Shared biological mechanisms of depression and obesity: focus on adipokines and lipokines

Shared biological mechanisms of depression and obesity

There is ample reason to assume that depression and obesity are interrelated via a vicious, mutually strengthening cycle of negative physiological adaptations. In this section, we review the mechanisms underlying the co-pathogenesis of obesity and depression, mainly around the inflammation, gut microbiota, gut-brain axis (GBA)/microbiota-gut-brain axis (microbiota-GBA), neuroplasticity and HPA axis abnormalities (Figures 1, 2).

Figure 1. Overview of the mechanisms underlying the co-pathogenesis of depression and obesity: based on adipokines and lipokines. In the body, there are many kinds of adipocytes and different adipocytes can selectively release related adipokines and lipokines. Abnormal secretion of adipokines and lipokines plays a crucial role in obesity and depression and may be related to increased inflammatory response, gut microbiota disturbance, neuroplasticity, dysfunction of HPA as well as GBA/microbiota-GBA disturbance. Note: HPA axis, hypothalamic-pituitary-adrenal axis; GBA, gut-brain-axis; PAI-1, Plasminogen activator inhibitor type 1; MCP-1, Monocyte chemoattractant protein-1; RBP4, Retinol Binding Protein 4; FABP4, fatty acid-binding protein 4; IL-6, Interleukin 6; Nrg4, Neuregulin 4; FAHFAs, fatty acid esters of hydroxy fatty acids; 12,13-diHOME, 12,13-dihydroxy-(9Z)-octadecenoic acid.

Figure 2. Summary map of common biological mechanisms of depression and obesity. Note: IL-6, Interleukin-6; IL-1β, Interleukin-1β; TNF-α, Tumor necrosis factor-α; CCL2, C-C motif chemokine ligand 2; CRP, C-reactive protein; PGE2, prostaglandin E2; IL-10, Interleukin-10; TGF-β, transforming growth factor-beta; ARC, arcuate nucleus of the hypothalamus; POMC, pro-opiomelanocortin; AGRP, agonist peptide-related peptide; NLRP3, NOD-like receptor family pyrin domain containing 3; BDNF. brain derived neurotrophic factor; Iba-1, ionized calcium binding adapter molecule-1; GFAP, glial fibrillary acidic protein; SCFAs, short-chain fatty acids; LTP long-term potentiation, LTD, long-term depression; mPFC, medial prefrontal cortex; mTOR, mechanistic target of rapamycin; AMPK, AMP-activated protein kinase; TrkB, tyrosine kinase receptor B; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; MEK, MAPK/extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinases; ERK, extracellular signal-regulated kinase; CRH, corticotropin-releasing hormone; AVP, arginine vasopressin; ACTH, adrenocorticotropic hormone; NEGR1, neuronal growth regulator 1; CADM2, Cell adhesion molecule 2; PMAIP1, phorbol-12-myristate-13-acetate-induced protein 1; PARK2, E3 ubiquitin-protein ligase parkin; FTO, Fat mass and obesity-associated gene; GABA, gamma-aminobutyric acid; MC4R, melanocortin 4 receptor; dBNST, bed nucleus of the stria terminus.

The potential role of inflammation in depression and obesity

Overactivation of the immune system is caused by several factors, such as difficult life situations, stress from society, and poor lifestyle habits (smoking, lack of exercise, HFD), all of which cause an increased inflammatory response and thus promote depressive symptoms [42]. Elevated levels of inflammatory markers such as IL-1β, IL-6, IL-2, TNF-α, CRP and PGE2 were found in patients with depression [43–47]. The cytokine hypothesis suggests that in depression, the number of pro-inflammatory cytokines such as IL-6, IL-1β and TNF-α is increased, while the number of anti-inflammatory cytokines such as IL-10 and TGF-β is decreased, tilting the overall immune response toward inflammation [48, 49].

The increase in macroglia peripheral nervous system and central nervous system (CNS) cytokines is coupled with the activation of microglia, the brain’s immunocompetent cells. This, in turn, has been linked to changes in synaptic plasticity, neurogenesis and emotional behavior [50]. A variety of key inflammatory markers also have been implicated in the risk of adverse outcomes of obesity and obesity-related diseases [48]. Adipocytes in abdominal, muscle and liver fat produce pro-inflammatory and chemotactic compounds such as IL-6, IL-1β, TNF-α and C-C motif chemokine ligand 2 (CCL2), as well as inflammatory hormones such as adiponectin and leptin [51, 52]. Overweight and obese individuals have adipocytes and macrophages in their adipose tissue that cause the secretion of cytokines and chemokines which can cross the blood-brain barrier (BBB) as well as stimulate neuroinflammation [53, 54].

