**1. Introduction**

Spexin (SPX), also known as Neuropeptide Q, is a novel peptide comprised of 14 amino acids and was described for the first time by Mirabeau et al. in 2007 [1]. SPX mRNA and protein were detected in many different tissues, both in animals and in humans. In rodents and humans, SPX mRNA was found in the central nervous system (e.g., hypothalamus [2], hippocampus) and in peripheral tissues (e.g., stomach, small intestine, liver, pancreas [3], fat and other endocrine tissues [4]). In human subjects, the lowest SPX gene expression was detected in muscle- and connective tissue [4]. The fact that SPX mRNA was identified in several different types of tissues suggests that SPX may be involved in various physiological processes and serve as a pleiotropic peptide.

SPX may be involved in fat tissue metabolism, through increasing lipolysis and inhibiting lipogenesis [5]. Furthermore, a decreased uptake of long-chain fatty acids in adipocytes,

**Citation:** Suhs, M.; Stengel, A.; Rudolph, A.; Schaper, S.; Wölk, E.; Kobelt, P.; Rose, M.; Hofmann, T. Circulating Spexin Is Associated with Body Mass Index and Fat Mass but Not with Physical Activity and Psychological Parameters in Women across a Broad Body Weight Spectrum. *J. Clin. Med.* **2022**, *11*, 5107. https://doi.org/10.3390/ jcm11175107

Academic Editor: David Rodríguez-Sanz

Received: 8 July 2022 Accepted: 27 August 2022 Published: 30 August 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

in rodents with diet-induced obesity after peripheral SPX administration, suggests that SPX may contribute to weight loss [6]. In line with this observation, several studies involving humans have demonstrated a negative correlation between serum SPX and serum triglyceride levels [4,7], as well as body mass index (BMI) [7]. In addition, higher circulating SPX levels were observed in non-obese compared to obese adults [8,9] and children [10,11], although not all studies seem to support these results (e.g., no correlation between BMI and body fat with serum SPX, as well as no difference in serum SPX level between NW and OB/overweight female adolescents [12]).

Not only body weight, but also feeding behavior, might be influenced by SPX [13]. It was shown that food intake led to an increase in SPX mRNA expression in the hypothalamus of Siberian sturgeons, possibly pointing towards an anorexigenic function of SPX [14]. Moreover, intracerebroventricular injection of SPX in goldfish resulted in downregulation of the expression of the orexigenic peptides neuropeptide Y (NPY), orexin, and Agouti-related protein (AgRP), and in higher expression of anorexigenic peptides such as proopiomelanocortin (POMC), cholecystokinin (CCK), and melanin-concentrating hormone (MCH) [15]. The postulated anorexigenic function of SPX is unlikely to be triggered by taste aversion [6].

Another important function of SPX is its possible role in the response to physical activity (PA). For instance, a study in mice showed increased locomotor activity after intraperitoneal SPX injection [6]. Furthermore, a recent report in humans demonstrated that circulating plasma SPX levels significantly were increased in a group of participants categorized as positive responders to exercise. Following a 3-month exercise program, they showed an increased maximal oxygen consumption (VO2max) during exercise and, compared to non-responders who did not show an amelioration of VO2max, greater improvement in their metabolic profile (total cholesterol, HbA1c, HOMA-IR) [9]. This may be of relevance, as PA plays an important role in maintaining body weight [16] and, in the form of hyperactivity, it is not only a symptom of anorexia nervosa (AN) [17], but also part of its pathogenesis [18]. In patients with obesity, PA has been shown to be inversely associated with the grade of adiposity [19].

Besides its possible functions in the regulation of metabolism, body weight, and physical activity, SPX may be involved in stress response. For instance, fish exposed to stress showed an increase in SPX mRNA expression in different brain areas (e.g., optic tectum, hypothalamus, and midbrain) [20]. Moreover, it was demonstrated that intrahippocampally injected corticotropin-releasing factor (CRF), which is crucially involved in the stress response, decreases SPX expression in different brain tissues (such as hippocampus, hypothalamus, or pituitary gland) in mice [21]. Additionally, another study in fish found that SPX may influence the serotoninergic system, through the upregulation of serotonin-related genes in the raphe nuclei [22]. Moreover, intraperitoneal administration of escitalopram, a serotonin reuptake inhibitor mostly used for the treatment of major depression and general anxiety disorder, led to the downregulation of SPX mRNA in the hypothalamus and upregulated expression of SPX mRNA in the hippocampus and striatum in rats [23]. Therefore, SPX may also be involved in the regulation of stress, anxiety, and depressiveness.

As some studies on SPX indicated its anorexigenic effects and its role in lipogenesis and PA, we hypothesized that SPX may be a factor involved in energy expenditure, and thus it may be associated with different patterns of PA. Furthermore, we hypothesized that SPX levels might be associated with eating disorder pathology, as well as perceived stress, anxiety, and depressiveness. Therefore, we aimed to further examine the link between plasma SPX levels and body composition and PA along with patient-reported outcomes under naturalistic conditions in an inpatient setting. We studied women across a wide BMI range, to examine the impact of body weight and to control for possible gender differences.

#### **2. Materials and Methods**

#### *2.1. Ethics Statement*

All investigations were conducted according to the Declaration of Helsinki and all patients gave written informed consent. The study was approved by the institutional ethics committee of the Charité–Universitätsmedizin Berlin (protocol numbers: EA1/130/16)
