# Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach
## 3 Exercise and Appetite-Reducing Metabolites, Myokines, and Hepatokines
High concentrations of circulatory IL-6 can access brain areas regulating appetite and energy intake, such as the hypothalamus after crossing the BBB [232]. Exercise increases BBB permeability by downregulating tight junction proteins and astrogliosis [233]. Additionally, IL-6 is expressed centrally by astrocytes, microglia, and neurons [234,235,236]. Some mechanisms by which peripheral and central IL-6 influence appetite and energy intake include the following:  
1. Increases in systemic IL-6 levels promote the production and secretion of GLP-1 and PYY from intestinal L-cells and pancreatic \(\alpha\)-cells [139,181,237], which has a negative correlation with appetite and energy intake [139,181,238] (Figure 3). Increased GLP-1 levels elevate insulin secretion and improve glucose tolerance while also having anti-obese effects by acting on the hypothalamus [139,140,239,240]. Peripherally produced GLP-1 crosses the BBB to bind to its receptors on the hypothalamus to increase the expression and release of POMC neuropeptide, followed by diminished energy intake and body weight [140,241,242]. Additionally, central GLP-1 stimulates the expression of hypothalamic IL-6 and IL-6 receptor \(\alpha\) (IL-6R\(\alpha\)) mRNA by neurons and glial cells to increase and decrease, respectively, the expression of POMC and NPY/AgRP neuropeptides, which in turn cause hypophagic effects and appetite suppression [140,243,244,245,246] (Figure 3). 2. Hypothalamic IL-6 is recognized by IL-6R, which has an intracellular signaling akin to ObR for leptin, to stimulate gp130 and activate STAT3. Thus, IL-6 activates or potentiates the same intracellular anorexigenic signaling for leptin [247,248,249] (Figure 3). IL-6 slows gastric emptying to reduce postprandial glycaemia to negatively impact appetite and energy intake [250] (Figure 3). Generally speaking, the effects of signals of energy balance, such as leptin, GLP-1, and amylin, are modulated by the effects of IL-6 on hampering food intake and body weight [140; 205; 230; 247] (Figure 3). Growth differentiating factor 15 (GDF15) is another factor regulating energy balance. GDF15 is a member of the TGF-\(\beta\) superfamily and is expressed in several tissues, including the liver, kidney, intestines, and placenta, and is upregulated in response to various stresses/diseases, such as tissue injury, some cancers [pancreatic, prostate, and lung], obesity, heart failure infection, and mitochondrial diseases [251; 252; 253; 254; 255; 256]. The expression of GDF15 mRNA in healthy mice is the highest in the kidney, followed by the liver, white and brown adipose tissues, and skeletal muscle [257; 258]. Individuals with obesity and obese mice have increased circulatory levels of GDF15 compared with healthy controls [259; 260; 261] (Figure 1). The infiltration of circulating immune cells into the liver [262; 263] activates downstream endoplasmic reticulum stress signaling proteins [including transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)] [258; 264; 265; 266], which may upregulate GDF15 expression in obesity. Increased tissue expression and circulation of GDF15 in obesity may be a compensatory mechanism in resisting obesity since treatment with recombinant GDF15 resulted in weight loss in mice that were fed a high-fat diet [267; 268; 269; 252]. The inhibition of appetite and energy intake induced by exercise is also associated with increases in GDF15 in healthy individuals, individuals with obesity, and athletic individuals in duration- and intensity-dependent manners [270] (Figure 3). Aerobic exercise at 67% VO2 max for 1 h in healthy individuals increased circulatory GDF15 levels [271], with similar findings also being reported following exercise with longer durations [272]. In this case, professional rugby players demonstrated elevated circulating GDF15 levels following a 12-week high-intensity training program [273], with comparable observations reported in healthy, lean individuals [274; 275].