Neuroinflammation triggered by obesity has recently been demonstrated to influence multiple brain structures like the hippocampus, cortex, brainstem or amygdala, in addition to being linked to an elevated incidence of central disorders including depression as well as impaired cognitive function [55]. Chronic overnutrition and obesity can lead to chronic low-level inflammation across the body, a state of chronic inflammation known as “meta-inflammation” mediated by macrophages located in the colon, liver, muscle as well as adipose tissue [56]. HFD is associated with the production of cytokines by non-neuronal cells in the hypothalamus that activate diverse inflammatory mediators in the arcuate nucleus of the hypothalamus (ARC), a primary region of the hypothalamus that regulates pro-opiomelanocortin (POMC) and agonist peptide-related peptide (AGRP) neurons, the primary neurons that sense and integrate peripheral metabolic signals and respond accordingly [57, 58]. Therefore, it is important to discuss the role of neuronal and non-neuronal cells in HFD-induced hypothalamic inflammation. The vagus nerve is linked to the visceral organs and the CNS, and the vagal afferent nerve conveys hunger signals to the hypothalamus via the gastric-derived orexigenic peptide ghrelin [59]. Studies have shown that intake of HFD triggers inflammatory responses in the gut, nodal ganglia and hypothalamus within a short period vagal afferent nerves can transmit inflammatory signals of gut origin to the hypothalamus through the nodose ganglion, while ghrelin can prevent inflammation induced by HFD [58, 59]. Ingestion of HFD leads to a lack of integrity of the gut barrier, causing the transfer of macromolecules, such as microbial or pathogen-associated molecular patterns (e.g., lipopolysaccharides) entering the systemic circulation [60]. Nucleotide-binding oligomerization domain–like receptor family pyrin domain-containing 3. (NLRP3) inflammatory vesicles are an essential component of the innate immune system, mediating caspase-1 activation and secretion of the pro-inflammatory cytokine IL-1β/IL-18 in response to microbial infection as well as cellular injury [61, 62]. Li et al. showed that microglia NLRP3 inflammatory vesicles induce neurotoxic astrocyte function by activating the neuroinflammatory caspase-1 pathway as a response to chronic stress [63]. Vandanmagsar et al. showed that NLRP3 inflammatory vesicles sense danger signals associated with obesity and lead to obesity-induced inflammation and insulin resistance [51]. The study by Schachter et al. suggests that reducing obesity-related neuroinflammation may have beneficial effects on depression [30]. Li et al. revealed that HFD-induced diabetes and obesity-related neuroinflammation activated the transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) in hippocampal neurons and that this factor suppressed BDNF expression and caused depression-like behavior in male mice [64]. This suggests that inflammation-activated neuronal C/EBPβ can contribute to HFD-induced depression by decreasing BDNF expression [53].

BDNF is mainly produced by microglia and astrocytes and has neuroprotective as well as anti-inflammatory effects [65, 66]. Obesity creates an environment of chronic inflammation that leads to negative physiological and neurological outcomes such as diabetes, cardiovascular disease, and depression. Although the entire body is involved in metabolic homeostasis, the neuroimmune system has recently emerged as a key regulator of metabolism [67]. Lam et al. found that 12 weeks of HFD feeding not only led to obesity in mice but also to depression-like behaviors and that astrocyte activation, which is closely associated with depression, was also evident in the ventral hippocampus [68]. Four weeks of pioglitazone treatment attenuated HFD-induced glucose metabolic dysfunction, upregulated ventral hippocampal GFAP (glial fibrillary acidic protein), reduced the total process length and number of branching sites of hippocampus CA1 GFAP-immunoreactive astrocytes in the ventral hippocampus, and attenuated the depressive phenotype, suggesting that pioglitazone may be a promising therapeutic agent for metabolic disorders and related depression [68]. Microglia are resident immune cells in the brain that respond directly and indirectly to dietary fat, and the environment in which microglia develop helps them to respond later in life [67]. Numerous studies have shown that chronic peripheral inflammatory states reduce adult hippocampal neurogenesis [69–71]. Peripherally released pro-inflammatory cytokines are implicated in communicating between the peripheral immune system and the brain via the activation of microglia in the brain [71]. Activated microglia may reduce neurogenesis by inhibiting the proliferation of neural stem cells, increasing apoptosis of neural progenitors, and decreasing the survival of newly developing neurons as well as their integration into existing neural circuits [69]. Stress-induced microglia activation and neuroinflammation play a vital role in the pathogenesis of depression [72, 73]. However, obese patients with chronic low-grade inflammation are at increased risk of developing depression [74]. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear transcription factor that moderates microglia polarization and neuroinflammation [72]. Qin et al. showed that chronic unpredictable mild stress (CUMS) was able to induce severe depression-like behavior, neuroinflammation and reduced PPARγ expression in leptin-deficient (ob/ob) mice compared to wild-type/C57BL/6J mice, suggesting that PPARγ mediates an activated phenotype of microglia, which may be related to the susceptibility of stressed ob/ob mice to develop depression [72].

