade inflammation (Thaler et al. 2016 ).Role of Central and Peripheral Dopaminergic Pathways in Obesity-Associated Inflammation.The presence of DA in the bloodstream suggests that dopaminergic signaling pathway must be an important regulator not only centrally but also in periphery mainly on the immune system (Pinoli et al. 2017 ; Cosentino and Marino 2013 ) and other organs such as AT (Borcherding et al. 2011 ; Ayala-Lopez et al. 2014 ) pancreas ((Rubí and Maechler 2010 ) and kidneys (Cuevas et al. 2013 ).Inflammatory pathways in the brain and in metabolic tissues induced by obesity dysregulate insulin and leptin sensitivity. Rodent models of diet induced obesity (DIO) (Apolzan and Harris 2012 ; la Fleur et al. 2014 ; Choi et al. 2014 ; Sinasac et al. 2016 ) have shown that high fat diet (HFD) feeding has impact upon hypothalamic pathways with changes on key genes expression related to feeding regulation (De Souza et al. 2005 ; Ahima and Antwi 2008 ). Preclinical (Avena et al. 2008 ; Stice et al. 2013 ; Kenny 2011 ; Volkow and Wise 2005 ) and clinical studies (Wang et al. 2001 ; Haltia et al. 2007 ; Volkow et al. 2008 ; Dunn et al. 2012 ) suggested that overeating, particularly high-fat high-sugar diets, and obesity induces alterations on neural brain regions of the reward dopaminergic circuit although the mechanisms are still unrevealed.Although food intake is regulated by the reward-related mechanisms through the mesolimbic dopaminergic pathways (Kelley and Berridge 2002 ) as well by stress HPA (hypothalamic-pituitary-adrenal) axis activity (Adam and Epel 2007 ; Lovallo and Buchanan 2017 ), we will focus on dopaminergic pathways.Dopaminergic signaling in the reward pathway in the brain has been shown to play an important role in food intake and the development of obesity (Kenny 2011 ). Obesity, adiposity, metabolic dysfunction and high- fat and -sugar diets induce changes in DA function at molecular, cellular and circuit levels with impact in wide DA-dependent functions such as compulsive behaviors (Adams et al. 2015 ; Johnson and Kenny 2010 ), food preference and nutrient sensing (Tellez et al. 2013 ; Han et al. 2016 ) and glucose metabolism regulation (DeFronzo 2011 ; Diepenbroek et al. 2013 ). Hence, DA genetic variants are expected to have effects in ingestive behavior and obesity. Indeed, genotypes that appear to be associated with reduced signaling of DA circuitry, including DR D2, DR D4 and DA transporter (DAT), are correlated with obesity (Stice and Dagher 2010 ). Thus, a possible scenario of a vicious cycle is set DA genetic variants influence brain function promoting an unhealthy diet and consequent weight gain in obesogenic environments, which in turn impacts brain function to induce metabolic and cognitive dysfunction and further weight gain.Since DA release has a key role in the pleasure perception, dysregulation of dopaminergic pathway is described to be linked to addiction behavior (Johnson and Kenny 2010 ), although being controversial the parallel established between drug and food “addiction” (Epstein and Shaham 2010 ). Indeed, striatal DR D2 were downregulated in obese rats (Johnson and Kenny 2010 ) who release less DA in the NAcc after food intake, and amphetamine stimulated striatal DA release is reduced in vivo in obese subjects, suggesting the involvement of DA hypofunction associated with hedonic dysregulation in the pathophysiology of obesity (Johnson and Kenny 2010 ). This finding in murine models is consistent with reports in humans suggesting that obesity was associated with altered DR D2 signaling in the striatum. DR D2 availability and striatal DAT correlated negatively with body mass index (BMI) in obesity and in healthy volunteers (Wang et al. 2001 ; Chen et al. 2008 ). The presence of the dopamine receptor 2/ankyrin repeat domain and content kinase 1 (DRD2/ANKK1) TaqIA polymorphism (rs1800497), which is associated with reduced DR D2, was found among individuals with blunted dorsal striatal response to a palatable food consumption and subsequent weight gain (Stice et al. 2008 ; Rivera-Iñiguez et al. 2018 ). In line with the Johnson and Kenny work, the blunted response was suggested to be a consequence rather than a cause of obesity, as it was associated with significant increase in BMI in a 6-month period (in women) (Stice et al. 2010 ), and not with risk for obesity by means of parental obesity (Stice et al. 2011 ; Ridaura et al. 2013 ). In human postmortem brain of obese subjects, radioligand binding assays in midbrain DA neurons demonstrated that the number of striatal DAT binding sites was inversely correlated with increasing BMI (Wu et al. 2017 . DAT and