Central and Peripheral Inflammation Link Metabolic Syndrome and Major Depressive Disorder

Abstract

Metabolic syndrome and major depression are two of the most common and debilitating disorders worldwide, occurring with significant rates of comorbidity. Recent studies have uncovered that each of these conditions is associated with chronic, low-grade inflammation. This is characterized by increased circulating pro-inflammatory cytokines, altered leukocyte population frequencies in blood, accumulation of immune cells in tissues including the brain, and activation of these immune cells. Cytokines that become elevated during obesity can contribute to the progression of metabolic syndrome by directly causing insulin resistance. During chronic stress, there is evidence that these cytokines promote depression-like behavior by disrupting neurotransmitter synthesis and signal transduction. Animal models of obesity and depression have revealed a bi-directional relationship whereby high-fat feeding and chronic stress synergize and exacerbate metabolic dysregulation and behavioral abnormalities. Although far from conclusive, emerging evidence suggests that inflammation in the central and peripheral immune system may link metabolic syndrome to major depressive disorder. In this review, we will synthesize available data supporting this view and identify critical areas for future investigation.

Introduction

Metabolic syndrome and major depressive disorder (MDD) represent two of the most debilitating disorders worldwide and are often reported with high rates of comorbidity. Although the definition of metabolic syndrome continues to evolve, it is typically characterized by a cluster of conditions, including obesity, hyperglycemia, insulin resistance, dyslipidemia, and hypertension that predispose individuals to cardiovascular disease and Type 2 diabetes (T2D) (54). In 2016, the World Health Organization (WHO) estimated that 650 million adults were obese—a number that tripled since 1975 and continues to rise (136). MDD is a complex psychiatric illness that negatively affects emotion, cognition, and motivation (3). It is estimated that over 300 million people are affected by MDD, with an estimated 16.6% lifetime prevalence (58, 137). In the most severe cases, MDD can lead to suicide, and the WHO cites MDD as the leading cause of worldwide disability (137).

MDD has many comorbidities spanning cardiovascular disease, neurological disorders, and psychiatric illnesses, among others (42, 103, 124). Comorbidity between MDD and metabolic syndrome has been well recognized, although individual risk varies dramatically across cohorts. For example, one study in a diverse adult population found that participants with metabolic syndrome had higher scores on the Hospital Anxiety and Depression Scale (depression subscale), with waist circumference and HDL cholesterol showing significant and independent correlations (33). A separate study found a U-shaped relationship between body weight and depression, with higher depression prevalence in both underweight and obese subjects relative to normal-weight controls (19). In cohorts comprised exclusively of women, severity of depressive symptoms and stressful life events correlate with concurrent metabolic syndrome or predict risk for its development (99, 100). Conversely, some studies including a longitudinal assessment of 5,698 participants as part of the Northern Finland Birth Cohort Project found no associations between metabolic syndrome and depression or anxiety (48). Thus this relationship remains incompletely understood, likely due to the heterogeneity of both metabolic syndrome and MDD as complex, multifactorial disorders involving lifelong interplay between genetics and the environment (76, 98). Moreover, since MDD is diagnosed exclusively by behavioral symptoms, there is a need to identify biological factors that contribute to its pathogenesis. Recent work has highlighted both MDD and metabolic syndrome as inflammatory conditions, involving both systemic and central immune cells. Surprisingly, the literature investigating depression, inflammation, and metabolic syndrome together remains sparse and mostly correlational. Here, we discuss common and divergent inflammatory features between metabolic syndrome and MDD to understand whether inflammation could be a potential mediator behind the comorbidity of these disorders.

Metabolic Inflammation Arises With Obesity

In 1993, Hotamisligil et al. observed that the pro-inflammatory cytokine TNF-α was increased in obese adipose tissue where it directly interfered with the ability of insulin to regulate blood glucose levels (53). Since then, the association between inflammation and insulin resistance, or “metabolic inflammation,” has become the major focus of a large body of research investigating how obesity could lead to T2D. Metabolic inflammation is broadly characterized by altered circulating cytokine profiles, immune cell infiltration into tissues, and activation of inflammatory pathways within tissue parenchyma.

