# Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach
## 4 Exercise, BDNF and Appetite
Exercise upregulates leptin expression in the brain and other tissues [410,411] to produce the melanocortin precursor of \(\alpha\)-melanocyte-stimulating hormone (\(\alpha\)-MSH) by binding to LEPR. Increases in \(\alpha\)-MSH leads to the upregulation of melanocortin 4 receptors (MC4R) that promote cerebral BDNF expression [412,413] (Figure 4). BDNF is a leading component of the hypothalamic pathway controlling body weight and energy homeostasis in addition to its role in metabolism through increasing fat oxidation in muscle [326,414,415,416]. BDNF and its receptors are mostly expressed in various hypothalamic nuclei and other brain areas related to monitoring energy balance, including the ventromedial nucleus of the hypothalamus (VMH), paraventricular hypothalamic nucleus (PVH), nucleus accumbens, nucleus tractus solitarius (NTS), ventral tegmental area (VTA), and ARC [enriched in TrkB without the expression of BDNF] [330,417,418,419,420,421,422,423]. Although the ARC does not synthesize BDNF synthesis, TrkB receptors and nervous fibers containing BDNF in this area suggest a role in influencing food intake [420]. These interactive central hubs integrate acute satiety, hunger signs, and chronic obese signals from periphery in response to food intake [424]. Preclinical document using chronic intracerebral BDNF administration in rats established its anorexia effects through body weight modulation, confirming BDNF's appetite-regulatory function [425]. Later investigations bolstered the role of BDNF in energy balance in modified genetic animals in which BDNF has been deleted. In this context, it has been disclosed that BDNF+/ - mice with reduced hypothalamic BDNF expression exhibit hyperphagia and develop an obese phenotype, both of which are reversible upon BDNF infusion [426,427,418,428,429,430,431,432,433,434,435,436,437,438,439]. There are many studies in animals and humans indicating that the genetic deletion/mutation of BDNF or its receptor in brain areas related to appetite leads to obesity and hyperphagia [428,429,430,432,418,433,434,435,436,437,438,439]. Acute and chronic intracerebral injections of BDNF suppresses food intake and boosts metabolic rate, resulting in a loss of body weight [433,416,423,434,435,436,437,438,439]. Similar findings of reduced energy intake were also shown after the peripheral and subcutaneous injection of BDNF in animal models of obesity caused by high-fat diets [436,437,438,439,440,436,439]. Thus, central BDNF mitigates food intake (appetite suppression and hypophagia) through central mechanisms and increasing energy expenditure by elevating heat production, resting metabolism, and the respiratory exchange ratio (RER) to promote body weight loss and fat mass reduction in adiposity. BDNF regulates energy balance by either directly activating its receptors in hypothalamic neurons monitoring food intake or indirectly by intensifying or hindering other endocrine hormones contributing to appetite regulation [441,439,440,441]. Changes in synaptic connectivity and neural activation in hypothalamic circuits primarily contributes to appetite control and feeding behavior [442]. BDNF activates MAPK, PI3K, and PLC after interacting with its receptor in the hypothalamus. These activated signals regulate synaptic maintenance and plasticity, synaptogenesis, neurite growth, and neural survive, which are key in forming neural circuits throughout the brain, including those regulating energy homeostasis and appetite [355,443,444,445,446,447,448,449,450,451,452,453,454,455,456,457] (Figure 5). Thus, BDNF increasesthe expression level of thrombospondin (TSP) receptors to promote the function of excitatory synapses [442], followed by alterations in behaviors related to food intake [446] (Figure 5). Additionally, BDNF is required for the growth and transmission of serotonergic fibers to reduce appetite and obesity, as BDNF deletion reduces serotonin levels and increases adiposity [426; 448; 449; 450] (Figure 5).