# Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach
## 3 Exercise and Appetite-Reducing Metabolites, Myokines, and Hepatokines
Increases in fasting GDF15 levels in individuals with obesity following 12 weeks of aerobic training on a treadmill/cycle ergometer (5 days/week, 60 min/session, at a 85% maximal heart rate) reduced fat mass [276]. Another report comparing changes in GDF15 after acute and chronic exercise [6-month moderate and vigorous exercise training] in individuals with overweight/obesity reported increases in circulatory GDF15 without other changes after exercise training [277]. In accordance with these findings related to increased GDF15 in adiposity, a study by [PERSON] and colleagues measured increases in muscle expression and serum GDF15 levels immediately and 3 h after acute exercise (1 h at 70% VO2 max) [278]. However, GDF15 levels are higher in sedentary individuals compared with active individuals [275]. Studies reporting that exercise lowers GDF15 levels in individuals with obesity [279] may also be related to lower body weights \(\backslash\) as there is an inverse relationship between resting plasma GDF15 levels and fitness [275; 280], suggesting that exercise training can counteract increases in GDF15 levels. While some tissues, such as the skeletal muscle, heart, kidney, adipose tissue, prostate, and brain, increase GDF15 levels in response to exercise [257; 258; 274; 281; 282; 283; 284; 285], the liver is the main source of its circulatory pool as the liver is energetically stressed during exercise [286; 287]. Although the regulatory factors of GDF15 synthesis and release during exercise are not well understood, some mechanisms have been proposed. Exercise increases physiological and metabolic stress, particularly in the liver [288; 289], to initiate ERS, which in turn activates the UPR and IRS pathways (IRE1\(\alpha\) and PERK) in order to increase GDF15 transcription [281; 290]. Exercise increases hepatic glucose production [291] and energetic stress [292; 293; 294], which in turn actuate hepatic AMPK activity to promote GDF15 levels [295]. Increased and decreased levels of circulating glucagon and insulin, respectively, after exercise directly promote Gdf15 gene transcription in the liver [290] (Figure 3). Increases in GDF15 leads to weight loss by impacting appetite, food intake, and lipid metabolism [296; 297; 298], likely by actions on the CNS [299] and by binding to a high-affinity GDNF family receptor \(\alpha\)-like (GFRAL) receptor, which is extensively expressed on cholecystn neurons located in the ARC, parabrachial nucleus (PBN), PVN, and area postrema (AP) in the hypothalamus [253; 268; 299; 300; 301; 302] to regulate appetite and food intake. The binding of GDF15 to GFRAL leads to the formation of a complex with the co-receptor of proto-oncogene tyrosine-protein kinase Ret (RET), which then phosphorylates and activates the extracellular signal-regulated kinase (ERK), Akt, and phospholipase C-gamma (PLC\(\gamma\)) pathways in the CNS [268; 300; 301; 302] to suppress appetite (Figure 3). Changes in food preferences, taste aversion, and slowing of gastric emptying are other mechanisms by which GDF15 reduces food/energy intake and body weight [251; 258; 303]. The effects of GDF15 treatment on body weight in mice fed a high-fat diet are related to changes in food/taste preferences, especially with a reduced consumption of high-caloric/high-fat diets [269; 304]. Loss of GDF15 activity in mice led to increases in body weight, while the pharmacological administration of GDF15 caused a taste aversion response [258]. GDF15-inducible taste aversion behaviors partly reduce appetite and food intake [258; 303; 305] and may be mediated by serotonin [306]. Additionally, treatment with GDF15 delays gastric emptying [269] that is mediated by afferent and efferent vagal signals that modulate postprandial gastric emptying [307]. Upon interaction with central GFRAL receptors, GDF15 reduces the activation of vagal nerves to slow gastric emptying [251; 269; 300; 308] (Figure 3).