The potential role of gut microbiota in depression and obesity

The degree of diversity and balance of gut microbiota strains is an essential indicator of the overall health status of the organism [75]. Depression and obesity have a high comorbidity in individuals, which may be due to sharing similar risk factors, including disruption of the gut microbiota. The gut microbiota is composed of over 100 trillion microorganisms, including a minimum of 1000 various species of bacteria, and plays a crucial role in the physiological and pathophysiological processes that occur in the body [76, 77]. The gut microbiota evolved together with the host and is an indivisible part of the body. Gut microbes are diverse and affect many processes, including immunity, metabolism as well as the CNS. Microbiota-GBA has emerged as a new candidate for depression [78, 79]. It has been shown that patients with depression, which includes those in remission, have a various gut microbiota composition than healthy controls [80]. Animal models of depression have shown changed gut microbiota compared to controls [81]. In a further meta-analysis, disturbances in the gut were found to be correlated with a decrease in certain anti-inflammatory butyrate-producing bacteria as well as an increased number of pro-inflammatory bacteria in patients with depression and other psychiatric disorders [82]. The fat mass and obesity associated gene (FTO) [83], an RNA demethylase [84, 85], is downregulated in the hippocampus of patients with MDD and in mouse models of depression [86]. Suppression of Fto expression in the mouse hippocampus results in depression-like behaviour in adult mice, whereas overexpression of FTO expression rescues the depression-like phenotype, suggesting that FTO is a modulator of depression-like behavioural mechanisms in mice [86]. Sun et al. showed that Fto deletion resulted in decreased body weight, reduced anxiety and depression-like behavior, and reduced sensitivity to stressful stimuli in Fto+/- mice [36]. In terms of intestinal flora, Fto-deficient mice were characterized by specific anti-inflammatory bacteria, importantly, the behavioral changes in Fto+/- mice were mediated by changes in the gut microbiota [36]. The results on the role of FTO in depression-obesity comorbidity are inconclusive, and further research is needed to deepen knowledge of the genetic basis of this comorbidity [87].

It has been shown that dysregulation of the gut microbiota in mice is associated with several neurobiological traits of depression, such as mild chronic inflammation, abnormal activity of the HPA axis, and reduced adult neurogenesis [88, 89] Recent studies suggest that chronic inflammation resulting from a HFD may exert a central role in the induction of neuroinflammation and depression [30]. Remarkably, the gut microbiota mediates some of the effects of HFD on human physiology and influences host mood and behavior. Pathogens, stressors, and predisposing factors can all contribute to excessive or protracted inflammatory responses (moderators include childhood trauma and obesity). The ensuing illness behaviors (such as pain, and sleep disturbance), depressive symptoms, and unhealthy lifestyle choices (such as a poor diet and sedentary lifestyle) may function as mediation pathways that result in unregulated inflammation and depression. Stress, nutrition, depression, and adverse childhood experiences can all affect the gut microbiome and increase intestinal permeability, which is another route to elevated inflammatory responses [42]. Studies have shown that fruits, vegetables and edible legumes contain high levels of phytochemicals that have anti-inflammatory effects [90, 91]. Camu Camu (CC) has significant antioxidant and anti-inflammatory potential [92]. Treatment of high-fat/high-sucrose (HFHS)-fed mice that are treated with CC prevent weight gain, reduce fat accumulation, attenuate metabolic inflammation and endotoxemia, and mice treated with CC exhibit enhanced glucose tolerance as well as insulin sensitivity [93]. Consuming fruits and vegetables rich in polyphenols may improve cognitive and emotional health by reducing oxidative stress and inflammation [94]. To investigate the effect of the gut microbiota on stress-induced depressive behavior, Chevalier et al. adopted an unpredictable chronic mild stress (UCMS) mouse model of depression as well as fecal microbiota transfer (FMT) from stress donors to naïve mice [95]. Results revealed that microbiota transfer conveyed behavioral symptoms of depression and reduced adult neurogenesis in recipient mice [95]. In addition, the metabolomic analysis demonstrated that FMT mice underwent changed fatty acid metabolism characterized by a deficiency of lipid precursors of endocannabinoid (eCB), which led to the compromised activity of the eCB system of the brain [95]. The eCB system plays its pleiotropic role via multiple neuronal processes. eCB system regulates adult neurogenesis through CB1 receptors expressed by neural progenitor cells [96]. CB1-deficient mice exhibit damage neural progenitor cell proliferation, self-renewal as well as neurosphere production, while CB1 receptor agonists enhance neurogenesis [97, 98].

A randomised controlled trial study by Ren et al. showed that an almond-based low carbohydrate diet (LCD) improved depression and glucose metabolism in patients with type 2 diabetes by modulating gut microbiota and glucagon-like peptide-1 (GLP-1) [99]. Almond-based LCD significantly reversed depressive-like behaviour and glycosylated haemoglobin, while significantly increasing the number of short-chain fatty acid (SCFA)-producing bacteria Roseburia, Ruminococcus and Eubacterium. This suggests that the role of almond-based LCD in improving depression in type 2 diabetic patients may be related to its stimulation of the growth of SCFA-producing bacteria, increased SCFA production and activation of the free fatty acid 2 (FFA2) receptor (known as GPR43), and further maintenance of GLP-1 secretion.

