Adipokines as emerging depression biomarkers: A systematic review and meta-analysis
Introduction
Current diagnostic practice for major mental disorders, including major depressive disorder (MDD) is based on the clustering of symptoms and other clinical features (Pizzagalli, 2011). MDD is frequently not properly recognized in diverse ‘real world’ clinical settings (Craven and Bland, 2013, Kessler et al., 2007, Lake and Baumer, 2010, Yan et al., 2013). This delay in diagnosis hinders early treatment intervention, leading to worse outcomes due to the dysregulation of several measureable pathophysiological pathways in the central nervous system, including but not limited to a dysfunctional activation of the hypothalamic-pituitary adrenal (HPA) axis (Pariante and Lightman, 2008), inflammation (Gold et al., 2013) and the generation of oxidative and nitrosative stress (O&NS) (Moylan et al., 2013). Despite this, there are currently no validated peripheral biomarkers for the diagnosis, treatment selection and response prediction in MDD (Breitenstein et al., 2014). The development of biomarkers for MDD and their incorporation into clinical practice promises to revolutionize the landscape of health care.
Since the discovery of leptin by Zhang et al. (1994), its role in metabolism and homeostasis has been extensively investigated (Berman et al., 2013, Licinio et al., 2004, Paz-Filho et al., 2008, Zhang et al., 1994). It is increasingly recognized that the adipose tissue is not an inert tissue devoted to energy storage, rather being a metabolically active endocrine organ capable of secreting a number of bioactive products referred to as ‘adipokines’, which include adiponectin (Maeda et al., 1996), leptin, and resistin (Steppan et al., 2001). Adipokines are also secreted by diverse tissues, including but not limited to macrophages, myocytes, and pancreatic cells (Arnoldussen et al., 2014). The adipocyte-brain crosstalk is mediated to a large extent by adipokines and this circuit plays a pathophysiological role beyond obesity and cardiometabolic conditions (Nakamura et al., 2013, Paz-Filho et al., 2010). Leptin influences neurotransmitters such as dopamine (Ishibashi et al., 2012) and impacts gray matter plasticity (London et al., 2011). Consequently, a putative role for leptin, adiponectin and resistin in the pathophysiology of neuropsychiatric conditions associated with metabolic abnormalities, including MDD has emerged (vide infra) (Diniz et al., 2012, Liu et al., 2012, Lu et al., 2006, Weber-Hamann et al., 2007, Yamada et al., 2010).
Adiponectin is a polypeptide that regulates glucose levels as well as fatty acid breakdown (Yildiz et al., 2004). It is exclusively secreted by adipocytes as an abundant adipose-derived serum protein. Adiponectin exerts insulin-sensitizing and either inflammatory or anti-inflammatory effects (Kwon and Pessin, 2013, Wan et al., 2014). AdipoR1 and AdipoR2, the cognate adiponectin receptors, are expressed in discrete brain areas related to mood regulation, including the hippocampus (Liu et al., 2012). Adiponectin exerts antidepressant-like effects in the social-defeat stress animal model of depression (Liu et al., 2012). Adiponectin haploinsufficiency blunts glucocorticoid-mediated negative feedback on the HPA axis (Liu et al., 2012). Notwithstanding that plasma levels of adiponectin are negatively correlated with obesity, waist circumference and visceral fat in humans, metabolically healthy obese subjects have peripheral levels of adiponectin similar to lean individuals (Arita et al., 2012, Cohen et al., 2011, Doumatey et al., 2012). Some reports point to higher adiponectin serum levels in MDD subjects compared to healthy controls (Jow et al., 2006), while other investigators found either lower levels (Cizza et al., 2010, Zeman et al., 2010) or unaltered (Kotan et al., 2012) peripheral levels in MDD individuals versus controls.
