The Command Center of Energy Balance: The Hypothalamic Feeding Center and the Regulatory Mechanism of the Brain-Gut Axis

3. Feeding Center and Endocrine Factors: Body weight is regulated by both the nervous and endocrine systems, ultimately influencing effector organs that regulate energy intake and expenditure. Feeding behavior is controlled by a single neural structure-the feeding center. Located in the hypothalamus, the lateral hypothalamus (LHA) is associated with hunger and feeding in animals and is called the "hunger center"; the ventromedial hypothalamus (VMH) is associated with cessation of feeding after satiety and is called the "satiety center." Under normal circumstances, the satiety center inhibits the hunger center. If this inhibition is distorted, the hunger center's function is significantly enhanced, leading to intense hunger, increased appetite, overeating, and ultimately obesity. The VMH and LHA functionally interact to control hunger and appetite, influence the rate of energy expenditure, and regulate the secretion of hormones related to energy storage, playing a crucial role in homeostasis and body weight regulation. The active substances in the body involved in regulating feeding behavior include: ① Factors that reduce feeding: β-adrenergic receptors, dopamine, serotonin, glucagon-like peptide-1 (GLP-1), and leptin, etc. ② Factors that increase feeding: α-noradrenergic receptors, neuropeptide Y, ghrelin, orexin, galanin, etc. ③ Metabolic products such as blood glucose and fatty acids. The hypothalamus is a key site for regulating the body's energy balance. Neuropeptide Y (NPY) and spiky mouse-associated protein (AgRP) secreted by the arcuate nucleus (ARC) of the hypothalamus can increase appetite, while pro-opioidin (POMC) and cocaine-amphetamine-regulated transcription peptide (CART) can inhibit appetite. Signals affecting the hypothalamic appetite center include afferent nerve signals (mainly from the vagus nerve, transmitting information from the viscera), hormonal signals (such as leptin, insulin, and various intestinal peptides), and metabolic products (such as glucose). After integration, the above signals are transmitted to target organs via the neuro-humoral pathway, regulating gastric acid secretion, gastrointestinal emptying rate, and thermogenesis. Abnormalities in any link of neuro-endocrine regulation can lead to obesity. 4. Gut microbiota-related obesity: A crucial factor in the development of obesity is a prolonged state of low-grade inflammation. Gut microbiota dysbiosis leads to increased intestinal permeability, increased free fatty acids in the body, oxidative stress, and endotoxemia caused by elevated bacterial lipopolysaccharide (LPS), all of which can promote inflammatory responses. Gut microbiota can also influence the transmission of brain-gut axis signals, thereby affecting the absorptive and secretory capacity of intestinal epithelial cells and altering signals to the central nervous system, thus regulating the body's food intake and energy metabolism. Under physiological conditions, gut microbiota regulates various appetite-suppressing endocrine peptides in the gut, such as cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY). These hormones can act on the arcuate nucleus of the hypothalamus, producing a feeling of satiety and thus inhibiting food intake. If the secretion of these hormones is insufficient, they cannot stimulate the hypothalamus, failing to produce a feeling of satiety and timely inhibit food intake. Secondly, the brain-gut axis metabolic mechanism: Numerous studies have confirmed that gut microbiota influences brain structure and function through the production or alteration of neurotransmitters by metabolites, activation of immune signaling pathways, and effects on the vagus nerve and immune system. Therefore, gut microbiota forms a new bidirectional interactive communication pathway with the enteric nervous system (ENS) and the central nervous system (CNS): the gut microbiota-gut-brain axis.

What is the brain-gut axis? The gastrointestinal tract is controlled by the central nervous system, enteric nervous system, autonomic nervous system (ANS), and hypothalamic-pituitary-adrenal (HPA) axis. The brain integrates received afferent information and transmits regulatory information to the nerve plexuses in the gastrointestinal tract via the autonomic nervous system and neuroendocrine system, or directly acts on the smooth muscle cells of the gastrointestinal tract. This bidirectional neural pathway connecting the brain, CNS, ENS, and ANS is called the brain-gut axis. Professor Michael Gersson, a neuroscientist at Columbia University, first proposed the concept of the "gut-brain axis," which is the human body's "second brain" formed by the intestines, enteric nervous system, and gut microbiota. The "gut-brain axis" is a bidirectional response system that connects brain and intestinal functions through the central nervous system and various enteric nervous systems of the gastrointestinal tract. Gut microbiota and their metabolites can participate in the regulation of nervous system function through the above pathways, thereby affecting the pathogenesis of nervous system-related diseases. Similarly, the nervous system can also affect the composition and quantity of gut microbiota through the above pathways, which is crucial for host metabolic homeostasis. While most existing research describes the role of the gut microbiota in the gut-brain axis, recent evidence suggests that hormones and the nervous system are key regulatory components of the gut-brain axis. The endocrine system is a crucial regulator of nutritional patterns, and the influence of the ANS and HPA axes on food intake may affect gut microbiota composition. The gut microbiota can modulate neuronal function in the peripheral nervous system and the ENS. Hormones that control eating habits are potent immunomodulators of CNS inflammation and are also associated with the ANS and HPA axes. Furthermore, animal studies have shown that the gut microbiota influences the gut-brain axis through gut hormones and vagal nerve connections (affecting energy expenditure and regions of the CNS associated with eating behavior).

The enteric nervous system is composed of nerve components within the gastrointestinal wall and is an independent integrated system that regulates and controls gastrointestinal function. (1) Vagus nerve: The interaction between the gastrointestinal tract and the brain is mainly achieved through the vagus nerve and spinal nerves, as well as their ganglia and spinal cord and other anatomical structures. The vagus nerve can be further divided into mechanical vagus nerve and chemical vagus nerve, which respectively sense mechanical stimuli such as expansion and contraction in the gastrointestinal tract under inflammatory conditions and neuropeptide chemical signals secreted by enteroendocrine cells. Preclinical studies have shown that the vagus nerve is the main pathway from the intestinal lumen to the nucleus tractus solitarius in the medulla oblongata and is also an important pathway for neural communication between intestinal microorganisms and behaviors regulated by the central nervous system. Selective vagotomy can prevent the corresponding bodily stress effects caused by microorganisms.