Leptin synthesis is influenced by various internal and external environmental factors, primarily including energy storage, nutritional status, insulin levels, glucocorticoids, sex hormones, and pro-inflammatory cytokines. These factors regulate the expression of the leptin gene (ob gene) via different signaling pathways, adjusting plasma leptin levels accordingly.
Leptin synthesis is closely linked to fat storage, with leptin mRNA expression and plasma leptin concentrations significantly higher in obese individuals than in lean individuals. Additionally, leptin levels rise shortly after feeding or in states of energy surplus and rapidly decline during starvation or fasting. This response indicates that leptin serves as a signaling factor for energy balance, conveying information on the body's energy status to the brain. Particularly during short-term fasting, leptin decreases more sharply than fat stores are actually reduced, suggesting that leptin acts as a sensitive indicator of energy state changes. Moreover, insulin peaks following food intake promote leptin synthesis. In vitro studies show that insulin directly stimulates leptin expression in cultured adipocytes, while insulin deficiency results in lowered leptin levels. Given leptin’s rapid fluctuation with feeding and fasting, this regulatory mechanism likely influences short-term energy balance via the insulin-leptin axis.
Chronic elevation of glucocorticoids (e.g., due to pharmacological treatment or high stress levels) is associated with increased leptin expression. However, the role of glucocorticoids at normal physiological levels in leptin regulation remains unclear, as acute cortisol elevations (e.g., triggered by CRH) typically do not affect leptin levels. This suggests that glucocorticoid effects on leptin may depend on both dosage and duration. Notably, leptin synthesis displays sex-specific differences, with women generally exhibiting higher leptin levels than men. Leptin expression is higher in female subcutaneous adipose tissue, and estrogen may promote leptin levels, although the extent of this effect varies individually; testosterone, in contrast, has been shown to suppress leptin expression.
Lastly, pro-inflammatory cytokines (e.g., TNF-α, LIF, and IL-6) stimulate leptin synthesis during acute infection or inflammatory responses, highlighting leptin’s dual role in immune and energy metabolism regulation. In contrast, stress responses, such as cold exposure or catecholamine release, may decrease leptin levels via β-adrenergic receptors, modulating energy storage under stress conditions.
Hypoleptinemia primarily occurs in cases of low body fat or insufficient leptin production, commonly seen in lipid metabolism disorders, malnutrition, extreme dietary restriction, and certain genetic conditions. The metabolic phenotype of hypoleptinemia primarily includes reduced energy expenditure and increased appetite (hyperphagia). Additionally, individuals with hypoleptinemia struggle to maintain stable blood glucose levels during fasting, as leptin typically supports glucose regulation by enhancing insulin sensitivity and limiting hepatic gluconeogenesis. Leptin deficiency also significantly impacts the neuroendocrine system. For instance, leptin is essential for reproductive function; its deficiency can reduce gonadotropin-releasing hormone (GnRH) secretion, subsequently affecting downstream hormonal signaling and sexual maturation. Individuals with leptin deficiency frequently present with reproductive issues such as amenorrhea, delayed puberty, and infertility.
Leptin also plays a crucial role in maintaining cognitive health, with low leptin levels associated with poorer cognitive function, particularly in learning and memory. Moreover, leptin exerts neuroprotective effects, and low leptin levels have been linked to depression-like behaviors, especially when leptin’s neurogenesis-promoting and anti-apoptotic functions are diminished.
Hyperleptinemia is commonly associated with obesity, chronic inflammation, and metabolic diseases. Elevated leptin levels are often driven by increased adipose tissue and are typically accompanied by leptin resistance, where leptin signaling is impaired despite high leptin levels. The metabolic consequences of hyperleptinemia are complex and generally negative, with prominent symptoms including persistent hunger, reduced energy expenditure, and weight gain due to decreased leptin sensitivity. Furthermore, high leptin levels are linked to increased insulin resistance and a higher risk of T2DM, independent of body fat index. Chronic hyperleptinemia is also closely associated with vascular inflammation and endothelial dysfunction, raising the risk of hypertension, atherosclerosis, and other cardiovascular diseases.
In hyperleptinemia, leptin receptor saturation and restricted leptin transport across the blood-brain barrier (BBB) contribute to leptin resistance, dampening leptin’s beneficial effects. Additionally, chronic exposure to high leptin levels leads to decreased receptor expression, reducing hypothalamic leptin sensitivity and subsequently driving energy imbalance.