Leptin circulates as a 16-kDa protein, and is the product of the ob gene. It is mainly synthesized by adipose tissue in proportion to percentage body fat (Zupancic and Mahajan, 2011). This peptide is transported across the blood–brain barrier by a saturable process to exert its central effects (Zupancic and Mahajan, 2011). Leptin has antidepressant and anxiolytic activities in rodents (Liu et al., 2010). Diet-induced obesity in mice is associated with an impaired antidepressant response to leptin which is related to a blunted leptin-induced increment in hippocampal BDNF levels compared to mice fed a standard diet (Yamada et al., 2011). The antidepressant activity of leptin may result from its modulatory effect upon the HPA axis. In food-deprived ob/ob mice, systemic administration of leptin lowers corticosterone levels and prevents the induction of CRH synthesis in the paraventricular nucleus (PVN) (Huang et al., 1998). Leptin levels were associated with an elevated risk of depression onset in older men with a significant amount of visceral fat (Milaneschi et al., 2012). Several studies have found lower serum leptin levels in individuals with MDD compared to healthy controls (Jow et al., 2006, Kraus et al., 2001), whereas other studies in women with MDD found that plasma leptin levels were significantly increased (Esel et al., 2005, Rubin et al., 2002, Zeman et al., 2009). Similarly, some studies reported that leptin levels are variously increased (Esel et al., 2005, Kraus et al., 2002) or not changed by antidepressant treatment (Kraus et al., 2002, Schilling et al., 2013). Lastly, some studies suggest that leptin may be a biomarker of risk for de-novo depression (Pasco et al., 2008).
The protein resistin is related to insulin resistance in rodents (Schwartz and Lazar, 2011). Some studies found elevated peripheral resistin levels in human obesity (Degawa-Yamauchi et al., 2003, Owecki et al., 2011), whereas other investigations found resistin down-regulated in obesity (Way et al., 2001). The findings relating resistin to MDD are inconsistent across studies. Lower resistin serum levels in individuals with MDD compared to healthy controls are reported (Aliyazicioglu et al., 2011a), but not replicated (Papakostas et al., 2013). In addition, resistin levels were positively correlated with cortisol levels in MDD patients (Weber-Hamann et al., 2007). Furthermore, there was a significant decrease in resistin serum levels in patients receiving antidepressant treatment who remitted from depression (Weber-Hamann et al., 2007).
In order to clarify the inconsistent findings on the associations between peripheral levels of adiponectin, leptin and resistin both as putative diagnostic as well as treatment response biomarkers in MDD, we performed a meta-analysis of the available evidence. We hypothesized that there would be significant heterogeneity between studies (for example, related to age, body mass index and gender). Therefore, this review also aimed to identify potential confounders. As far as we know no previous meta-analyses had been published on the role of akipokines as depression biomarkers.
Section snippets
Search strategy
Articles for review were identified from the PubMed/MEDLINE, EMBASE, and Web of Science databases from inception to January 12, 2014. The standardized search algorithms are detailed in Supplementary Material S1. Search terms included ‘akipokines’, ‘leptin’, ‘adiponectin’ and ‘resistin’ cross-referenced with ‘depression’, ‘major depressive disorder’ and ‘depressive’. This search strategy was augmented by manual searches were performed on reference lists of included articles. We also tracked
Search results and study characteristics
Of 1185 unique references, 1120 were excluded after title/abstract screening. Sixty five references were selected for full-text review. Finally, 23 original studies were included in the systematic review (Fig. 1). Please see Tables S1A and S1B for a description of primary reasons for exclusion (Supplementary Material). The authors of meeting abstracts were electronically contacted by the authors. Characteristics of the included diagnostic (i.e., MDD individuals vs. healthy controls) and
Discussion
The goal of this study was to perform a systematic review and meta-analysis of diagnostic and intervention studies of adipokines, namely adiponectin, leptin and resistin in MDD. While there were no significant differences in adiponectin and leptin peripheral levels between participants with MDD and healthy controls, the study identified relevant moderators and potential confounders. Resistin serum levels were significantly lower among MDD participants compared to healthy volunteers. However,
Conclusions and future research directions
In conclusion, these meta-analyses provide evidence that the initial enthusiasm regarding the possible utility of adiponectin and leptin as diagnostic depression biomarkers is not justified. Our findings underscore the need for a more uniform methodology in future studies (i.e., a better control of confounders like BMI, depression severity and type of assay) to estimate the potential validity of these adipokines as emerging depression biomarkers. Few studies were performed on the potential
Role of funding source
None.
Contributions
AFC, DQCR, LMM, PMGC, CAK and RSM designed the study. AFC, CAK and PMGC analyzed the data. AFC, RMV, CAK, RSM and MB wrote the paper. All authors contributed to and had approved the final version.
Conflicts of interest
The authors declare no competing financial interests relevant to the present work.
Acknowledgments
AFC was supported by a research scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil; Level 2). MB is supported by a NHMRC Senior Principal Research Fellowship 1059660.
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