In humans, a vast array of circulating pro-inflammatory cytokines becomes elevated in obese individuals, including monocyte chemoattractant protein 1 (MCP1/CCL2), IL-1β, IL-5, IL-6, IL-8, IL-10, IL-12, IL-18, IFNγ, and TNF-α, and C-reactive protein (CRP) (9, 10, 29, 43, 56, 97, 108). Similarly, in rodents, plasma levels of the cytokines CCL2, CXCL1, CXCL5, IL-1β, IL-6, and TNF-α are higher in genetic or diet-induced models of obesity (22, 60, 92). Many of these cytokines have been implicated in metabolic inflammation and subsequent metabolic dysfunction. For example, IL-1β, IL-6, and TNF-α have been demonstrated to directly contribute to insulin resistance by activating stress kinases, such as IKK, JNK, and p38 MAPK in muscle and fat cells, which phosphorylate inhibitory serine residues on insulin receptor substrate 1 (IRS1), immediately downstream of the insulin receptor, thereby blocking signal transduction (13, 51, 52, 59, 104). The cytokines IL-12 and IFNγ play key roles in activating the immune system; IL-12 promotes Th1 differentiation of naive CD4⁺ T cells, and IFNγ promotes pro-inflammatory M1 polarization of macrophages (8, 49, 77). Importantly, these immune cell activation states have been correlated with obesity and insulin resistance in both humans and rodents (70, 79). Furthermore, chemokines such as CCL2 and CXCL1 are capable of chemoattraction, leading to immune cell egress from bone marrow and eventual migration into tissues (26, 111).

During metabolic syndrome or obesity, blood leukocyte frequencies become significantly altered, with humans and mice both displaying leukocytosis (89, 125). More specifically, total monocyte, neutrophil and lymphocyte counts increase and positively correlate with body mass index (BMI), body fat percentage, and insulin resistance (105, 143). Diet-induced obese mouse models have additionally revealed increases in the frequencies of these cell types along with their progenitors in the bone marrow (114, 115, 125), implicating mechanisms that drive both differentiation and release from bone marrow stores. Phenotypically, there have been reported increases in non-classical (CD14⁺ CD16⁺⁺) and intermediate (CD14⁺⁺ CD16⁺) monocytes and decreased classical (CD14⁺⁺ CD16⁻) monocytes in blood from obese patients (30, 97). Interestingly, although classical monocytes are typically associated with greater expression of CCR2, the receptor for CCL2, surface levels of chemokine receptors, including CCR2 and CCR5, rise with obesity (62). Additionally, monocytes from obese patients appear primed for activation, since they produce higher amounts of cytokines when stimulated ex vivo with lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria (30). In parallel, high fat feeding in mice increases circulating Ly6C^hi monocytes (114), the subset which has greater CCR2 expression and which is considered to be more inflammatory in nature (41). Moreover, monocytes from obese patients exhibit a stronger capability to migrate toward the chemokines CCL2 and CCL5 (62). This suggests that obesity could enhance monocyte migration from bone marrow to blood and eventual tissue infiltration.

A defining feature of obesity-linked metabolic inflammation is the infiltration of immune cells into tissues that regulate whole-body glucose metabolism. This phenomenon was first observed as an increase in total macrophages in the adipose tissue from obese patients (130, 141), but a series of subsequent studies have now established that T cells, B cells, eosinophils, mast cells, dendritic cells, natural killer cells, and neutrophils can all infiltrate adipose tissue to varying degrees and contribute to the regulation of insulin sensitivity (23, 69, 123, 131, 132, 138, 139). Substantial attention has been given to the role of tissue macrophages during the development of T2D, since they increase in other metabolic tissues such as liver and skeletal muscle as well, although other leukocyte subtypes such as neutrophils have also been reported to infiltrate these tissues (38, 39, 88, 123). Macrophages that accumulate in tissues during obesity are largely monocyte-derived with their appearance in tissues dependent on CCL2 and CCR2 (22, 129). However, there is also some evidence that obesity triggers local proliferation of tissue resident macrophages in adipose tissue (2, 144). Metabolic status can also influence macrophage differentiation to produce a spectrum of inflammatory states. For example, in adipose tissue from lean humans or mice, macrophages assume an anti- or non-inflammatory M2 polarization, whereas high fat feeding or obesity stimulates a conversion to pro-inflammatory M1 macrophages (70). These M1 macrophages are characterized by elevated CD11c surface expression, as well as heightened production of pro-inflammatory cytokines including CCL2, IL-6, and TNF-α (68, 70). Mechanistically, saturated fatty acids, a major component of obesogenic and atherogenic diets, but not unsaturated fatty acids, are able to directly activate pro-inflammatory pathways in macrophages ex vivo (20, 112). Notably, selectively depleting total or CD11c⁺ macrophages from adipose tissue or interfering with CCL2/CCR2 alleviates diet-induced insulin resistance (15, 37, 94, 129), demonstrating that macrophages contribute to whole-body glycemic dysregulation. Accompanying the inflammatory response by immune cells is activation of intrinsic pro-inflammatory pathways in parenchymal cells of metabolic tissues such as adipocytes, hepatocytes, and myocytes. For example, exposure of these cells to excess saturated fats or inflammatory stimuli can directly induce insulin resistance or release of chemoattractants, which exacerbate leukocyte tissue infiltration, thus propagating the cycle of metabolic inflammation (96, 121).

