Spexin-Based Galanin Receptor Type 2 Agonist for Comorbid Mood Disorders and Abnormal Body Weight.

Seongsik Yun,Arfaxad Reyes-Alcaraz,Yoo-Na Lee,Jong-Ik Hwang,Soon-Gu Kwon,Jeewon Choi,Dong Sik Kim,Hyun Kim,Gi Hoon Son,Jae Young Seong,Jong-Woo Sohn,Dong-Hoon Kim,Byung-Joo Ham,Hyo Jeong Yong,Bong Chul Kim

doi:10.3389/fnins.2019.00391

Seongsik Yun, Arfaxad Reyes-Alcaraz + Show 13 more

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https://doi.org/10.3389/fnins.2019.00391

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Abstract

Despite the established comorbidity between mood disorders and abnormal eating behaviors, the underlying molecular mechanism and therapeutics remain to be resolved. Here, we show that a spexin-based galanin receptor type 2 agonist (SG2A) simultaneously normalized mood behaviors and body weight in corticosterone pellet-implanted (CORTI) mice, which are underweight and exhibit signs of anhedonia, increased anxiety, and depression. Administration of SG2A into the lateral ventricle produced antidepressive and anxiolytic effects in CORTI mice. Additionally, SG2A led to a recovery of body weight in CORTI mice while it induced significant weight loss in normal mice. In Pavlovian fear-conditioned mice, SG2A decreased contextual and auditory fear memory consolidation but accelerated the extinction of acquired fear memory without altering innate fear and recognition memory. The main action sites of SG2A in the brain may include serotonergic neurons in the dorsal raphe nucleus for mood control, and proopiomelanocortin/corticotropin-releasing hormone neurons in the hypothalamus for appetite and body weight control. Furthermore, intranasal administration of SG2A exerted the same anxiolytic and antidepressant-like effects and decreased food intake and body weight in a dose-dependent manner. Altogether, these results indicate that SG2A holds promise as a clinical treatment for patients with comorbid mood disorders and abnormal appetite/body weight.

Highlights

Mood disorders such as anxiety and depression are often associated with abnormal eating behaviors, leading to either obesity or a poor diet (Simon et al, 2006), and endocrine and metabolic conditions are both exacerbated in major depression (Simon et al, 2006; Marijnissen et al, 2011)
The effects of spexin-based galanin receptor type 2 agonist (SG2A) were first addressed in corticosterone pelletimplanted (CORTI) mice, which exhibit markedly lowered body weights and anhedonia, anxiety, and depression-like behaviors (Figure 2)
The sucrose preference test (SPT) was performed first for 2 days, followed by 1-day break, and the elevated plus maze test (EPMT) was performed for 2 days, open filed test (OFT) for 1 day, and TST for 1 day. 3 to 4 h after SG2A administration on the last day, blood and brain samples were collected (Figure 2A)

Summary

Introduction

Mood disorders such as anxiety and depression are often associated with abnormal eating behaviors, leading to either obesity or a poor diet (Simon et al, 2006), and endocrine and metabolic conditions are both exacerbated in major depression (Simon et al, 2006; Marijnissen et al, 2011). SPX mRNA levels are markedly decreased in the fat tissues of obese humans (Walewski et al, 2014), whereas the circulating GAL levels, along with neuropeptide Y and leptin, are significantly higher in obese women (Baranowska et al, 1997). These differences likely reflect the activities of the targeted receptors: SPX binds with high affinity to GAL2 receptor and GAL3 receptor but not GAL1 receptor, whereas GAL has high potencies for GAL1 receptor and GAL2 receptor but a low potency for GAL3 receptor (Kim et al, 2014). Whereas GAL exerts both Gq- and β-arrestin-mediated signaling of GAL2 receptor, SPX shows a biased agonism favoring G-proteinmediated signaling (Reyes-Alcaraz et al, 2018)

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