TH gene expression were decreased in the somatodendritic compartment of obese subjects suggesting that obesity is associated with hypodopaminergic function (Wu et al. 2017 ).The fat mass and obesity associated gene (FTO) and the TaqIA restriction fragment length polymorphism (RFLP) rs1800497 are two common variants in driving gene-environment interplay promoting obesity, metabolic dysfunction and cognitive impairment via their influence on DR D2 signaling. Indeed, FTO gene inactivation impairs DR D2-dependent neurotransmission and function in mice (Hess et al. 2013 ) and DR D2-dependent learning in humans (Sevgi et al. 2015 ). TaqIA RFLP, which is associated in humans with variation in DR D2 receptor density (Thompson et al. 1997 ; Jönsson et al. 1999 ), was shown to interact with a variant of FTO gene to influencing adiposity, central and peripheral insulin resistance and DRD2-dependent learning (Sevgi et al. 2015 ; Heni et al. 2016 ). Indeed, TaqIA1 allele in DRD2 is associated with lower DR D2 availability in the striatum, reduced dopamine signaling and obesity (Stice et al. 2008 ).Another important research area is the gut-brain axis concerning diet-induced gut regulation of central dopaminergic circuits and food reward (Sanz and Moya-Pérez 2014 ). Mice fed with low-fat diet showed a significant rise in extracellular DA in the striatum and reduced sensitivity to orally presented lipids upon intralipid infusion into the gut in comparison with high-fat fed animals (Tellez et al. 2013 ). This report demonstrates that gut lipid messengers, depleted in an HFD, blunted DA and perceptual responses to fat independently of adiposity since the two groups of mice showed no differences in body weight (Tellez et al. 2013 ). So, diet may contribute to downregulate DR D2 despite weight gain. Moreover, in murine experimental models, diets with higher ratio fat/carbohydrate promotes DR D2 downregulation (van de Giessen et al. 2013 ; Adams et al. 2015 ) and this specificity supports the parallel between food and drug addiction approach (DiFeliceantonio et al. 2018 ). After Tellez and colleagues (Tellez et al. 2013 ) prolonged saturated-fat intake induces depletion of gut lipid messengers such as oleoylethanolamine, reducing intestinal sensitivity to fat intake and blunts vagal afferent signaling and therefore DA release. Moreover, oleoylethanolamine dopaminergic effect relies on a peroxisome proliferator–activated receptor alpha (PPARα)-gastrointestinal-brain axis. Notwithstanding, it is still unrevealed the molecular mechanism by which receptors are downregulated. It has been argued that overeating of nutritional lipids triggers inflammatory responses in the brain through partial mediation of lipid-activated receptors and activation of TLR and NF-κB, which in turn acts on transcriptional regulation of DR D2 (Sun et al. 2017 ). Microbiota composition changes induced by DIO (Sonnenburg and Bäckhed 2016 ; Torres-Fuentes et al. 2017 ) promote hypothalamic inflammation and alter hypothalamic gene expression leading to central leptin resistance and obesity (de Git and Adan 2015 ).It should be noted that apart from central dopaminergic pathways related to modulation of the hedonic properties of food and food intake (Kenny 2011 ), TH neurons are sensitive to hunger signals and directly modulate the activity of hypothalamic neurons involved in energy homeostasis by DA release in the hypothalamic arcuate and paraventricular nucleus (Zhang and van den Pol 2016 ). Moreover, neuroactive metabolites produced by microbiome can regulate appetite, since DA and more than half of its peripheral production occurs at gut level (Eisenhofer et al. 1997 ). Gut microbiome-mediated inflammation associated with obesity (Shen et al. 2013 ) affects the neuroendocrine and neurotransmitter metabolism in dopaminergic system and basal ganglia (Carabotti et al. 2015 ).Chronic social stress has been proposed to lead to low-grade systemic inflammation (Rohleder 2014 ). In a rodent model, a chronic social stressor induced immune activation in the VTA- NAcc DA pathway, reduced VTA-NAcc DA pathway functioning, reduced NAcc DA-dependent reward-directed behavior and in the periphery immune-inflammation activation (including higher levels of inflammatory monocytes) (Bergamini et al. 2018 ). Thus, stress leads to peripheral and central immune activation which is associated with blunted DA neural function (Bierhaus et al. 2003 ; Liu et al. 2017 ; Azzinnari et al. 2014 ; Bergamini et al. 2018 ). We can argue that inflammatory pathways could explain the downregulation of DR in the CNS (Sun et al. 2017 ) and in peripheral blood mononuclear cells (PBMCs) in obesity (Leite et al. 2016 ) with a key role for the gut-brain axis.So far, most of the studies concerning the relationship between DA and obesity has mainly focused in the CNS (Blum et al. 2014 ; Kenny et al. 2013 ; Baik 2013 ; Rubí and Maechler 2010 ; Cho et al. 2018 ). However, an association between obesity and hyposensitivity of dopaminergic systems, both within the CNS (Wang et al. 2001 ; Heni et al. 2016 ; Rivera-Iñiguez et al. 2018 ) and in peripheral tissues (Perez-Cornago et al. 2014 ) has been established. In opposition to DA brain functions related to metabolism, the role of peripheral dopaminergic signaling pathways in obesity is unknown and recognized as an emergent research area (Carlin et al. 2013 ; Kaczmarczyk et al. 2013 ).Peripheral DA, released into the circulatory system, may have its origin from diet and neuronal and non-neuronal sources (Goldstein and Holmes 2008 ; Eisenhofer and Goldstein 2004 ) such kidney, adrenal gland and neuroendocrine cells (Rubí and Maechler 2010 ). As stated before, human obesity is characterized by SNS activation (Lambert et al. 2010 ), thus this condition is suggested to be associated to increased DA plasma levels (Van Loon 1983 ; Bell 1988 ). DA is involved in several peripheral functions, including the control of both glucose metabolism and body weight, blood pressure modulation, inhibition of gastric acid secretion and apoptosis of tumoral cells (Pernet et al. 1984 ; Eliassi et al. 2008 ; Rubí and Maechler 2010 ).In a group of healthy men, DA at pharmacological dosage had minor effects although DA enhanced lipolysis and ketogenesis during somatostatin-induced insulin deficiency and at higher dose of DA a hyperglycemic effect was detected (Pernet et al. 1984 ). In a cohort of RESMENA (Metabolic Syndrome Reduction in Navarra), a randomized clinical trial, the group subjected to a 6-month weight loss intervention showed higher blood levels of DA in comparison with the group without intervention and plasmatic DA concentration inversely correlated with the carbohydrate intake during the study. In addition, basal DA levels predicted a greater decrease in body weight and anthropometric parameters (Perez-Cornago et al. 2014 ).The role of peripheral DA in obesity has been restricted to its influence on pancreatic β cells, with a dopaminergic phenotype, regulating insulin release (Farino et al. 2019 ; Rubí et al. 2005 ) and to the modulation of insulin effects on adipocytes (Rubí and Maechler 2010 ; Borcherding et al. 2011 ). DA release from hypothalamic cells inhibits prolactin secretion from the pituitary gland and indirectly regulate insulin and dopamine production on islet cells, which express TH, DOPA-decarboxylase (Teitelman et al. 1981 ) and DR (Chen et al. 2014 ; Rubí et al. 2005 ). DR D2 blockade with sulpiride, an antagonist with poor penetration of the BBB, increases food intake and body weight in female rats due to hyperprolactemia (Parada et al. 1989 ). Prolactin stimulates receptors expressed in α and β cells of rat pancreatic islets (Sorenson and Stout 1995 ) inducing β cell proliferation and insulin secretion (Brelje et al. 1994 ). So, DR antagonists may induce hyperinsulinemia and obesity via regulation of prolactin. DA inhibits directly the secretory response of pancreatic β cells mediated by DR D2 ((Rubí et al. 2005 ). DA reach pancreas from several sources: adrenal medulla, as transmitter along with NA release from sympathetic nerve that innervate both exocrine and endocrine pancreas (Kirchgessner and Gershon 1990 ) and DA production by pancreatic islets. Thus, in pancreatic tissue, there is an autocrine/paracrine dopaminergic signaling pathway that contribute for insulin secretion regulation. Moreover, immune cells namely, resident and nonresident macrophages, which are in close proximity with DA-producing islet cells have shown, in NOD mice, a key role in pancreatic function (Carrero et al. 2017 ). Changes in insulinemia DA- mediated in addition with the inflammatory phenotype of DA exposed immune cells, suggest that DA may contribute to pancreatic diseases such as diabetes (Boldison and Wong 2016 ). The DA-insulin pathway can also explain in brain the loss of responsiveness of striatal DA release to insulin in rats with obesogenic diet (Stouffer et al. 2015 ).In AT, it has been suggested a regulatory role of peripheral DA as human adipocytes cell lines express DR and DA is able to directly affect differentiation and proliferation of adipocytes themselves (Borcherding et al. 2011 ). DR D2 is abundantly expressed on human pancreatic β cell and adipocytes (Auriemma et al. 2018 ). So far, DA has been shown to have an inhibitory