Brain-gut axis plays important role in depression and obesity. The gut microbiota has been proven to interact with various organs, including the brain. Gut microbiota and its metabolites may act directly or indirectly on the brain via vagal stimulation to regulate metabolism, obesity, body homeostasis and energy balance as well as central appetite and food reward signals, which play a vital role in obesity [100]. There is a growing body of data suggesting that the gut microbiota coordinating multiple bodily functions is closely linked to the immune, metabolic and nervous systems and that dysbiosis of the gut dysbiosis disrupts the homeostasis between these systems [101]. The GBA is a bidirectional connection between the gut microbiota and the brain [100]. GBA influences physiological function and behavior through three different pathways (neural pathways, endocrine pathways, and immune pathways) [100, 102]. The neural pathway mainly consists of the enteric nervous system and the vagus nerve; the endocrine pathway mainly affects the neuroendocrine system of the brain, especially the HPA axis as well as the immune pathway [100, 102]. In particular, the signals from a brain influence the motor, sensory and secretory patterns of the gastro-intestinal tract, regulate inflammatory processes and influence the structure of the gut microbiota, and in turn, visceral information from gastro-intestinal features can affect brain function [103]. For example, neuroendocrine hormones (e.g., corticosterone) alter intestinal permeability, barrier function, and communicate with immune cells regarding cytokine secretion, and immune cells release cytokines important in the host responses to inflammation and infection [104]. Some alterations in the gut microbiota can modulate host metabolic pathways and dietary behavior through GBA, leading to obesity [105]. Recently, the role of the microbiota as an important factor in regulating gut-brain signaling has emerged and the concept of the microbiota-GBA has been established [105]. The GBA is proposed as the focus of new scientific and clinical research on its possible sites of systemic therapeutic interventions for depression and obesity [106].

The potential role of neuroplasticity in depression and obesity

Neuroplasticity is characterized as the potential of the brain to undergo neurobiological changes in responding to external stimuli [107]. It is currently accepted that the mammalian brain shows continuous plasticity at all stages of life. The plasticity of neurons enables the CNS to learn newly acquired skills and to engage in ongoing learning and memory. In addition, neuronal plasticity allows the reorganization of neuronal networks in response to environmental stimuli as well as recovery after lesions [108]. Neuronal plasticity can be achieved through neurogenesis, apoptosis, synapse-dependent activity, as well as reorganization of neuronal networks [109]. Stress and depression are usually correlated, and studies have shown that chronic stressful events commonly accelerate depressive episodes in vulnerable individuals. Advanced brain functions are proposed to require synaptic frequency decoding, and changes in synaptic activation frequency may cause an increase or decrease in the long-term efficiency of these synapses, which may lead to long-term potentiation (LTP) or long-term depression (LTD) [110]. Hwang et al. showed that the intensity of synaptic plasticity (LTP and LTD) at Schaffer lateral branch-CA1 synapses in hippocampal isolated slices of obese male mice was lower compared to sex-specific controls [111]. This suggests that, like mice in the depression model, HFD-obese mice also affect hippocampal synaptic plasticity. In neuroscience research, depressive-like behaviors and chronic stress have been related to damage to neuroplasticity, like neuronal atrophy as well as synaptic loss in the medial prefrontal cortex (mPFC) and hippocampus [112]. Neuroplasticity as a downstream mechanism of the effect of novel fast-acting antidepressants such as ketamine has stimulated great interest in the mechanisms of neuroplasticity [113]. Among them, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation, BDNF and mammalian/mechanistic target of rapamycin (mTOR)-mediated signaling, synaptic protein expression and synaptogenesis are framed with a focus on neuroplasticity to explain the potent and sustained depression treatment effects of these compounds [113].

The hypothesis of neuroplasticity in depression suggests that downstream effects of antidepressants, such as increased neurogenesis, contribute to improved cognition and mood [21]. BDNF is a growth factor that modulates neurite growth, functional neuronal connections, synapse formation, as well as synaptic plasticity in the CNS [114]. BNDF signaling was proved to be required for the antidepressant effect of ketamine [115]. Activation of the high-affinity BDNF receptor, tropomyosin receptor kinase B (TrkB), is essential for antidepressant-related behaviors [114]. Numerous reports using depression-like behaviors or different animal models manipulating the expression of BDNF or its receptor TrkB suggest that BDNF/TrkB participates in the pathophysiology of depression as well as the mechanism of action of antidepressant treatments [114, 116]. Enhanced translation and/or release of BDNF and activation of the BDNF receptor target TrkB may lead to further activation of downstream pathways essential in synaptic plasticity. BDNF-mediated activation of the TrkB receptor activates the PI3K/Akt signaling pathway and downstream activation of the MEK-MAPK/Erk signaling pathway [115]. Both pathways promote protein translation by activating the mechanistic target of rapamycin complex 1 (mTORC1) [117]. The acute activation of mTOR and protein translation may trigger sustained changes in synaptic plasticity leading to long-term effects of ketamine. Preclinical studies have shown that sodium-glucose co-transporter 2 inhibitors (SGLT2i) improve cognitive dysfunction, reduce oxidative stress, and neuroinflammation, and improve neuronal plasticity and mitochondrial brain pathways in obese and type 2 diabetes mellitus (T2DM) mice [118]. The mTOR serves as a trophic sensor with critical homeostatic functions in modulating energy metabolism, supporting neuronal growth as well as plasticity [115]. In addition, SGLT2i restored mTOR to its activated physiological state and prevented the onset or progression of neurodegenerative diseases [118].

