# Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach
## 3 Exercise and Appetite-Reducing Metabolites, Myokines, and Hepatokines
Plasma increases in Lac-Phe correlate with lactate concentrations [34]. Thus, increased circulating levels of Lac-Phe in response to intense exercise can temporally suppress appetite after intense exercise [34]. The limited investigation on this metabolite has not produced details on its mechanisms of action. Circulating levels of Lac-Phe during intense exercise targets GPCRs expressed on neurons in the central nervous system involving regulating appetite (Figure 3). Myokines (muscle-derived factors), which have a role in reducing and maintaining body weight, are produced in response to energy demands and during cell proliferation and differentiation [196; 197; 198]. Some myokines inhibit eating behaviors and energy intake and are thought to be beneficial in obesity suppression and treatment. Inteleukin-6 (IL-6) is a myokine and also a pro-inflammatory cytokine that partly mediates the effects of exercise on appetite suppression and energy intake [199; 199; 200; 201]. The inhibition of IL-6 by pharmacological agents, such as toclizumab, triggers an obesogenic state [202], while the overexpression of IL-6 [203] and its central or peripheral administration results in hunger and anorexia effects [204; 205; 206]. Metabolic diseases such as obesity and type 2 diabetes are associated with increased inflammation and pro-inflammatory cytokine levels such as IL-6 released by adipose tissue [207; 208; 209] (Figure 1). In contrast to adipose tissue and plasma, IL-6 levels in the central nervous system (CNS) are dampened in obesity, suggesting different roles of peripheral and central effects of IL-6 in obesity [205; 210] (Figure 1). Incontrast, other studies report constant increases in hypothalamic IL-6 in response to an obesogenic diet [211,212]. Exercise also alters the expression and concentration of IL-6, as shown in individuals with normal weight and adiposity following high-intensity exercise, where IL-6 levels are negatively correlated with appetite and energy intake [213] (Figure 3). Exercise increases circulatory IL-6 concentrations in intensity-, duration-, and glycogen content-dependent manners [181,214]. Adipose tissue and immune cells release IL-6 in obesity and autoimmunity, respectively, while skeletal muscles are the main source of circulatory levels of IL-6 during exercise bouts, which peak immediately post-exercise and return to baseline levels \(\sim\)2-3 h after exercise cessation [215,216]. The increase in IL-6 levels is dependent on exercise duration, intensity, and muscle mass involved [214,216]. Several mechanisms have been proposed by which IL-6 transcription and expression responds to exercise, including the following: (1) Muscle contraction is accompanied by increases in intracellular and nuclear calcium that activate PI3K to stimulate IL-6 transcription [217] (Figure 3). (2) The production and secretion of IL-6 during exercise is regulated by the muscle glycogen content and glucose ingestion [218,219,220]. The expression of IL-6 mRNA and its protein in working muscles is diminished when intramyocellular glycogen stores decline, so IL-6 serves as an energy sensor [218,221] (Figure 3). Although acute exercise elevates plasma IL-6 concentrations, regular exercise lowers the IL-6 baseline levels of both circulating and muscle mRNA levels [222]. Exercise increases the expression of IL-6 receptors (IL-6R) in muscle, suggesting increased muscle sensitivity to IL-6 [223]. Increased energy demands during exercise stimulate IL-6 production by contracting skeletal muscles and increase the plasma levels of IL-6 [224,25,225,226]. IL-6 activates membrane-bound gp130 receptors to stimulate JAK and the phosphorylation of tyrosine in the gp130 cytoplasmic domain, leading to its activation and phosphorylation, followed by the formation of STAT dimerism and then translocation to the nucleus to increase the transcription of some genes involved in inflammation, immune response, cell survival, and tissue repair [227,228,229]. The CNS is the main site where IL-6 exerts its metabolic and anorexigenic effects [230,231].