In addition to peripheral inflammation that occurs with obesity, emerging literature has explored inflammation in the central nervous system (CNS), with many of these studies focusing on the hypothalamus given its role in regulating appetite and satiety (109). Importantly, high saturated fat diets trigger hypothalamic inflammation, leading to central leptin and insulin resistance, resulting in increased food intake and weight gain (84). These findings have prompted further investigation into the involvement of central immune cells in metabolic dysfunction. In obese humans (BMI > 30), accumulation of microglia (CNS-resident macrophages) as defined by expression of ionized calcium-binding adaptor molecule 1 (Iba1) is increased in the hypothalamus compared with healthy (BMI < 25) controls (11). BMI has also been positively correlated with frontal cortex expression of iNOS, a hallmark M1 macrophage marker, and negatively correlated with expression of IL-10, an M2 macrophage marker (65). In mice, high-fat diets induce hypothalamic and hippocampal cytokine expression, including IL-1β, IL-6, and TNF-α (31, 83), as well as CNS macrophage infiltration, with one study proposing that these cells originate from blood monocytes (16). However, the ability of peripheral leukocytes to enter the brain parenchyma is controversial and may be an artifact of experimental techniques such as irradiation (85). Some authors have hypothesized that high-fat diets or diet-associated inflammation can result in the breakdown of the blood-brain barrier (BBB), thus permitting access to the CNS by peripheral immune cells or cytokines. Indeed, one study has suggested that BBB permeability as assessed by the CSF-to-serum albumin ratio is higher in overweight or obese humans compared with healthy controls (45). Obese mice and rats also show BBB breakdown as measured by a sodium fluorescein permeability assay (119), with one report highlighting this occurrence specifically at the hippocampus, but no differences were observed in the prefrontal cortex or striatum (57). Additionally, this permeability is accompanied by decreased gene expression of tight-junction proteins, occludin, claudin-5, and claudin-12 in BBB capillaries and choroid plexus (57). Other studies have shown that saturated fats increase adhesion molecule expression on microvascular endothelial cells, thus promoting monocyte adhesion and transmigration (95). Cytokines may also be produced by endothelial cells, with one study compellingly demonstrating that adiponectin, which stimulates negative energy balance and is decreased in obesity, suppresses adluminal IL-6 secretion from BBB endothelial cells into the brain (116). Furthermore, compromised BBB integrity has been directly correlated with the appearance of CD45⁺ CD11b⁺ (myeloid) and CD11b⁺ Ly6c^hi (inflammatory monocyte) cells in the forebrain (119). These immune cells may provoke metabolic syndrome, since depleting microglia using a colony-stimulating factor 1 receptor (CSF1R) inhibitor or preventing their activation via genetic manipulation in the mediobasal hypothalamus has beneficial metabolic effects, primarily by suppressing food intake and weight gain (126). Collectively, these studies underscore a critical role for immune cells, along with central and peripheral inflammation in the development of metabolic syndrome, and have given rise to the field of “immunometabolism.”