effect on leptin release from human adipocytes through D1-like DR receptors (Borcherding et al. 2011 ) and to modify the secretion of insulin in peripheral tissues of humans and animals (Leblanc et al. 1977 ; Quickel Jr et al. 1971 ). In fact, DA inhibited insulin secretion in a pancreas preparation from golden hamster, mouse and rabbit (Feldman and Lebovitz 1972 ; Quickel Jr et al. 1971 ) and a decrease in insulin levels was also shown in Parkinson disease patients in the early phase of treatment with L-DOPA (Rosati et al. 1976 ).Yu et al. (2014 ) described in A10 cell culture model, a smooth muscle cell line from rat thoracic aorta, a negative effect through DR D4 activation on insulin action via decreasing insulin receptor expression. Blocking peripheral DR could therefore increase insulin release, adipogenesis, weight gain and insulin resistance (Rubí and Maechler 2010 ); these detrimental metabolic effects have been associated to neuroleptics use (Deng 2013 ) as discussed later in this review.Human visceral adipocyte cells were shown to express 10-fold greater DR D2 protein than subcutaneous adipocytes in non-overweight, non-diabetic donors undergoing elective abdominal surgery (Wang et al. 2018 ). In this work, mouse 3 T3-L1 cell cultures were treated with quinpirole, a DR D2-like receptor agonist which increased the protein and mRNA expression of leptin and IL-6 and as well the expression of TNF-α, MCP1, and NFkB-p50. These quinpirole effects on leptin and IL-6 expression were blunted by the DR D2 antagonist and mimetized by siRNA-mediated silencing of Drd2. The DR D2-mediated increase in leptin expression was abolished by a phosphoinositide 3-kinase inhibitor. In C57Bl/6 J mice, acute treatment with quinpirole increased serum leptin concentration and leptin transcript in visceral but not in subcutaneous adipocytes suggesting that the stimulation of DR D2 increases leptin production and subsequent pro-inflammatory effect in adipocytes tissue-specific (Wang et al. 2018 ). In opposition, Auriemma et al. (2018 ) state that in patients with hyperprolactinemia, implicated in obesity pathogenesis, medical treatment with dopamine- agonists bromocriptine and cabergoline significantly improve metabolic profile and induce weight loss. These opposite results show the complexity of the dopaminergic pathways involved in the multifactorial nature of the obesity-associated inflammation. The different models of studies and the intricate crosstalk between neuro-immune metabolic network infers a challenge to unravel the molecular mechanisms that regulate dopaminergic signaling in obesity.Obesity can also be related to dysfunction of the peripheral dopaminergic system (Rubí and Maechler 2010 ; Leite et al. 2016 ). Adipocytes express DR and possess an active ARSA (Borcherding et al. 2011 ), indicating a regulatory role for peripheral DA converted back from DA-S in AT functions. In a metabolic healthy population of blood donors, we found central (visceral) obesity (CO) associated with inflammation with higher plasma levels of leptin and a more inflammatory pattern of non-classical monocytes (Leite et al. 2016 , 2017a , b ). In addition, PBMCs from CO individuals exhibited reduction of the expression of DR D2, DR D4 and DR D5 as well as lower levels of TH mRNA in comparison to the non-obese group; DR D2 and DR D5 expression in PBMCs strongly correlated with lower weight, BMI and waist circumference (WC), lower plasma levels of leptin and with a lower inflammatory pattern, while DR D4 mRNA correlated with lower glycated hemoglobin (HbA1c) and TH mRNA correlated with lower WC and leptin levels. (Leite et al. 2016 ).Moreover, it has been revealed that in a cohort of adults within the Methyl Epigenome Network Association Project the methylation status on DA signaling genes may underlie epigenetic mechanisms contributing to obesity (Ramos-Lopez et al. 2018 ). As stated before and importantly, the modulation by DA of immunity has a major role in the modulation of immune-mediated diseases as it is obesity, namely in hematopoiesis (Cosentino et al. 2015 ) and on cells involved in the immune response (Cosentino et al. 2012 ; Pinoli et al. 2017 ). DR D2 agonists increase the secretion of antiinflammatory cytokines in human lymphocytes (Besser et al. 2005 ). In PBMCs from patients with multiple sclerosis, an immune-mediated inflammatory disease, DR D5 was reported to be reduced (Giorelli et al. 2005 ; Cosentino et al. 2014 ) and to be a predictor for therapeutic response to immunomodulating treatment with interferon- β (Cosentino et al. 2014 ). PBMCs expression of DR D2 and D5 (and to a lesser extent also of D4 and