# Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach
## 3 Exercise and Appetite-Reducing Metabolites, Myokines, and Hepatokines  
Several metabolites have been identified in response to endurance, resistance, and combined exercise by using metabolomics analysis [177; 178]. Lactate is a small molecule with roles ranging from being a signaling molecule to being an alternative fuel source [179]. In addition, lactate also suppresses appetite after exercise [63; 180; 181]. Muscles release more lactate after high-intensity exercises (near maximal, maximal, or supramaximal), which leads to greater reductions in appetite and energy intake [182; 181] (Figure 3). Lactate is released into the circulation and exerts its anorexigenic function through several mechanisms:  
Figure 3: Pathways influenced by exercise (shown in blue) to mitigate appetite in anorexia centers. Abbreviations: ACC, acetyl-CoA carboxylase; AgRP, agouti-related protein; Akt, protein kinase B; AMPK, adenosine monophosphate-activated protein kinase; ERK, extracellular signal-regulated kinase; ERS, endoplasmic reticulum stress; GDF15, growth differentiation factor 15; GRAL, glial cell-derived neurotrophic factor (GDNF) family receptor alpha-like; GLP-1, glucagon-like peptide 1; IRE1\(\alpha\), inositol-requiring transmembrane kinase/endoribonuclease 1\(\alpha\); Lac-Phe, N-lactoyl-phenylalanine; NPY, neuropeptide Y; PERK, PRKR-like endoplasmic reticulum kinase; PI3K, phosphatidylinositol 3-kinase; PLCy, phospholipase C gamma; POMC, pro-opiomelanocortin; PYY, peptide YY; ROS, reactive oxygen species; SNS, sympathetic nervous system. (a) It hinders ghrelin production from gastric cells. Lactate binds to GPCR81, which is highly expressed on ghrelin-releasing gastric cells [183] to inhibit ghrelin release from gastric mucosal cells [37; 181; 183; 184]. Additionally, lactate inhibits the activation of GOAT, which alters ghrelin activation [183]. (b) It modulates hypothalamic neuropeptide release. Lactate produced by exercising muscle is secreted into the circulation through monocarboxylate transporters (MCTs), which allow for bidirectional exchange between tissues/cells and is extensively expressed on hypothalamic oreeigenic and anorexia neurons, enabling lactate to activate energy intake-regulating signaling pathways such as STAT3, protein kinase B (Akt) [185; 186; 187], and inactivating AMPK [188]. AMPK is a leading factor in regulating energy intake [189], and its inhibition activates acetyl-CoA carboxylase (ACC) to increase hypothalamic malonyl-CoA concentrations, resulting in decreased and increased NPY/AgRP and POMC neuropeptides, respectively [188; 189; 190]. (c) It suppresses hypothalamic ghrelin signaling. Ghrelin upregulates the expression of NPY/AgRP neuropeptide (accompanied with increased appetite) by acting on growth hormone secretagogue receptors (GHRSs), which are expressed in hypothalamic nuclei related to appetite [191; 192], and antagonizing GHRSs dampens appetite. Lactate administration (0.3 mg/mL) to HEK-293a cells exhibiting an overexpression of GHRSs reduced GHRS signaling [193] and may underlie the effects of lactate in mitigating ghrelin signaling and NPY/AgRP expression to inhibit appetite [190; 193]. Lactate is a precursor in the synthesis of N-lactoyl-phenylalanine (Lac-Phe), a metabolite with anorexia effects in rodents [34]. Lac-Phe is an enzymatically conjugated product of lactate and phenylalanine amino acid that is catalyzed by carnosine dipeptidase II (CNDP2), which is expressed by macrophages, other immune cells, and in epithelial cells the of kidney, gut, and lung [194]. Exercise, especially at high intensity, increases circulatory levels of Lac-Phe in humans and predicts the loss of adipose tissue in individuals with overweight/obesity [34; 194; 195] (Figure 3). Acute administration of Lac-Phe in obese mice suppresses energy intake over 12 h by 50% [34]. The plasma levels of Lac-Phe increase after endurance, resistance, and sprint exercises in humans, racehorses, and mice, with increases in sprint and resistance exercises being greater than those after endurance exercise [34].