The energy substances (mainly carbohydrates and fats) are the basis and guarantee of life activity, especially the oxidative phosphorylation for energy supply. However, excessive absorption and accumulation of these substances can lead to metabolic diseases such as obesity, hyperlipidemia, diabetes, and cancers. A large amount of studies demonstrate that G protein-coupled receptors (GPCRs) play a key role in identification and absorption of energy substances, and the signaling network of nerves, immune, and endocrine regulates their storage and utilization. The gastrointestinal mucus layer not only identifies these substances through identification in diet components but also transfers immune, metabolic, and endocrine signals of hormones, cytokines, and chemokines by promoting interactions between receptors and ligands. These signaling molecules are transferred to corresponding organs, tissues, and cells by the circulatory system, and cell activity is regulated by amplifying of cell signals that constitute the wireless communication network among cells in the body. Absorption, accumulation, and utilization of energy substances in the body obey the law of energy conservation. Energy is stored in the form of fat, and meets the demand of body via two coupled mechanisms: catabolism and oxidative phosphorylation.