TH) were found associated with lower weight, with better metabolic/endocrine parameters and with a less inflammatory pattern. Moreover, logistic regression analysis suggested that DR D2 expression in PBMCs could have a protective role for the existence of CO (Leite et al. 2016 ). The associations between the expression of DR and TH in immune cells and more favorable metabolic/endocrine and inflammatory parameters suggest a possible role for dopaminergic pathways in the crosstalk between immunity and metabolism.Dopaminergic Therapy: a New Perspective for Old Drugs in Obesity.Dopaminergic regulation of the immune response has been subject of reflection considering the repurposing of dopaminergic drugs for immune mediated diseases (Cosentino and Marino 2013 ) and as modulators of hematopoiesis related malignancies and cancer -induced bone disease (Cosentino et al. 2015 ). The complexity of dopaminergic pathways involved in the regulation of immunity, metabolism and neuronal functions is truly a challenge to identify DA molecular targets that putatively impact obesity-associated inflammation. However, in diseases which drugs of choice are dopaminergic agents, it should be emphasized clinical metabolic- and non-metabolic-related effects.It is well documented the association of drugs with dopamine D2-like receptor antagonism, such as antipsychotics, and weight gain and type2 diabetes (Nicol et al. 2018 ) although the cellular mechanism is still completely unrevealed. Apart from DA effects on food behavior and endocrine function, DA regulates the action of insulin in peripheral tissues. For instance, clozapine and olanzapine induced increased secretion of insulin in isolated rat pancreatic islets (Melkersson 2004 ), while DA agonists in ob/ob mice restored β cell hyperplasia and reduced insulinemia in vivo (Jetton et al. 2001 ). The risk of weight gain and obesity depends on the type of antipsychotics [higher with olanzapine than with risperidone in youths (Nicol et al. 2018 )]. In mice, atypical antipsychotics (clozapine, olanzapine and risperidone), via action on adipocytes, induced insulin resistance, altered lipogenesis and lipolysis contributing to a progressive adiposity accumulation (Vestri et al. 2007 ). Atypical antipsychotic drugs act not only on DR D2 but also on type-2 serotonin receptors. Thus, caution should be taken in establishing causality between these medical agents and obesity notwithstanding some genetic studies provided insights favoring such relationship. DR D3 knockout mice showed increased adiposity (McQuade et al. 2004 ). Recently, in β-cell from transgenic DR D2 or DR D3 knockout mice, it has been suggested a new mechanism where D2-like receptors modify DA release to modulate glucose-stimulated insulin secretion with marked postprandial hyperinsulinemia in vivo in selective DR D2 knockout mice (Farino et al. 2019 ). The above studies suggest that blockade of peripheral D2-like receptors by antipsychotic drugs may significantly contribute to the metabolic dysfunctions observed in clinic.Human genetic association studies evidence DA regulatory role in metabolism. Monoamine oxidase A (MAO), an enzyme involved in DA degradation, is partially expressed in human pancreatic islet cells. In male humans, associations were found between MAOA promoter variable number tandem repeat and categories of BMI (Fuemmeler et al. 2008 ). Moreover, even not consensual (Guo et al. 2006 ), the seven-repeat allele of DR D4 gene, related to impaired cellular DA response, has been associated with higher BMI compared with probands without this allele (Levitan et al. 2004 ). In addition, similarly to the human study demonstrating that DR D2 availability and striatal dopamine transporter (DAT) correlated negatively with BMI both in obesity and in healthy volunteers (Wang et al. 2001 ; Chen et al. 2008 ), molecular imaging studies in mice showed that high levels of DAT and DR D2 in brain correlated with resistance to high-fat-diet-induced obesity (Huang et al. 2006 ; South and Huang 2008 ).It is well established a relationship between DA signaling at central and peripheral levels and glucose metabolism, body weight and cardiovascular risk markers (Rubí and Maechler 2010 ). In opposition of antipsychotic drugs that impair DR D2 signaling and are associated with weight gain, treatment with D2-like receptor agonist bromocriptine in obese women improves metabolic parameters (Kok et al. 2006 ). Patients with prolactinomas tend to have increased body weight in comparison to healthy individuals. DA agonists are the treatment of choice in patients with prolactinoma that may result in weight loss (Schmid et al. 