# Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach
## 4 Exercise, BDNF and Appetite
Elevated intracellular Ca\({}^{2+}\) activates transcription factors (CaRF), including CaRF 1 and CaRF3, PKC, CaMK, and MAPK, which in turn activate/phosphorylate the transcription factors of CREB, NF-\(\kappa\)B, and AP-1 to increase central and peripheral BDNF mRNA and protein levels [352, 353, 354, 355, 356, 357] (Figure 4). Increased synaptic activation by exerciseinduced shear stress is accompanied with increased blood flow in sensory-motor regions involved in cognitive capacity [358; 359; 360]. Central and peripheral endothelial cells are the most active in BDNF synthesis, secretion, and its regulation [361; 362]. Increased vascular shear stress stimulates the production, influx, and activation of tissue plasminogen activator (tPA) from endothelial cells. Circulating tissue plasminogen activator (tPA), derived from skeletal muscle endothelial cells, crosses the blood-brain barrier (BBB) via low-density lipoprotein receptor-related protein (LRP)-mediated transport. Central endothelial cell-derived tPA enhances brain-derived neurotrophic factor (BDNF) expression through two distinct mechanisms: (1) direct cleavage of pro-BDNF to mature BDNF, and (2) facilitation of neuronal NMDA receptor activation, which stimulates Ca\({}^{2+}\) influx and subsequent BDNF upregulation [363; 364; 365]. Shear stress activates endothelial nitric oxide synthase (eNOS) and the production of endothelial NO, leading to increased BDNF expression [358] (Figure 4). As with skeletal  
Figure 4: Pathways activated by exercise to increase BDNF levels in various tissues. Abbreviations: \(\alpha\)-MSH, alpha-melanocyte stimulating hormone; Ach, acetylcholine; AMPA, \(\alpha\)-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid; AMPK, adenosine monophosphate-activated protein kinase; AP-1, activating protein-1; BDNF, brain-derived neurotrophic factor; BHB, beta-hydroxybutyrate; cAMP, cyclic adenosine monophosphate; CaMKII, calcium/callmodulin-dependent kinase; CaRFs, calcium response factors; CREB, cyclic AMP response element binding; CAT-B, cathepsin B; eNOS, endothelial nitric oxide synthase; FGF21, fibroblast growth factor 21; FNDC5, fibronectin domain-containing protein 5; GLP-1, glucagon-like peptide 1; H2O2, hydrogen peroxide; HDAC, histone deacetylase; HIF-1\(\alpha\), hypoxia-inducible factor 1-alpha; IP3, inositol 1,4,5-trisphosphate; KAT, kynure-nine aminotransferase; NF-kB, nuclear factor-kappa B; NMDA, N-methyl-D-aspartate receptor; NO, nitric oxide; Nrf2, nuclear factor erythroid 2-related factor 2; OC, osteoclast; PGC-1\(\alpha\), peroxisome proliferatorator-activated receptor-\(\gamma\) coactivator; PKC, protein kinase C; ROS, reactive oxygen species; SIRT1, sirtuin 1; tPA, tissue plasminogen activator. muscles during exercise, the activation of excitatory synapses and neuronal action potentials to restore transmembrane ionic gradients requires ATP, leading to energetic stress in the brain [352; 367; 368]. Energetic stress increases ROS production by neurons and leads to the expression of transcription regulating factors such as cAMP response element-binding protein (CREB), nuclear factor-kappa B (NF-kB), nuclear factor erythroid 2-related factor 2 (Nrf2), hypoxia-inducible factor 1\(\alpha\) (HIF-1\(\alpha\)), and peroxisome proliferator-activated receptor-\(\gamma\) coactivator (PGC-1\(\alpha\)), leading to increased BDNF expression [369; 370; 371] (Figure 4). Additionally, increased energy demand elevates the AMP/ATP ratio and activates the AMPK pathway, causing increases in nicotinamide adenine dinucleotide (NADH+) to activate sirutin 1 (SIRT1) factor and the transcription factor of methyl CpG binding protein 2 (MeCP2), which increase BDNF expression by activating CREB [372]. Activated SIRT1 in the brain can also downregulate miRNA-134 levels, which inhibits CREB translation and increases BDNF expression [373] (Figure 4). Skeletal muscle releases myokines in response to exercise to change the expression of local genes or genes in other organs [199].