Regulation of appetite and fat metabolism by the neuroendocrine system

The melanin-4 receptor (Mc-4R) and its ligand melanocyte-stimulating hormone (MSH). Mc-4R is mainly expressed in the hypothalamus. It is a G protein-binding receptor that plays an important role in thermoregulation. There are two types of nerve fibers at the Mc-4R site: one is the pro-opioid pro-fibrillary nerve fiber, which releases the Mc-4R agonist-melanocyte-stimulating hormone (aMSH), and the other is the NPY nerve fiber, which releases the Mc-4R antagonist AgRP. The ratio of aMSH to AgRP determines the state of Mc-4R and causes the corresponding biological effects.

Using Mc-4R receptor agonists reduces food intake, while using Mc-4R receptor antagonists increases it; knockout of Mc-4R receptors leads to obesity. MSH agonists inhibit food intake, while their antagonists stimulate it. AgRP, in addition to its antagonistic effect on Mc-4R, can increase leptin mRNA expression; this effect is unrelated to Mc-4R and may be related to increased food intake. Intraventricular administration of AgRP (10–100 pmol) to the paraventricular nucleus of the hypothalamus induces feeding in satiety- or fasted mice and has a synergistic effect with neuropeptide Y. Starvation promotes AgRP expression, while a high-fat diet inhibits it.

Orexin. First discovered in 1998 by Yanagisawa's research group, orrexin is a neuropeptide with the opposite effect of leptin. It can increase appetite, but its effect is weaker than that of neuropeptide Y. Orexin exists in two subtypes: orrexin A and orrexin B. Peroxidase proliferator-initiated receptor γ (PPARY). PPARY is one of the nuclear receptors that translates nutrient signals into gene expression. It can be activated by fatty acids and regulates the synthesis of various genes involved in intracellular and extracellular lipid metabolism, making it one of the important gene regulatory mechanisms of lipid metabolism in the body.

Tumor necrosis factor-α (TNFα). TNFα can be produced by various cells in the body and plays an important role in immune responses. Recent findings have also revealed that TNFα participates in the regulation of lipid metabolism. TNFα is synthesized by adipocytes and secreted into the bloodstream. It rapidly acts on the hypothalamus via periventricular nerve cells and axons, transmitting information about the body's fat storage, thereby regulating the hypothalamus's functions in controlling appetite and thermogenesis, and maintaining the body's energy metabolic balance. The regulatory mechanism of eating and metabolism: Serum leptin is a signal receptor that transmits energy storage status from adipose tissue to the brain. It acts on receptors in the brain, providing feedback regulation of the body's eating activities and energy consumption behavior.

Eating and increased body fat can promote increased leptin secretion from adipose tissue. Once leptin is secreted into the bloodstream by adipocytes, it binds to Lep-Re in the blood and is transported to the choroid. There, leptin binds to Lep-Ra and is transported into the cerebrospinal fluid. It then binds to Lep-Rb in the hypothalamus, acting on the ventromedial nucleus (VMH), paraventricular nucleus (PVN), and arcuate nucleus (ARC) of the hypothalamus. After leptin binds to its receptors in the hypothalamus, it alters the expression of specific neuropeptides produced by other genes in hypothalamic neurons. These neuropeptides include: neuropeptide Y (NPY), agouti-related peptide, pro-opioid melanocyte-stimulating hormone (POMC), α-melanocyte-stimulating hormone (α-MSH), melanocyte-stimulating hormone-4 receptor, adrenocorticotropic hormone (CRH), melanocyte-concentrating hormone, and orexin.

After leptin binds to its receptor, it decreases the synthesis and release of NPY, increases POW expression, increases α-MSH, reduces the activation of Mc-4R and agouti-related peptide, decreases orexin, and inhibits food intake. The decrease in NPY relieves the inhibition of the sympathetic nervous system, allowing it to activate, increasing activity, increasing energy expenditure, and reducing fat storage. When any link in the above pathway is disrupted, weight gain, or even obesity, can occur. Environmental factors. The causes of obesity are very complex; in addition to genetic factors, environmental factors are also an important cause of obesity.

Studies have reported that genetic factors account for 30% of obesity development, while environmental factors account for 70%. Since environmental factors also play a crucial role in obesity, although it's not yet possible to prevent or treat obesity by altering genetic factors, it's possible to mobilize the positive effects of environmental factors within the context of genetic predisposition, delaying or weakening the effects of genes, thereby achieving the goal of preventing and treating obesity. In this sense, obesity is largely preventable and treatable. Diet and Obesity: Obese individuals often have a history of increased food intake, larger food portions, a preference for sweets, or snacking between meals, leading to excess energy consumption.

Under the same energy expenditure conditions, a habit of eating before bed and eating more at dinner can lead to obesity. Insufficient physical activity or bed rest due to fractures, tuberculosis, hepatitis, or other reasons results in low energy expenditure and can cause obesity. Especially after middle age, as physical activity levels gradually decrease, fat often accumulates in the abdomen and buttocks. Most people develop obesity after ceasing regular exercise. One of the direct causes of obesity is long-term excessive energy intake, leading to overnutrition. Overnutrition is a major factor contributing to obesity, especially childhood obesity.