Neuroplasticity due to chronic sugar intake has been shown to reduce impulse control and thus resistance to high-fat/high-sugar foods, leading to an obesity epidemic [119]. Akhaphong et al. showed that placental mTORC1 is the mechanistic connection between placental function and the programming of obesity as well as insulin resistance in adult offspring [115]. A study by Li et al. found that 8 weeks of HFD-feeding was effective in inducing metabolic disorders, including obesity as well as hyperlipidemia, in mice. Interestingly, the mice also exhibited depressive and anxious behaviors [120]. Li et al. concluded that HFD-feeding inhibited AMPK phosphorylation and induced mTOR phosphorylation [120]. After 28 days of treatment with the mTOR inhibitor rapamycin, autophagy and BDNF levels were elevated [120]. This suggests that improvement of lipid metabolism or enhancement of autophagy via the AMPK/mTOR pathway may be a potential candidate target for the therapy of obesity and depression.

The potential role of HPA axis dysregulation in depression and obesity

The HPA axis, which consists of the hypothalamus, pituitary and adrenal glands, modulates the production of glucocorticoids and is associated with the pathophysiology of psychiatric disorders [40]. During stress conditions, the HPA axis promotes transient physiological adaptations that usually resolve after the stress stimulus is not present. Both psychological and physiological stresses activate the HPA axis, which stimulates the release of corticotrophin-releasing factor (CRF) and arginine vasopressin (AVP) from the hypothalamic paraventricular nucleus (PVN), and the HPA axis is an essential component of the stress response system [40, 121]. AVP activates the locus ceruleus-norepinephrine neuromodulatory system, triggering a “fight or flight” response (regulated by the epinephrine and the norepinephrine), while CRH acting on the pituitary gland, which in response secretes adrenocorticotropic hormone (ACTH) into the bloodstream [40]. Once ACTH arrives in the adrenal glands, it initiates the release of cortisol or corticosterone, an anti-inflammatory hormone, and mediates the physiological behavioral response to stress [40]. In normal conditions, negative feedback from cortisol on CRH and ACTH ensures HPA homeostasis via the activation of glucocorticoid receptors (GRs) as well as mineralocorticoid receptors (MRs) [40]. CRF and AVP both induce the secretion of ACTH from the anterior pituitary gland, which increases the release of ACTH, causing an elevated level of circulating glucocorticoid (GC) and inhibiting the secretion of CRF and AVP from the hypothalamus, forming a reverse feedback circuit [122]. Chronic stress is known to overstimulate the HPA axis and the regulation of corticosterone secretion, which is associated with abdominal obesity [123, 124]. Studies have shown that increased physical activity can normalize corticosterone secretion and thus have a positive impact on physical and mental health. A randomized controlled trial by Lasselin et al. found that immune and behavioral responses to lipopolysaccharide (LPS) differed little between obese and normal-weight subjects, but that cortisol responses to LPS were significantly attenuated in obese individuals and that higher body fat percentage was associated with lower cortisol responses to LPS [125]. This suggests that young and healthy obese individuals do not have increased behavioral sensitivity to cytokines, but have diminished cortisol responses to immune challenge.

Over the last decades, several hypothalamic axis abnormalities associated with stress overreaction have been identified in patients with depression. These include alterations such as excessive CRF secretion in the paraventricular nucleus of the hypothalamus, impairment of negative feedback in the HPA axis, enlarged adrenal glands, hypercortisolism, and reduced inhibition of cortisol by dexamethasone [126]. Neuroendocrine studies have demonstrated HPA axis hyperactivity in patients with MDD. Changes in the HPA axis in depressed patients have been consistently reported, with approximately 30% of depressed patients having higher cortisol levels [127]. It has been shown that over 40-60% of depressed patients experience hypercortisolemia. Increased stress-induced GC secretion may enhance mood and motivation [128]. Microbiota-induced hyperactivity of the HPA axis and inflammation have also been implicated in causing depression [129]. Pro-inflammatory cytokines exert the potential to activate the HPA axis, and patients with depression also have a hyperactive HPA axis. Furthermore, HPA axis dysfunction decreases BDNF expression, inhibits 5-HT synthesis, reduces Glu receptor expression, and even disrupts neuroplasticity as well as neural circuits [122, 130]. Related studies suggest that an excess of pro-inflammatory cytokines inhibits the negative feedback of the HPA axis, growing the permeability of the BBB, reducing 5-HT synthesis, interfering with the glutamatergic system, and ultimately leading to depression [131, 132]. More than half of depressed patients display negative feedback dysfunction of the HPA axis, including chronic increases in circulating GC and ACTH [133]. Chronic stress and stress hormones such as glucocorticoids trigger metabolic changes, including obesity and diabetes.