Major Depressive Disorder is Associated With Central and Peripheral Inflammation

A major revelation in understanding the etiology of mood disorders including MDD has been the discovery of an inflammatory component to these conditions. A key observation was reported in 1987 when a subset of hepatitis C patients treated with the pro-inflammatory cytokine interferon alpha were found to develop depression, which then subsided upon cessation of treatment (102). Further parallels have been observed between immune/inflammatory illness and depression, which share some common behavioral changes, including lethargy, anhedonia, and social withdrawal—a concept termed “sickness behavior” (25). Evolutionarily, these now maladaptive behaviors have been hypothesized to have previously played a role in facilitating recovery while preventing transmission of infectious disease (86). Current research has confirmed that pro-inflammatory cytokines or pathogenic compounds such as LPS can produce depression-like behavior in both humans and rodents (40, 44, 61, 142). These findings have fueled a necessity to elucidate inflammatory changes during MDD and develop potential novel drug targets.

Similar to what is seen in patients with metabolic syndrome, individuals with MDD display a chronic, low-grade inflammation, which can be characterized through circulating cytokine profiles. A number of studies involving patients meeting Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for MDD have found significant elevations in plasma or serum levels of CCL2, IFNγ, IL-1α, IL-1β, IL-2, IL-6, IL-8, IL-12, and TNF-α, along with CRP (32, 50, 73, 113, 133). The “cytokine hypothesis of depression” postulates that these cytokines play a causative role in MDD progression (107). One study found that, in treatment-resistant MDD patients, administration of the TNF-α antagonist infliximab relieved depressive symptoms in individuals with high baseline inflammatory markers (101). Although human MDD is challenging to model in animals, a variety of paradigms, such as chronic unpredictable stress, learned helplessness, chronic social defeat stress, and witness defeat, have been established to recapitulate stress-induced long-lasting depression-like behavior in rodents (for review, see Ref. 80) that have been used to test causal hypotheses about the role of inflammation in depression. Compared with control mice, stressed mice displaying depression-like behaviors exhibit increased circulating cytokines including CCL2, CXCL1, IL-1β, IL-6, and TNF-α (14, 50, 118, 120). Central infusion of IL-1 receptor antagonist, which inhibits IL-1β signaling, prevents social defeat stress-induced social avoidance in rats (5). Furthermore, antibody-mediated neutralization of IL-6, or genetic depletion of IL-6 from peripheral leukocytes by bone marrow transplantation, attenuates susceptibility to chronic social defeat stress (50). These studies emphasize an important bi-directional interaction between the brain and immune system. However, several key questions remain. First, what are the mechanisms that trigger cytokine production? Studies of individual differences in stress-induced cytokine production among inbred C57BL/6J mice suggest that there may be cell intrinsic differences in leukocyte reactivity that promote inflammation and depressive-like behaviors (50). Next, how does inflammation influence behavior, and how do specific immune cell subtypes or compartments contribute to these processes?

To begin to address these questions, studies have focused predominantly on three compartments of immune cells: CNS resident immune cells, splenic macrophages, and peripheral leukocytes in the systemic circulation that may communicate with the brain. Leukocytosis has been identified in blood from both MDD patients and mouse models of depression (50, 75). When specific populations of immune cells were investigated, monocytes and neutrophils have been reported to increase, whereas lymphocytes decrease, with perceived stress and depression in humans and with chronic unpredictable stress in mice (28, 35, 47, 75). Studies in mice have shown that chronic stress activates hematopoiesis in the bone marrow and promotes an increase in circulating Ly6C^hi monocytes (47). Moreover, subthreshold stress following social defeat triggers Ly6C^hi monocyte egress from the spleen, and splenectomy before social defeat prevents monocyte traffic to the brain (78). During stressful events, activation of the hypothalamus-pituitary-adrenal (HPA) axis causes release of glucocorticoids such as cortisol from the adrenal glands into the bloodstream (145). Although glucocorticoids are normally immunosuppressive, it is hypothesized that chronic stress elicits HPA hyperactivity, leading to glucocorticoid resistance, which begets pro-inflammatory activation of immune cells (4, 91). Interestingly, peripheral leukocytes from stress-susceptible mice release greater amounts of IL-6 following stimulation with LPS compared with leukocytes from stress-resilient mice (50). Additional studies are required to further evaluate how chronic stress affects immune cell differentiation and function.

