# Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach
## 4 Exercise, BDNF and Appetite
High-intensity exercise increases the production of lactate that is released into the circulation and enters the brain via MCTs to activate GPRs and SIRT1, which then stimulate the expression and activation of proteins involved in mitochondrial biogenesis, including PGC-1\(\alpha\), ERR\(\alpha\), and FNDC5/irisin. Elevated PGC-1\(\alpha\) levels in both skeletal muscle and the brain increase FNDC5 expression, which then undergoes proteolytic cleavage to produce irisin. Peripheral irisin produced by muscle crosses the BBB to activate the cAMP/PKC//CREB pathway to upregulate central BDNF by binding to integrin \(\alpha\)v\(\beta\)5 receptors on cerebral endothelial cells [374; 375; 376; 377; 378] (Figure 4). Elevated levels of lactate following high-intensity exercise also activates CREB to increase BDNF levels by stimulating neuronal glutamatergic transmission and activating NMDA receptor signaling [379; 380]. Vigorous levels of exercise increase hydrogen peroxide (H\({}_{2}\)O\({}_{2}\)) and TNF-\(\alpha\) levels to activate PGC-1\(\alpha\) signaling that promotes central BDNF synthesis [381]. The central and peripheral activation of PGC-1\(\alpha\) stimulates kynure amineotransferase (KAT), which converts kynure to kynure acid to increase the plasma levels of kynure acid and the upregulation of central BDNF expression [382] (Figure 4). IL-6 is another myokine released into the circulation in response to exercise and influences osteocytes to liberate non-carboxylated osteoclast, which binds to the orphan type of the GPR receptor (Gpr158) in the brain to boost the production of IP3 in neurons and stimulate the production of BDNF in a Ca\({}^{2+}\)-dependent manner [383; 384; 385] (Figure 4). Exercising muscle also expresses cathepsin-B (CAT-B) mRNA and protein to increase cerebral BDNF levels [386] (Figure 4). Exercise-induced release of hepatokines, such as insulin-like growth factor 1 (IGF-1), \(\beta\)-hydroxybutyrate (BHB), fibroblast growth factor 21 (FGF21), and glycosylphosphatidylinositol specific phospholipase D1 (GPLD1), is another mechanism by which central BDNF levels are increased [349; 387; 388; 389; 390; 391]. For instance, circulatory BHB crosses the BBB and then binds to histone deacetylase 2/3 (HDAC2/3) to inhibit their inhibitory function on the BDNF gene promotor [349] (Figure 4). Additionally, exercise releases FGF21 from hepatocytes due to increases in the glucagon-to-insulin ratio and enters the brain to activate the AMPK pathway, leading to an increase in central BDNF levels [388; 391; 392; 393; 394] (Figure 4). Platelets are a rich source of circulatory BDNF that is secreted following exercise-induced thrombocytosis [395; 396] that ceases 15-30 min after exercise [396] (Figure 4). Exercise stimulates epithelial gut cells to produce and release GLP-1 into the circulation, which then enters the brain to bind to its neural receptors that are coupled with cAMP production to activate CREB and increase BDNF expression [122; 397] (Figure 4). Epigenetic modulations represent another mechanism through which exercise affects central and peripheral BDNF expression. Exercise influences the activation of enzymesresponsible for DNA methylation (DNMT), histone acetylation (HAT), or histone deacetylase (HDAC) on BDNF promotors to increase BDNF transcription [349,398] (Figure 4). In this context, HDAC inhibition is followed by the increased expression of muscle BDNF levels after exercise [399,400]. In addition, exercise removes the inhibition of trimethylated histone H3 at lysine 4 (H3K4 me3) on the BDNF promotor gene, leading to increased BDNF expression [401]. Elevated DNA demethylation on promotor areas of BDNF is another pathway by which exercise overshadows BDNF expression in favor of its expression [398] (Figure 4). High levels of glucose curb the output of BDNF by the brain [402,403]. Increases in neurotransmitter release during exercise, such as acetylcholine, norepinephrine, dopamine, and serotonin, promote BDNF expression [404,41,42,43,44,45,46,47,48,490] (Figure 4).