A growing body of research suggests that chronic stress-related stimulation of the HPA axis and the causing excess glucocorticoid exposure may exert a fundamental role in the development of visceral obesity [134]. FGF21 is a longevity factor that coordinates the interaction between energy metabolism and stress response [135, 136]. FGF21 is a general stress factor that not only alters energy metabolism but also activates multiple rescue processes directly or indirectly by stimulating the secretion of lipocalin and hormones in the HPA axis through the AMPK signaling pathway and several other pathways [137]. Recent studies have shown that FGF21 therapy can relieve many metabolic diseases, such as obesity, type 2 diabetes as well as some cardiovascular diseases. FGF21 can control stress response and metabolism by regulating the function of the somatotropic axis and HPA pathway [135]. Werdermann et al. showed that obese animals show an overactive HPA axis, leading to adrenal hyperplasia [137].

The potential role of the neural cell nucleus and neural circuit in depression and obesity

Although neuroplasticity is important for depression and obesity co-morbidity, there is growing evidence that it is significant to explore the neural mechanisms of depression and obesity co-morbidity at the level of the neural cell nucleus as well as the neural circuit [138]. Xia et al. suggest that melanocortin 4 receptor (MC4R) neurons, located in the bed nucleus of the stria terminus (dBNST), are involved in psychiatric-related body weight regulation by receiving α5-containing GABA_A receptor and serotonergic GABAergic projections from hypothalamic AgRP neurons [138]. Overall, targeting GABA_AR-α5 and 5HT₃R within MC4R^dBNST neurons contributed to rescuing HFD-induced anxiety and depression, thereby reducing body weight by simultaneously reducing HFD cravings and enhancing a healthy low-fat diet in mice [138]. In addition, studies have shown that mixtures of zonisamide-granisetron cocktail restore mental normalcy and promote weight loss by targeting the GABA_AR-α5 and 5HT₃R pathways, respectively, by altering food preferences toward a healthy low-fat diet [138].

Recent studies by Hallihan et al. have found that affective neural circuits and inflammatory markers are associated with symptoms of depression and anxiety in comorbidities of obesity [139]. They used the current feasibility study using functional neuroimaging and biospecimen data to identify whether changes in inflammatory markers, fecal short-chain fatty acids, as well as neural circuit-based targets predicted depression and anxiety outcomes in comorbid obese participants, and preliminary correlation analyses showed significant correlated changes in three inflammatory markers (IL-1RA, IL-6, and TNF-α) and five neural targets (negative influence circuit, positive influence circuit, and default mode circuit) at 2 months [139]. Further, they found that changes in IL-1RA and TNF-α at 2 months, as well as changes in three neural targets (negative influence circuit and positive influence circuit), correlated with changes in depression and anxiety symptoms at 6 months [139]. Perinatal exposure to maternal obesity, metabolic disorders (including diabetes and hypertension), and unhealthy maternal diets have long-term effects on the behavior and physiology of offspring [123]. Evidence from epidemiological studies suggests that maternal obesity and metabolic comorbidities increase the risk of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, schizophrenia, eating disorders (food addiction, anorexia nervosa, as well as bulimia nervosa), and cognitive impairment in offspring [140]. In addition, during pregnancy, inflammation in the offspring’s brain impairs the development of neural pathways critical to behavioral regulation, such as the serotonergic, dopaminergic, and melanocortinergic systems [123].

The potential role of genetic association in depression and obesity

Mendelian randomisation (MR) studies have shown that obesity and the development of depression are causally related [141]. To provide a better comprehension of the relationship between obesity and depression, Speed et al. conducted a MR study of the relationship between adiposity, non-adiposity, height and depression, using results from the UK Biobank (n = 332,000) and the Psychiatric Genomics Consortium (n = 480,000) genome-wide association studies [141]. The results of the study found that both adiposity and height (short stature) were causal risk factors for depression, whereas non-adiposity was not [141]. In addition, they note that reducing fat mass will reduce the risk of depression. O’Loughlin et al. performed a two-sample MR using genetic summary statistics (15771 cases and 178777 controls) from the recent Genome-Wide Association Study (GWAS) of depression in East Asian ancestry. i.e., single nucleotide polymorphisms (SNPs) associated with BMI and SNPs associated with waist height ratio (WHR) were selected as genetic instrumental variables and inverse variance weighting (IVW) method to estimate the causal relationship between BMI and WHR and depression [142]. This GWAS data provides the first MR evidence that high obesity is associated with a lower risk of depression in a population of East Asian ancestry living in East Asia. Liao et al. performed genome-wide genotyping of 106,604 unrelated individuals from a Taiwanese biobank to derive polygenic risk scores for BMI and MDD to assess their effects on obesity-associated traits [143]. This study showed that MDD polygenic risk score (PRS) was positively associated with waistline, hipline, waist-hip ratio, body fat percentage, BMI, overweight (BMI ≥ 25), and obesity (BMI ≥ 30) [143]. The results of the meta-analysis of interactions suggest a genetic mechanism for the increased risk of obesity in patients with depression [144]. Rivera et al. showed that depression enhanced the effect of FTO variants on BMI, with a 2.2 increase in BMI per rs9939609 risk allele (A) in depressed patients compared to mentally healthy controls [144]. This suggests that alterations in key biological processes associated with depression may interact with FTO risk alleles to increase BMI or obesity risk.

