Genetic factors and energy metabolism: the underlying physiological mechanisms of obesity
The influence of genetic factors on energy metabolism: When energy expenditure and intake are in balance, a person's weight remains relatively constant; however, when energy expenditure is less than energy intake, the excess energy is stored as fat, leading to weight gain and obesity. The basal level of energy expenditure at rest and during activity is genetically determined, and there are significant differences in energy expenditure levels among individuals. Many obese patients complain that they "gain weight even from drinking water," even though they do not consume more calories than normal people, and may even consume less, yet they are still obese. This is related to their lower basal level of energy expenditure at rest and during activity compared to normal individuals. Genetic factors can influence energy metabolism in several ways.
Resting metabolic rate (RMR) differs from basal metabolic rate (BMR). BMR is measured after a 12-hour fast, 30 minutes after waking up in the morning while the subject is resting quietly; RMR, on the other hand, is measured after 30 minutes of quiet rest. RMR accounts for a large portion of daily energy expenditure, approximately 70%. Observations of monozygotic and dizygotic twins have revealed that genetic factors have a significant impact on RMR, with heritability reaching up to 80% in monozygotic twins. Individuals with a high RMR are less likely to be obese, while those with a low RMR are relatively more likely to be obese.
The thermic effect of food. The thermic effect of food refers to the increase in energy expenditure after eating. It is generally believed that the heritability of the thermic effect is around 50%, with a higher correlation coefficient the closer the kinship. The correlation coefficient is 0.30 between parents and children, 0.35 between dizygotic twins, and 0.52 between monozygotic twins. People with a high thermic effect are less likely to become obese, while those with a low thermic effect are more prone to obesity. Metabolic rate during exercise. For the same exercise intensity and volume, the energy expenditure level varies among individuals, largely determined by genetic factors.
People with a high metabolic rate during exercise burn more energy and are less prone to obesity, while those with a low metabolic rate burn less energy and are more likely to become obese. The ratio of fast-twitch and slow-twitch muscle fibers is a crucial factor determining metabolic rate during exercise. Fast-twitch fibers, also known as white muscle fibers, primarily generate energy from glucose during exercise; slow-twitch fibers, also known as red muscle fibers, primarily generate energy from fat. The ratio of fast-twitch to slow-twitch muscle fibers in the body is genetically determined and does not change with training or lifestyle habits.
A high content of fast-twitch muscle fibers results in a low metabolic rate during exercise and a higher likelihood of obesity, while a high content of slow-twitch muscle fibers results in a high metabolic rate during exercise and a lower likelihood of obesity. Key obesity-related genes: At the genetic level, weight regulation is determined by a relatively large genome, and the genetic phenotype of obesity is a complex polygenic system. With the development of molecular biology techniques, several genes related to obesity have been identified, the most important of which include: the obesity gene (ob), the leptin receptor gene (LEPR), the neuropeptide Y (NPY) gene, the β3-adrenergic receptor gene, the pro-opioid melanocyte-stimulating hormone (POMC) gene, the PCI gene, the MC-4R gene, and the PPARY gene. Abnormalities in these genes and their expressed proteins are closely related to the occurrence of obesity.
The main bioactive protein associated with obesity is leptin. Leptin is a protein hormone encoded by the obesity gene (OB, also known as the leptin gene) and secreted by adipose tissue. It is one of the most important bioactive proteins related to obesity. Leptin expression is regulated by various factors, including receptor lipids, food intake, fasting, and insulin levels. It regulates the body's fat metabolism through several pathways: suppressing appetite, reducing calorie intake, increasing calorie expenditure, inhibiting fat synthesis, and promoting fat breakdown.
Neuropeptide Y (NPY). NPY is primarily derived from neurons in the arcuate nucleus (ARC) of the hypothalamus, where it is present in high concentrations. NPY is a single-chain polypeptide with 36 amino acid residues, belonging to the pancreatic polypeptide family. The polypeptide chain folds into a hairpin structure, bringing the two ends of the molecule close together to facilitate receptor binding. The "Y" refers to the tyrosine residues at both ends of the molecule. NPY is the central site of leptin action, playing a mediating role in leptin's regulation of lipid metabolism.
Uncoupling proteins (UCPs). UCPs are special proteins on the inner mitochondrial membrane that regulate proton transmembrane activity. They are present in high concentrations within mitochondria. By transporting anionized free fatty acids, uncoupling proteins can reduce the proton electrochemical gradient, decoupling electron transport and ATP synthesis during respiration, thus releasing stored heat energy. β3-Adrenergic receptors (β3ARs). β3ARs are mainly distributed in adipose tissue, especially visceral adipose tissue such as the perirenal region and omentum, and are closely related to thermogenesis and lipolysis.
Human β3AR consists of 408 amino acid residues with a molecular weight of 42,281 and exhibits structural characteristics of the G protein-coupled receptor family. Excitation of β3AR by catecholamines can initiate adenylate cyclase, increasing the activity of cAMP-dependent esterases, enhancing lipolysis in adipose tissue, and increasing thermogenesis. β3AR dysfunction can reduce visceral fat breakdown, leading to visceral obesity. β3AR gene mutations are closely related to obesity; when tryptophan (Trp) at position 64 of the β3AR gene is replaced by arginine (Arp), forming the Trp64Arp allele, the incidence of obesity increases significantly.