2006 ) and improvement in metabolic parameters such as lipid profile and insulin resistance in some patients (dos Santos Silva et al. 2011 ). A nonrandomized matched prospective study showed that patients with prolactinomas treated continuously for 6 months with cabergoline, a DR D2 agonist, had a decrease of body weight, BMI, waist circumference, waist-to-hip ratio, total body fat, plasma glucose and leptin levels (Pala et al. 2016 ). Moreover, in a cohort of 44 prolactinoma patients with continuous 2-year dopaminergic treatment a significant mean weight loss was verified regardless of the Taq1a status (Athanasoulia et al. 2014 ).As stated before, beyond the central dopaminergic tone and its implications in weight loss, there is a crucial role of peripheral DA, since human adipocytes express functional DR (Borcherding et al. 2011 ), suggesting a regulatory function of peripheral DA in AT.Bromocriptine was also approved by the Food and Drug Administration (FDA) in 2009 for the treatment of type 2 diabetes mellitus, as monotherapy or in association with the available drugs (metformin, sulfonylureas, thiazolidinediones and insulin). In fact, bromocriptine has been shown to decrease plasmatic fasting and postprandial glucose, glycated hemoglobin (HbA1c) and cardiovascular events in diabetic population (Lamos et al. 2016 ). Evidence exists concerning the effect of bromocriptine administration on weight and body fat loss in obese normoprolactinemic patients (Cincotta and Meier 1996 ). Although the mechanisms are still unknown, it seems that in ob/ob mice bromocriptine effects on glucose homeostasis are associated with a decrease in serum prolactin levels (Furigo et al. 2019 ) and prolactin levels modulate glucose homeostasis.Cabergoline, a potent DR D2 agonist, has been shown to decrease HbA1c and fasting glucose levels in a type 2 diabetic population (Bahar et al. 2016 ) but independently of weight loss (Gibson et al. 2012 ).Patients with Parkinson’s disease (PD) or restless legs syndrome that are being treated with DA agonists showed an increased frequency of impulse control disorders (ICD) (Voon et al. 2009 ), including compulsive binge eating and weight gain (Nirenberg and Waters 2006 ). The occurrence of ICD may be due to overstimulation of mesolimbic DR in the central dopaminergic reward system (Voon et al. 2009 ), in particular DR D3 (Ali et al. 2010 ), but the predisposing factors for the development of these central side effects of thoroughly administered DA agonists are yet not known.Scientific evidence amounts establishing a role for central and peripheral dopaminergic pathways in human obesity, similarly to other human immune mediated diseases such as multiple sclerosis (Cosentino and Marino 2013 ; Marino and Cosentino 2016 ), and PD (González et al. 2013 ; Kustrimovic et al. 2016 ). However, better characterization of the molecular mechanisms is needed considering the regulation and transduction signaling of DR activation either at central level or in peripheral immunity as well as the implications of DR polymorphisms may have on the DA neuro-immune- endocrine network response. Chemogenetics is a novel molecular tool using engineered receptors to selectively respond to an inert ligand, so-called Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), that enables pharmacological remote control of neuronal activity. This technology has been useful to study DA signaling, such as the metabolism of the DREADD ligand clozapine N-oxide (CNO) to the D2 receptor antagonist clozapine (Runegaard et al. 2019 ). Such tool may be useful to investigate dopaminergic agonists representing interesting potential drugs as adjuvant for the treatment of obesity. DA agonists currently in clinical use have a favorable therapeutic index at low cost and this could be a strength point for obese patients. Therefore, as inflammatory pathways are also crucial for homeostasis a new multifactorial therapeutic paradigm should be able to solve inflammatory obesity without undesired immunosuppression.Future Perspectives and a Model for the Role of Dopaminergic Pathways in Obesity-Associated Inflammation.Dopaminergic pathways have a role in the regulation of immunity, metabolism and neuronal functions with a putative impact on obesity-associated inflammation. Intricate crosstalk between neuro-immune metabolic network infers a challenge to unravel the molecular mechanisms that regulate dopaminergic signaling in obesity. The physiological communication between different tissues and organs has been considered crucial for the systemic involvement of obesity in disease manifestation (Lee et al. 2009 ) and inflammatory pathways