# Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach
## 4 Exercise, BDNF and Appetite  
Several other genes can also regulate obesity and food intake [320]. Satiety and increased energy expenditure are the two leading regulators of total energy balance that are mediated by BDNF, a member of the neurotrophin family [321] that is expressed in peripheral neurons and the CNS where it regulates synaptic activity, neurotransmission, and plasticity in mature neurons [322]. This trophic factor interacts with p75 neurotrophin receptor (p75 NTR) and tyrosine kinase B receptor (TrkB); pro-BDNF preferentially binds to P75 NTR and initiates apoptosis, while mature BDNF (mBDNF) binds to TrkB to trigger neural development and differentiation, cell survival, and synaptic plasticity. Binding BDNF to TrkB activates mitogen-activated protein kinase (MAPK), PLCy, and phosphoinositide 3-kinase (PI3K) activity [323]. The expression of BDNF mRNA and protein is abundant in the CNS compared with other tissues during development [324], and both its mRNA and protein levels are extensively distributed in the hippocampus, amygdala, cerebellum, brain cortex, and hypothalamus in the adult brain [323]. The expression of BDNF and TrkB is often constrained to neurons [325], although they are also expressed in other non-neurogenic tissues, such as skeletal muscle [326], airway smooth muscle [327], and ovarian tissue [328]. Peripheral tissue-produced BDNF does not enter the circulation, while its central production can cross the BBB and is stored in peripheral tissue such as platelets [329]. The levels of BDNF mRNA in the brain, particularly in the hypothalamus, are highly dependent on nutritional status or energy availability. Thus, fasting and food restriction mitigate BDNF mRNA levels in various parts of the hypothalamus [330, 331, 332] and are elevated after refeeding [333]. These studies suggest an important role for BDNF in controlling body weight and energy homeostasis that is beyond neurological plasticity. There is a bidirectional negative correlation between BDNF and obesity, where low circulatory levels of BDNF are associated with severe obesity, hyperplasia [334], and adiposity [335] (Figure 1). Several endogenous and exogenous factors, such as stress, exercise, brain damage, and diet, regulate BDNF gene expression [336]. Obesity increases circulatory cortisol (in humans) or corticosterone (in rodents) [337, 338], pro-inflammatory cytokines [339, 340], and oxidative stress [341] to reduce peripheral and central BDNF mRNA and protein levels. The effects of physical activity on increasing circulatory BDNF levels are dependent on exercise duration and its intensity; thus, acute and chronic high-intensity exercises (>85% maximum heart rate or >80% VO2 max) increased BDNF levels in males with obesity [342, 343, 344, 345], with similar findings being observed in women with obesity after moderate-intensity resistance training (55-65% 1 RM) [346]. In addition, high- and moderate-intensity aerobic training in healthy individuals [297] and those with obesity [298] for 12 weeks raised the resting serum levels of BDNF. Exercise in an animal model upregulates the expression levels of hippocampal BDNF and its TrkB receptor [347, 348]. Exercise not only changes the expression of BDNF and its receptor in the hippocampus, but it also does so in the hypothalamus; it was observed that 4 weeks of running promoted BDNF expression in the hypothalamic ARC [349, 350, 351]. Exercise increases BDNF levels by several mechanisms, including elevated neuronal activity, improved cerebral blood flow and energetic stress, and the release of humoral molecules such as adipokines, myokines, and hepatokines. Exercise stimulates the release glutamate, which then interacts with its postsynaptic receptors (AMPA and NMDA) to facilitate the influx of Na\({}^{+}\) and Ca\({}^{2+}\) via ligand and voltage-gated Ca\({}^{2+}\) channels into neural cells.