In a cross-trait meta-analysis, Amare et al. identified 14 genetic loci (including NEGR1, CADM2, PMAIP1, and PARK2) linked to obesity and response to treatment with Selective serotonin reuptake inhibitors (SSRIs) [145]. Weight gain is a side effect of antidepressants and antipsychotics that can cause many comorbidities and reduce life expectancy [146]. The majority of included studies demonstrated a 5% weight gain in individuals treated with antidepressants; however, Quetiapine, Haloperidol, Trifluoperazine, Risperidone, Aripiprazole, Olanzapine, and Clozapine resulted in≥7% weight gain from baseline [146]. Some antidepressants, such as Mirtazapine, show significant levels of weight gain, while others, such as Bupropion, show weight loss effects [147]. Therefore, controlling undesired weight effects is an important consideration in the selection of antidepressants.

Potential and future treatment of depression and obesity

The multifaceted effects of adipokines and lipokines on neurological and brain health and the dysregulation of adipokine and lipokine secretion may contribute to the co-morbidity of obesity and depression [166]. Exploring the pathogenesis of obesity and depression from the perspective of multiple adipokines and lipokines has beneficial implications for the future treatment of obesity and depression. Adipokines and lipokines such as leptin, adiponectin, PLA, and LPA may be critical targets for the future treatment of obesity and depression. Clinical studies have shown that individuals with POMC or LepRb deficiency typically experience severe obesity, bulimia and comorbidities, which can severely impact the patient’s quality of life and depressive behavior [246].

Diet and obesity have been proven to have a direct effect on mood, and stress-related mental diseases might result in alterations in eating patterns that affect weight [247]. Recent studies suggest that dietary interventions and energy restriction may help prevent depression and anxiety, which would serve as complementary therapies [248]. Ganoderma lucidum is a medicinal mushroom commonly used to improve quality of life, promote health, as well as enhance vitality. Studies have shown that ethanolic extract of Ganoderma lucidum ethanol extract (EEGL) has significant effects on feeding behavioral parameters, depression-like symptoms and locomotor activity in Swiss mice, as reflected by a significant decrease in body weight gain and food intake, a dose-dependent increase in water intake, and a decrease in immobility time in the forced swim test (FST) and the tail suspension test (TST) in Swiss mice [249]. These findings suggest that EEGL can reduce body weight gain and produce antidepressant-like effects.

Unhealthy eating patterns might be connected with an increased risk of depression or anxiety, while healthy eating patterns might reduce that risk. The first human study to show a link between diet and hippocampus volume mirrored findings from previous preclinical investigations in animal models, in which low nutritional food intake and excessive unhealthy food intake were independently linked with decreased left hippocampal volume, respectively [250]. Recent clinical studies have shown that diet can influence the physiological and immune functions of the body and has potential therapeutic strategies. The study found that 83% of participants who adhered to a ketogenic diet experienced significant reductions in fat mass and nearly 50% decreases in self-reported fatigue and depression scores over the study period [251].

Functional brain imaging research confirms that image and verbal cues associated with foods and beverages high in sugar produce higher preferences and higher emotional activation, making it harder for overweight people to resist eating unhealthy foods [252]. Several variables, including inflammation, oxidative stress, and insulin resistance, have been postulated to contribute to diet-induced brain damage, all of which can be affected by dietary consumption and are related to the onset of depression [48]. Maintaining a balanced diet with anti-inflammatory properties may aid in the prevention of depressive symptoms, particularly in men, smokers, and those who are inactive [253].

In observational studies, adherence to a healthy diet, particularly a traditional Mediterranean diet or avoidance of a pro-inflammatory diet, appears to have a protective effect against depression [16]. A population-based cohort study showed that people who adhered to a Mediterranean diet during midlife had a lower risk of depression later in life [16, 254]. Although the relationship between obesity and depression is known, there is little research on the clinical benefits of nutritional therapy for obese patients. A clinical study evaluating the effects of a traditional Brazilian diet (DieTBra) and extra virgin olive oil (EVOO) on anxiety and depressive symptoms in severely obese participants showed that both DieTBra and olive oil interventions were effective in reducing anxiety and depressive symptoms in severely obese adults and that these interventions could be combined with clinical protocols for the treatment of anxiety and depressive symptoms in severely obese patients [255].

Current evidence suggests that diet quality is a modifiable risk factor for affective disorders, however, further research is needed to investigate the impact of dietary patterns and weight loss on improving psychological symptoms. Rodriguez-Lozada et al. randomly assigned overweight and obese participants (n=305) to two low-calorie diets with different macronutrient distributions: a moderately high protein diet and a low-fat diet for 16 weeks to assess the effects of prescribed energy restriction on anxiety and depressive symptoms in overweight and obese participants, as well as some baseline potential predictive value of psychological characteristics for weight loss [256]. The nutritional intervention demonstrated beneficial effects of weight loss on trait anxiety scores in women, depression scores in all populations, and especially in women and subjects following a low-fat diet. In addition, weight loss can be predicted by anxiety status at baseline, which occurs primarily in women and those on a low-fat diet, and this trial suggests that weight loss triggers improvements in psychological traits, while anxiety symptoms predict those volunteers who benefit most from a balanced calorie restriction intervention, which would help to personalize precise nutrition [256]. In addition, a randomized clinical trial study by Hariri et al. demonstrated the beneficial effects of sumac (Rhus coriaria L.) supplementation with a calorie-restricted diet on anthropometric indices, oxidative stress, and inflammation in overweight or obese women with depression [257].