have been shown to be of most importance in the network of inter-tissue crosstalk (Samdani et al. 2015 ). Since it has been suggested that obesity is associated with hypodopaminergic function at central (Wu et al. 2017 ) and peripheral levels (Leite et al. 2016 ) we can argue that inflammatory pathways are the cause of DA function impairment.Central and peripheral dopaminergic pathways communicate at different levels in the brain, BM, AT, gut and pancreas. A bidirectional connection exists between the brain and the gut in which central and enteric nervous systems communicate through endocrine, immune and neural pathways. The dysbiosis of the gut microbiome induced by HFD promote intestinal inflammation with increased permeability, metabolic endotoxemia and higher production of pro-inflammatory cytokines by tissue macrophages (Sun et al. 2018 ). The accumulation of LPS from the membrane of gram-negative bacteria residing in gut microbiota (Yamashita et al. 2018 ) through the activation of innate and adaptative immunity is a major trigger linking excessive fat intake and the development of obesity-associated inflammation (Cani et al. 2007 ). Systemic inflammation can induce central inflammation through humoral, cellular and neural pathways (Capuron and Miller 2011 ). At central level, fat diet is associated with lower DA concentration independently of adiposity (Tellez et al. 2013 ) meaning that diet may contribute to downregulate neuronal DR despite weight gain. A possible explanation is that fat induced inflammatory responses partially due to lipid-activated receptors and activation of TLR and NF-kB which in turn acts on transcriptional regulation of DR (Sun et al. 2017 ). Moreover, inflammation in the hypothalamus alters gene expression related to feeding behavior (De Souza et al. 2005 ; Ahima and Antwi 2008 ) and causes leptin and insulin resistance and obesity (Mulders et al. 2018 ). The Table 1 represents our proposed model explaining the dopaminergic pathways in obesity-associated inflammation.Table 1 Model for the role of dopaminergic pathways in obesity -associated inflammation Open image in new windowLegend- Model for the role of dopaminergic pathways in obesity- associated inflammation. An obesogenic diet modifies the gut microbiome promoting intestinal inflammation and increasing the levels of LPS in the bloodstream. This metabolic endotoxemia induces systemic inflammation with immune activation. Immune cells are a dopaminergic organ expressing DR and producing DA. DA modulates immune response by its effects on hematopoiesis and immune cells (special role for monocytes/macrophages in metaflammation) with an inflammatory phenotype producing cytokines that promote inflammation at local tissues (AT, gut, pancreas, liver, BM, among others) and the inflammatory signaling induces DR downregulation in PBMCs. Systemic inflammation (through humoral, neural, cellular pathways) induces central inflammation, triggering altered dopaminergic circuit in the brain involved in reward and feeding behavior and as well in energetic hemostasis dysregulating leptin and insulin sensitivity. Central inflammation causes hypofunction of the dopaminergic system with metabolic impairment due to leptin/insulin resistance promoting obesity. Dopaminergic pathways in obesity- associated inflammation is an emergent research area and several questions are herein raised. See text for additional explanations. The blue arrows have a meaning of causality or association depicting the relationship between HFD/DIO and obesity (and metabolic disease clusters) and the several variables that can be colliders. AT, adipose tissue; BM, bone marrow; BMI, body mass index; DA, dopamine; DAT, dopamine transporter; DR, dopaminergic receptor; DIO, diet-induced obesity; FA, fatty acids; HFD, high fat diet; IL-6, interleukin-6; LPS, lipopolysaccharide; NF-KB, nuclear factor-κB; PBMCs, peripheral blood mononuclear cells; STAT3, signal transducer and activator of transcription 3; TH, tyrosine hydroxylase; TLR, Toll-like receptorsIn AT, there is a crosstalk between macrophages and sympathetic neurons based on anatomical and functional associations in WAT (Camell et al. 2017 ; Pirzgalska et al. 2017 ) and BAT (Wolf et al. 2017 ). Since DR are present in human adipocytes (Borcherding et al. 2011 ) and monocytes/macrophages (McKenna et al. 2002 ; Pinoli et al. 2017 ), DA is a key molecule in the neuro-immune- metabolic crosstalk in AT. DA reach adipocytes from infiltrating or resident immune cells, namely monocytes/macrophages, through sympathetic neuronal terminals or via circulatory DA-S (Borcherding et al. 2011 ). DA, in human adipocytes, via