# Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach
## 2 Exercise and Appetite-Regulatory Hormones
While exercise often leads to a reduction in circulatory leptin levels due to a decreased body fat content, it can enhance leptin sensitivity in the brain, particularly in the hypothalamus [97; 98] (Figure 2). Improved hypothalamus sensitivity to leptin that occurs by reducing inflammation, enhancing insulin sensitivity, and promoting neurogenesis and synaptic plasticity boosts its ability to regulate appetite and energy balance [97; 99; 100]. Upon binding to receptors, primarily the long isoform receptor (ObRb) located in the hypothalamus, leptin activates several signaling pathways, with the most notable being the JAK2/STAT3 pathway, which leads to the transcription of genes that promote satiety and reduce food intake [101]. Among the genes induced by this pathway are POMC, suppressor of cytokine signaling 3 (SOCS3), and brain-derived neurotrophic factor (BDNF) [85; 102]. Additionally, leptin inhibits excitatory neurons (AgRP/NPY neurons) in the hypothalamic ARC that stimulate appetite and activates inhibitory neurons (POMC neurons) that suppress appetite [103]. Leptin also affects the brain's reward system by suppressing the activity of dopamine neurons in the hypothalamus, which reduces the reward value of food, to further decrease food intake [104] (Figure 2). There is an inverse relationship between fat mass and adiponectin levels, so as fat mass increases, adiponectin levels decrease (Figure 1). Adiponectin is primarily produced and secreted by adipose tissue, and its secretion is regulated by the size and number of adipocytes. Adipose tissue in individuals with obesity is characterized by adipocyte hypertrophy, inflammation, and insulin resistance, which reduces adiponectin production and secretion [105]. In contrast, weight loss increases adiponectin levels in individuals with obesity by reducing adipose tissue mass, improving adipose tissue function, and reducing inflammation, culminating in increases in adiponectin production and secretion [106]. Exercise training increases circulatory adiponectin levels through several molecular mechanisms [70; 107]. Adiponectin is primarily produced and secreted by adipose tissue but can also be produced by skeletal muscle and other tissues [108]. Exercise stimulates the production and secretion of adiponectin from both adipose tissue and skeletal muscle, leading to increased circulatory adiponectin levels (Figure 2). Exercise stimulates the AMP-activated protein kinase (AMPK) pathway in skeletal muscle [109], which in turn enhances glucose uptake and fatty acid oxidation in skeletal muscle, leading to improved insulin sensitivity and reduced fat accumulation in adipose tissue and increased adiponectin levels. Importantly, exercise stimulates the peroxisome proliferator-activated receptor gamma (PPAry) pathway in adipose tissue [110], which enhances insulin sensitivity and reduces inflammation in adipose tissue, resulting in increased adiponectin levels. Exercise induces the production and secretion of myokines (cytokines produced by skeletal muscle in response to exercise), such as IL-6, that stimulate adiponectin production and secretion from adipose tissue (Figure 2). The decreased production of pro-inflammatory cytokines and increased production of anti-inflammatory cytokines, such as IL-10, are additional mechanisms by which exercise increases adiponectin levels [111]. Adiponectin affects appetite via actions on brain centers regulating food intake. Adiponectin interacts with its receptors expressed on some neurons in several regions of the brain, including the hypothalamus [112; 113], to regulate and modulate the expression of neuropeptides such as AgRP and POMC [113; 114]. Adiponectin increases POMC expression and decreases AgRP expression by activating the AMPK pathway in hypothalamic neurons, leading to a decrease in food intake and an increase in energy expenditure [115]. In addition, adiponectin also inhibits the activity of orexin neurons in the hypothalamus, which are involved in the regulation of food intake and arousal [116; 117] (Figure 2).