The pathophysiological mechanisms of obesity and the brain-gut axis theory
Obesity is a chronic metabolic disease caused by the interaction of multiple factors, including genetics, environment, and endocrine dysregulation. Its core mechanism lies in energy intake exceeding energy expenditure. Genetic studies show that 40% to 70% of the difference in BMI between individuals is attributed to genetics. If both parents are obese, their children have approximately a 70% chance of being obese. Key loci such as FTO (a gene associated with body fat mass and obesity) and MC4R (a melanocortin-4-receptor gene) have been identified.
The "thrifty gene theory" is a crucial mechanism explaining obesity. These genes (such as β₃adrenergic receptors and PPAR-γ) were efficient at utilizing energy during times of food scarcity, but in modern environments, they lead to abdominal obesity and insulin resistance. Leptin, a key hormone produced by adipocytes, reduces appetite and increases energy expenditure. The leptin content, a product of the obesity gene OB, directly affects fat metabolism, but leptin resistance is common in obese individuals. Environmental factors such as high-energy diets, sedentary behavior, and endocrine disruptors like bisphenol A (BPA) accelerate fat synthesis by activating ERα and ERβ receptors, further exacerbating the obesity effect.
The brain-gut axis metabolic mechanism is at the forefront of obesity research in recent years. The gastrointestinal tract engages in complex bidirectional communication through the central nervous system (CNS), enteric nervous system (ENS), autonomic nervous system (ANS), and hypothalamus-pituitary-adrenal (HPA) axis. After the brain integrates the afferent signals, it regulates gastrointestinal motility, gastric acid secretion, and thermogenesis through the autonomic nervous system or neuroendocrine system.
The vagus nerve is crucial to the brain-gut axis. The mechanotropic vagus nerve senses stimuli such as gastrointestinal distension, while the chemotropic vagus nerve senses neuropeptides secreted by enteroendocrine cells. Studies show that gut microbiota can activate the vagus nerve, influencing brain function and behavior. In terms of neuroendocrinology, microorganisms can synthesize biologically active norepinephrine and dopamine. Furthermore, products of gut microbiota metabolism, such as serotonin (5-HT), gamma-aminobutyric acid (GABA), and short-chain fatty acids (SCFAs), can act directly on the ENS and vagus nerve, and also influence the CNS via paracrine mechanisms.
The HPA axis plays a central role under stress. Stress leads to the secretion of CRH by the hypothalamus, ultimately resulting in elevated cortisol levels, which not only promotes abdominal fat accumulation but also increases intestinal permeability. When the intestinal barrier is damaged, lipopolysaccharide (LPS) produced by Gram-negative bacteria enters the bloodstream, causing endotoxemia. LPS recognizes CD14/TLR4 receptors, activating the TLR4-MyD88-NFkb signaling pathway and inducing the expression of inflammatory factors such as IL-1, TNF-α, and IL-6. This low-grade chronic inflammation is a significant contributing factor to obesity.
The relationship between gut microbiota and obesity is also reflected in energy acquisition capacity. Obese individuals have an increased proportion of Firmicutes and a decreased proportion of Bacteroidetes. Firmicutes can more efficiently convert polysaccharides into absorbable monosaccharides and short-chain fatty acids (especially acetic acid), thereby increasing energy gain. Simultaneously, the gut microbiota can regulate fasting-induced adipokines (Fiaf), promoting fat storage in cells.
Furthermore, a balanced gut microbiota can regulate appetite-suppressing hormones such as cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and pyrotypin (PYY), which act on the arcuate nucleus of the hypothalamus to produce a feeling of satiety. If the gut microbiota is imbalanced, these inhibitory signals weaken, leading to overeating. Butyrate, a short-chain fatty acid, can reduce inflammation levels and maintain immune balance. The discovery of the gut microbiota-brain-pancreatic β-cell axis provides new targets for intervening in obesity through multiple pathways, including energy regulation, inflammation activation, and neuroendocrine mechanisms.