The concept of peripheral immune cells infiltrating the brain during chronic stress and MDD, however, is controversial. Some studies have reported stress-induced, CCL2/CCR2-dependent recruitment of peripheral monocytes to the brain (78, 135). Others have shown that, although BBB permeability increases in both humans and mice during depression or chronic stress, respectively, in a manner similar to what has been reported during metabolic syndrome, monocytes may remain in the ventricular space and vasculature without entering the brain parenchyma (81, 90). Importantly, stress-induced BBB breakdown was observed to occur at the nucleus accumbens (NAc), a region of the striatum involved in motivation and reward, along with the hippocampus, but not the prefrontal cortex or hypothalamus (81). Although the specific mechanisms driving stress-induced alterations in the BBB are not well established, there is evidence from a learned helplessness model of depression to suggest that peripheral cytokines, such as TNF-α, may promote the breakdown of the BBB (21). These studies establish a potential interface for peripheral signals to affect brain and behavior. There is also significant evidence to show that resident immune cells in the brain adopt an activated phenotype during chronic stress and depression. In one study, a positron emission tomography approach was applied to measure translocator protein density measured by distribution volume (TSPO V_T), a marker of activated microglia, in MDD patients experiencing a major depressive episode. The authors found significantly increased TSPO V_T in the prefrontal cortex, anterior cingulate cortex, and insula in subjects with MDD compared with controls (110). Similar microglia activation has been seen following chronic unpredictable stress in the hippocampus of rats (128).

Within the brain, there have been several proposed mechanisms by which cytokines and immune cells could affect behavior. Cytokines such as IL-1β, IL-6, and TNF-α become elevated in the brain during chronic stress or depression, and arise from local production in the CNS or translocation across the BBB from the periphery (81, 93, 134). MDD pathophysiology has been characterized by defective signaling of monoamine neutrotransmitters, such as serotonin (5-HT), dopamine (DA), and norepinephrine (NE). Inflammatory cytokines including IL-6 and TNF-α have been shown to activate indoleamine-2,3-dioxygenase (IDO), consequently reducing 5-HT synthesis by reducing the availability of its precursor tryptophan (74). IDO activation favors conversion of tryptophan into metabolites of the kynurenine pathway, 3-hydroxykynurenine, and quinolinic acid. These metabolites, which are thought to increase with anxiety and depression, are excitotoxic and can also activate monoamine oxidase (MAO), a target of antidepressants that degrades 5-HT, DA, and NE (107). However, a meta-analysis of nine studies found that circulating kynurenine levels decrease in patients with unipolar depression compared with healthy controls (6), indicating that further research is required to elucidate the role of kynurenine in depression. Similarly, cytokines may interfere with DA synthesis by reducing bioavailability of tetrahydrobiopterin (BH4), an important enzyme co-factor involved in metabolism of phenylalanine to DA (36). There is also a growing literature to suggest that cytokines are capable of acting directly on neurons through cytokine receptors within the plasma membrane to change excitability, synaptic strength, and synaptic scaling (12, 67, 117, 127). Furthermore, cytokines such as IL-1β can contribute to heightened activation of the HPA axis, thus compounding the inflammatory response to stress (106). Recent work has suggested that microglia also exhibit enhanced phagocytic activity during chronic stress, which may be involved in synaptic remodeling (66). Together, these studies illustrate multiple pathways whereby chronic stress—through activation of the immune system—can promote depressive-like behavior.

Metabolic Syndrome and Major Depressive Disorder Exhibit a Bi-Directional Relationship

With both metabolic syndrome and MDD showing many inflammatory perturbations in common, it is tempting to speculate that inflammation mediates their frequent comorbidity. One clinical evaluation of MDD patients reported elevated circulating IL-6 and CRP, most notably in patients with the highest BMI (87). This association is often seen in atypical depression, where subjects show increased appetite along with symptoms of depression, which then correlate with greater serum TNF-α and CRP (64). A genome-wide association study also identified that these patients carry genetic risk variants for increased BMI, CRP, and leptin levels (82). In a surgery-induced weight-loss intervention study, formerly obese patients displayed reduced inflammation and significant improvements in emotional status following weight loss (17). Additional studies found positive correlations between CRP levels and depressive mood in obese but not non-obese subjects (27, 63), suggesting that inflammation may mediate a subset of depressive disorders commonly concurrent with obesity and metabolic syndrome. Intriguingly, in a twin study involving 323 pairs of male twins with or without metabolic syndrome, the authors observed that incidence of metabolic syndrome is associated with higher depressive symptoms, with inflammation (circulating IL-6 and CRP) identified as a determinant variable in this relationship (18). However, it is difficult to determine causative effects in humans, so investigation using preclinical rodent models can provide valuable and complementary mechanistic insights.

