# Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach
## 4 Exercise, BDNF and Appetite
Other studies report that the intracerebral injection of BDNF in rats increased the hypothalamic 5-Hydroxylindoleacetic acid/5-hydroxriptamine (5-HIAA/5-HT) ratio and increased 5-HT turnover to hinder feeding and suppress appetite [426; 434; 450; 451] (Figure 5). BDNF modulates the expression of hypothalamic orexigenic and anorexia genes, such as thyrotropin-releasing hormone (TRH), TrkB, POMC, LEPR, corticotropin-releasing hormone (CRH), and urocortin (UCN) [440; 441; 452; 453]. Hypothalamic TrkB is localized to CRH and increases BDNF in the hypothalamus, either by external administration or by exercise, and upregulates CRH and UCN mRNA [351; 433; 454]. CRH is a stress response hormone, and UCN is a member of the CRH peptide family, and after binding to their receptors (CRH-R1 and CRH-R2), they activate the adenylate cyclase-PKA, PLC-PKC, and ERK-MAPK pathways to suppress food intake and appetite (Figure 5) and increase energy expenditure by augmenting SNS function [455; 456; 457; 458; 459]. The inhibition of both CRH-R1 and CHR-R2 in the hypothalamus with anti-SG30 reduces the anorexia and anti-obese effects of BDNF [433]. Increased CRH mRNA in PVN neurons, which is extruded into the locus coeruleus and rostral medial medulla, where sympathetic neurons are activated, is associated with increases in epinephrine and norepinephrine as well as increased oxygen consumption [460; 461; 462]. These catecholamines then activate \(\beta\)-adrenergic receptors in adipose tissue to increase thermogenesis by upregulating UCP-1, leading to a reduction in body weight [463; 464]. There is a close interaction of CRH neurons and NPY neurons in the hypothalamus that results in a neuroanatomical circuit that downregulates NPY [465] (Figure 5). In addition to generating anorexia signals, BDNF also inhibits orexigenic pathways [423]. The paraventricular nucleus (PVN) sends efferent projections to neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC). These ARC neurons subsequently release appetite-modulating peptides [466]. Increased expression of BDNF in hypothalamic areas can interfere with NPYergic pathways to downregulate and normalize hypothalamic NPY expression, followed by suppressing NPY-mediated feeding or its orexigenic pathways [423; 467] (Figure 5). The NPY that is secreted inhibits TRH neurons in the hypothalamus [468]. In contrast, BDNF upregulates hypothalamic TRH expression after binding to TrkB receptors on TRH neurons to exert part of its actions to reduce appetite and food intake [441; 453; 469]. TRH neurons in the hypothalamus, especially in the PVN, project Raph pallidus (RP\(\alpha\)) neurons in the hindbrain, after which preganglionic sympathetic neurons in the spinal cord activate thermogenesis in skeletal muscle and adipose tissues [468; 470; 416]. Increases in thermogenesis due to sympathetic activation increase energy expenditure in part due to the upregulation of UCP-1, leading to increased energy expenditure [416; 435; 471]. Additionally, TRH neurons also increase the thermogenic effects of norepinephrine in both skeletal muscle and adipose tissue by releasing thyroid-stimulating hormone (TSH) from the pituitary gland [472; 473]. BDNF suppresses appetite by promoting the function of alpha2/delta 1 (\(\alpha\)28-1) (Figure 5), a hypothalamic protein involved in feeding behaviors and the function of BDNF in appetite-regulating pathways. The inhibition of this protein in normal mice increased food intake and weight gain, while reducing BDNF levels diminished hypothalamic function [442]. Increases in \(\alpha\)28-1 protein increase the appetite-hindering function of BDNF by several mechanisms, including increasing synaptic connectivity in hypothalamus via interactions with TSPs, increasing the density and force of excitatory synapses of anorexia neurons by excitatory synaptogenesis, facilitating the trafficking of voltage-gated calcium channels on cells associated with neurotransmitter release, and boosting synaptogenesis in a Ca2+-independent manner [474; 475; 476] (Figure 5).