D2-like and D1-like receptors, showed differential effects of the dopaminergic system on leptin, IL-6 and prolactin release (Borcherding et al. 2011 ) and further research should explain the molecular mechanisms involved. Unraveling the molecular mechanisms that underlie these findings, namely, the identification of the epigenomic alterations that determine macrophage sensitivity to metabolically driven inflammatory signals (Fan et al. 2016 ) and ATM-secreted molecules that attenuate insulin signaling will provide possible therapeutic targets for inflammation obesity-associated.A more inflammatory pattern in the CD16+ monocytes subset was found in subjects with CO in comparison with the non-obese counterpart (Leite et al. 2016 , 2017a , b ). These results suggest that the non-classical monocytes, the more mature subtype of monocytes, may be the main CD14+ cells subset implicated in the anti-inflammatory effects of DA (Leite et al. 2018 ). Indeed, DA reduced IL-6-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in CD14+ monocytes (Leite et al. 2018 ). We found downregulation of DR expression in PBMCs and higher inflammation in a population with central obesity in comparison with non-obese. Although the mechanisms of DR downregulation are unknown, we could claim that our findings could obey to the mechanisms argued for the central dopaminergic pathways in obesity: inflammatory pathways driven by HFD induce downregulation of DR expression in neurons and reduced DA concentration at CNS. The bidirectional communication between the gut, where DA is also produced by the microbiota, and the brain, determines the gut-brain axis which links peripheral to central dopaminergic pathways with the hypothalamus a key target altering important genes that control energy balance and feeding behavior. Moreover, hypothalamic inflammation seems to occur before weight gain, which infers the importance of the HFD that rapidly changes the microbiome and systemic inflammation orchestrated by endocrine, immune and neural networks, where dopaminergic pathways play a major role. In addition, the characterization of the signaling pathways from the brain to the gut represents a promising but yet underestimated research area.The dopaminergic system in human adipocytes is largely unknown, thus an important challenge is to identify the mechanisms by which DA regulates adipose metabolism and function in the crosstalk between immune cells and adipocytes. It is also unknown if immune cells endogenous DA in AT has a role in lipid metabolism and related immunometabolic disease clusters. We may argue that chemogenetics using DREADDs, that enables pharmacological remote control of neuronal activity (Runegaard et al. 2019 ), could be applied to peripheral immune cells and metabolic tissues for the study of peripheral dopaminergic signaling pathways. Such tool may also be useful to identify dopaminergic agonists representing interesting drugs with potential to be valuable as adjuvants for obesity treatment.Nevertheless, our proposed model brings several open questions claimed to be definitely answered: the different pattern of DR and TH expression on PBMCs associated with CO is a cause or consequence of inflammatory obesity? How is translated weight loss on DR expression in peripheral immune cells? What is the pattern of possible differential DR expression on distinct mononuclear cell subsets in obesity? How the dopaminergic system (e.g. synthesis and degradation machinery, and DR) is locally regulated in AT, and crosstalk with immune cells, under this low-grade inflammatory state? Are these cells corroborating or challenging each other? Do diet, adiposity, and metabolic factors interact or produce specific effects on DA signaling?Untangling the molecular pathways by which diet and adiposity induce DR alterations, as well as the implications of DR polymorphisms may have on the DA neuro-immune- endocrine network response, these studies could identify new therapeutic targets for obesity and related comorbidities in which dopaminergic circuits are affected. Further research on the impact of changes in DA on AT is, also, important to manage metabolic dysfunction associated with chronic treatment with dopaminergic drugs such as antipsychotics (Panariello et al. 2011 ). Such studies would enable and strengthen the rational basis for the development of clinical trials of dopaminergic drugs for immune-mediated diseases as obesity and its comorbidities. Besides having a favorable therapeutic index (Pinoli et al. 2017 ), dopaminergic agents could be developed without economic burden which will benefit patients and healthcare systems.