Animal models of depression and obesity have revealed a bi-directional relationship between these disorders. For example, high fat-fed mice show decreased social interaction, sucrose preference, and grooming during splash test, along with increased immobility time during forced swim and tail-suspension tests, with no differences seen in open-field or the elevated plus maze (46, 55, 140). One study comparing control diet, diet-induced obesity, and isocaloric high-fat diet suggests that diet-induced behavioral changes are affected by diet, independent of weight gain and obesity (122), indicating that specific dietary factors or metabolites can confer depression-like symptoms. Inversely, chronic mild stress in rats has been shown to worsen glucose tolerance (7). The detrimental effects of chronic stress or high-fat diet appear to be additive, as social defeat exacerbates diet-induced elevations in plasma glucose and lipid levels. Moreover, high-fat feeding in the Flinders sensitive line genetic rat model of depression resulted in higher immobility time in forced swim test, interpreted as behavioral despair, and worsened insulin tolerance (1, 24). These observations, however, are mixed, since some studies do not find an effect of diet on stress-induced depression-like behavior (24). Conversely, caloric restriction has been shown to promote resilience to social defeat stress through regulation of a variety of feeding peptides, such as orexin and ghrelin (71, 72). However, to our surprise, there is remarkably little research exploring a functional link between inflammation, metabolic dysfunction, and depression. One recent report by Dutheil et al. (34) found that high-fat diets promoted anxiety- and depression-like behavior assessed by the novelty suppressed feeding and sucrose preference tests, alongside expected increases in glucose intolerance and hippocampal IL-1β, IL-6, and TNF-α levels. Interestingly, when these high-fat-fed rats were treated with a P2X7 receptor antagonist, which blocks inflammasome activation and cytokine production, diet-induced behavioral abnormalities were attenuated (34), indicating that inflammation may indeed be the common link between metabolic and behavioral dysfunction. Future questions examining the role of specific immune cells and cytokines in the relationship between metabolic syndrome and depression remain an open topic.

Conclusions and Future Directions

The prevalence and comorbidity of metabolic syndrome and MDD is a continuously growing epidemic with major health and economic burdens. The revelation that both of these debilitating disorders may have common inflammatory origins, involving both the central and peripheral immune system, has afforded us a greater understanding of the heterogeneity of these conditions (FIGURE 1). Although research to date in the fields of immunometabolism and neuroinflammation has produced encouraging preliminary results, there remains a vast expanse of unexplored questions requiring the interdisciplinary knowledge of metabolism, neuroscience, and immunology. Animal models remain an invaluable tool to establish causal links between inflammation, metabolism, and depression. Although correlational data from human cohorts suggest that inflammation associated with depression is exacerbated by obesity, studies in rodents have yet to determine whether chronic stress and obesity have additive or synergistic effects on whole-body inflammation. Moreover, genetic manipulation or neutralizing antibodies can be used to test whether specific cytokines or leukocyte subsets that increase in the CNS or circulation during obesity contribute to depression-like behavior, or whether those that increase with chronic stress lead to dysregulated appetite and glucose metabolism. Elucidating these mechanisms linking metabolic syndrome, depression, and inflammation could generate potential new therapeutic targets or cell type-specific strategies to combat both metabolic syndrome and MDD.

FIGURE 1.

Chronic, low-grade inflammation during metabolic syndrome and major depressive disorder

In the CNS, indexes of inflammation, including microglia accumulation and activation, cytokine expression, and blood-brain barrier (BBB) permeability, appear in both metabolic syndrome and depression. During obesity and metabolic syndrome, this is observed primarily in the hypothalamus and hippocampus, while the nucleus accumbens (NAc) and hippocampus are afflicted with chronic stress or major depressive disorder. In the periphery, pro-inflammatory cytokines, along with circulating monocytes and neutrophils, increase in both disorders; however, there is a reported decrease in blood lymphocytes during depression. Peripheral tissue infiltration by immune cells occurs during metabolic syndrome, but less is known about the effects of depression on these tissues. These inflammatory changes are associated with increased appetite and glucose intolerance during metabolic syndrome, and anhedonia and reduced reward-seeking behavior during depression. Increases and decreases expressed in text boxes are relative to healthy subjects.