Probiotics have been demonstrated to have antidepressant responses and anti-inflammatory effects. Borges et al. conducted a systematic review and meta-analysis of overweight or obese patients to determine the effects of prebiotics on blood biomarkers of obesity, depression, and anxiety (including ACTH, cortisol, leptin, ghrelin, thyroid stimulating hormone (TSH), parathyroid hormone (PTH), vitamin D, and BDNF) [258]. Prebiotics were found to possibly facilitate the regulation of blood concentrations of ghrelin and CRP in overweight or obese individuals. A double-blind, randomized, placebo-controlled trial was conducted in obese men (n = 45) and women (n = 60), consisting of a 12-week weight loss period based on moderate energy restriction and a 12-week weight maintenance period [259]. Each subject consumed two capsules per day of either a placebo or probiotic supplement Lactobacillus rhamnosus CGMCC1.3724 (LPR) [259]. During both phases of the program, LPR supplementation increased weight loss in women, which was associated with an increased desire to eat on an empty stomach. In addition, the LPR female group showed a more pronounced decrease in food cravings as well as a decrease in Beck Depression Scale scores [259]. Significant benefits of LPR on fasting satiety and cognitive restraint were also observed in men [259]. These clinical observations support the hypothesis that the gut-brain axis may influence appetite control and related behaviors in obesity management. Hulkkonen et al. studied the efficacy of probiotics and/or fish oil in improving prenatal and postnatal depression and anxiety symptoms and found that diet quality was negatively associated with depressive symptoms in early pregnancy and 6 months postpartum and with anxiety symptoms in early pregnancy [260].

Probiotics, prebiotics, and mushroom extracts may be used to simultaneously prevent and treat obesity and depression, and further research is required to optimally use these substances in humans [30]. Furthermore, the using dietary interventions may demonstrate to be an appealing and cost-effective alternative or adjunctive treatment for the clinical management of these conditions. Prospective investigations of the connection between diet and mental health ought to use clearer definitions to define diet and include or control for significant confounding factors. Regulation of gut microbiota might be a new strategy for the treatment of both neuroinflammation and depression [30]. Biochemical markers are positively associated with the development and severity of obesity, depression as well as anxiety, and are regulated by changes in the composition of the gut microbiota [258]. The gut microbiota is a potentially important regulating pathway between diet and brain health. Altered gut microbiota may be a therapeutic strategy for depression and obesity. FMT is currently the most effective gut microbiota intervention [261]. FMT may be a promising therapeutic choice for neurological disorders, however, the available evidence remains sparse, with a limited number of human studies conducted or ongoing, and for some diseases, only animal trials have been conducted. To further elucidate the role of FMT in neurological disorders, large-scale double-blind randomized controlled trials are required [261].

With the growing insight into the mechanisms underlying the complex interactions between diet and gut microbiota and their effects on depression, specific dietary patterns that aid in the prevention of anxiety and mood disorders may be identified [248]. Furthermore, preclinical studies have shown that exercise can improve various types of behaviors, such as depression and anxiety [262–264]. Morgan et al. showed that aerobic exercise had significant beneficial effects on depression-like, anxiety-like and cognitive-like behaviors during the healthy adult lifespan of C57BL/6 mice [265]. A combined treatment for both obesity and depression improves weight and mood risk factors more than treatment for each disease alone [266]. In a randomized controlled trial of 63 overweight/obese participants, Pilates and aerobic training were found to improve depression, anxiety levels and quality of life in overweight and obese people [267]. Recent clinical studies have shown that virtual reality exercise programs have a positive impact on BMI, depression levels, exercise enjoyment and exercise immersion in overweight middle-aged women. This is an effective home exercise program for people undergoing obesity management [268]. Developing tailored treatments according to a personalized medical approach to the biology of obesity-depression co-morbidities may ultimately benefit the patients involved. In Figure 3, we summarized the potential and possible future treatment options for obesity and depression (Figure 3).

Figure 3. Map of potential and possible future treatment options for depression and obesity comorbidity. LTP, long-term potentiation; LTD, long-term depression; HPA axis, hypothalamo-pituitary-adrenal axis.

Author Contributions

XYF and FYZ drafted the manuscript. YCW, WX and QQL made critical revisions. RJC made substantial revisions to the logic of the article. WY completed the conception, design, editing and acquisition of funding. All authors approved the final version of the manuscript for submission.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding

This work was supported by grants from the Natural Science Foundation of China (Grant No.81971276), Jilin Science and Technology Agency (20220203124SF, 20220204031YY, 20210204028YY, YDZJ202301ZYTS079, 20210204006YY, YDZJ202301ZYTS058) and Jilin University Bethune Program Project (2022B35).

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