In-depth analysis of leptin regulation mechanism and leptin resistance phenomenon

The mechanism by which leptin regulates energy balance: Leptin is a signaling molecule that transmits information about the body's fat storage levels to the brain. It regulates the body's energy balance and fat storage levels through NPY, Mc-4R receptors, and MSH. After leptin binds to its receptors, it decreases NPY synthesis and release, increases POW expression, reduces Mc-4R activation, decreases agouti-related peptide, and decreases orexin, thus inhibiting food intake. The reduction in NPY relieves the inhibition of the sympathetic nervous system, allowing it to activate, increasing sympathetic activity, and leading to increased energy expenditure.

Leptin suppresses appetite and reduces energy intake. After being secreted from adipocytes into the bloodstream, leptin binds to Lep-Re in the blood and is transported to the choroid. There, it binds to Lep-Ra and is transported into the cerebrospinal fluid. Leptin then binds to Lep-Rb in the hypothalamus, acting on the ventromedial nucleus (VMH), paraventricular nucleus (PVN), and arcuate nucleus (ARC) of the hypothalamus. This reduces the synthesis of NPY in the hypothalamus and simultaneously stimulates Mc-4R receptors and their ligand MSH, thereby suppressing appetite and reducing calorie intake. Hypothalamic neuropeptides play a mediating role in the action of leptin.

Among them, neuropeptide Y (NPY) is the most noteworthy. This neurotransmitter is widely distributed in the brain and is secreted and produced by neurons in the arcuate nucleus of the hypothalamus. It promotes food intake, inhibits energy expenditure, and promotes insulin secretion, thus contributing to the accumulation of body fat. NPY's regulation of energy balance originates in the arcuate nucleus and acts on the paraventricular nucleus via axons; the paraventricular nucleus is the main site for regulating energy balance. Leptin's appetite-suppressing effect is achieved through melanocortin receptor-4 (MCR4), and MCR4 dysfunction is accompanied by hyperappetite, inducing obesity.

Leptin increases energy expenditure, inhibits fat synthesis, and promotes fat breakdown. Receptors are distributed in the sympathetic nerve centers of the hypothalamus, such as the PVN, LHA, and VMH. Binding to these receptors increases the activity of the sympathetic nervous system, leading to increased release of peripheral norepinephrine and luteinizing hormone-releasing hormone secretion. This stimulates receptors on adipocyte membranes, increasing the expression of uncoupling proteins, promoting fat breakdown, increasing energy expenditure, and inhibiting fat synthesis. Simultaneously, the sustained action of norepinephrine directly expresses the UCP1 gene, further leading to the proliferation of BAT cells.

Leptin can also directly inhibit lipid synthesis in adipose tissue and promote its degradation by inhibiting the expression of acetylcholine (COA) carboxylase gene and regulating the expression of lipoxygenase mRNA. Leptin resistance: Leptin deficiency accounts for only 5% of obesity cases. In the vast majority of obese individuals, leptin mRNA levels and blood leptin concentrations not only do not decrease but are also significantly higher than in normal individuals. One of leptin's physiological functions, the "weight loss" effect, does not occur; this is what is commonly referred to as leptin resistance. The reasons for leptin resistance are still unclear, but several possibilities exist.

Leptin receptor abnormalities. Long-term high leptin levels lead to a decrease in the number of receptors or impaired function. Studies have shown that obese individuals have decreased numbers of OBRLs and OBRs, and downregulated mRNA expression. Imbalance in the ratio of free to bound leptin in the blood. Studies have shown that the ratio of free to bound leptin in the blood differs between obese and lean individuals. Generally speaking, hormones in their protein-bound form exhibit lower biological activity, while a higher proportion of free hormones has a greater impact on the organism. 10%–40% of leptin in the blood binds to a high-affinity macromolecule, rendering it inactive.

The OBRe receptor, lacking a membrane-permeable region, may be equivalent to this binding protein. This indicates a barrier in the transmission mechanism of leptin to the central nervous system. Studies have found that serum (plasmal) leptin concentrations in obese individuals are three times higher than in normal individuals, while their cerebrospinal fluid leptin levels are only 30% higher. Therefore, the ratio of serum to cerebrospinal fluid concentrations in obese individuals is lower than in normal individuals, suggesting a saturation phenomenon in the human choroid plexus for leptin transport. This slows the rate at which leptin enters the brain, resulting in impaired leptin transport to the cerebrospinal fluid and contributing to obesity.

Defects in the leptin signaling pathway. For example, defects in the gene encoding proopiomelanocortin (POMC) and α-MSH receptor defects can indirectly cause leptin resistance. A result of long-term evolution. Flier, using the thrifty genotype theory, suggests that leptin resistance may be a result of long-term evolution. Pathological changes in obesity. Normal adipose tissue is mainly composed of adipocytes, a few fibroblasts, and a small amount of intercellular collagen. The fat contained in adipose tissue is all located within adipocytes, and under the influence of neural and humoral factors, the synthesis and catabolism of neutral fats are extremely active.

Adipose tissue typically contains about 80% fat, 18% water, and 2% protein. Deep adipose tissue contains slightly more water than subcutaneous adipose tissue. Obese individuals have a higher water content in their adipose tissue than lean individuals. As obese individuals lose weight, their adipose tissue decreases, and its water content also decreases. The size of fat cells in subcutaneous adipose tissue varies in different areas during obesity. In normal individuals, subcutaneous fat cells average 67–98 micrometers in length, with each cell containing approximately 0.60 micrograms of fat. In obese individuals, fat cells are significantly enlarged, reaching lengths of 127–134 micrometers, an increase of 50%–100%.