Disorders of lipid metabolism and adipocyte remodeling: the pathophysiology and pathogenesis of obesity

II. Fat Metabolism in Obesity

Obesity and Changes in Lipid Metabolism: Obesity is a significant contributing factor to dyslipidemia. In obese individuals, lipid metabolism is characterized by disordered lipid metabolism, specifically reduced mobilization and utilization of free fatty acids (FFAs) by body tissues, increased plasma FFA levels and accumulation, elevated blood lipid volume, and generally elevated levels of cholesterol, triglycerides (TG), and total lipids. Studies show that for every 10% increase in body weight, plasma cholesterol increases by 0.3 mmol/L. Overweight individuals have a 1.5 to 2 times higher relative risk of developing hypercholesterolemia than non-overweight individuals, and 55.8% of obese individuals have plasma cholesterol levels above 5.2 mmol/L. Research confirms that the dyslipidemia in obese children and adolescents is similar to that in adults. Anatomical observations have shown that individuals with more metabolic syndrome symptoms in early life tend to have more severe atherosclerotic damage. Obesity-related dyslipidemia is a recognized risk factor for cardiovascular disease, partly due to the same mechanisms described above. Its characteristics include elevated plasma levels of FFAs and TG, decreased high-density lipoprotein cholesterol (HDL-c) levels, and altered low-density lipoprotein cholesterol (LDL-c) levels. The driving force behind dyslipidemia is the uncontrolled release of FFAs from adipocytes, a release caused by damaged adipocytes and a local pro-inflammatory environment. As mentioned above, FFAs reach the liver via the portal vein, promoting VLDL synthesis and subsequently inhibiting chylomicron lipolysis, leading to hypertriglyceridemia. Hypertriglyceridemia is the cause of triglyceride exchange between VLDL (rich in TG) and LDL-c/HDL-c (rich in cholesterol esters). This leads to decreased HDL-c levels and the formation of small, dense LDL cholesterol, a associated risk factor for cardiovascular disease. The inflammatory response (IR) and systemic inflammatory state observed in obese patients, along with elevated plasma FFA levels, reflect similar hepatic metabolic changes, including the production of IR, secretion of pro-inflammatory cytokines, and storage of circulating FFAs. These metabolic changes lead to NAFLD, defined as liver fat exceeding 5% of total liver volume or weight. In NAFLD, the liver increases gluconeogenesis, releasing more VLDL produced from FFAs despite high plasma glucose levels, leading to hypertriglyceridemia and increased secretion of hepatic cytokines and thrombotic factors. Furthermore, not only liver fat accumulation but also fat buildup in other internal organs can trigger pathological changes.

Adipocytes in adipose tissue possess an extraordinary ability to rapidly change their size, a capability generated through two main growth mechanisms: cell size reduction (hypertrophy) and cell number increase (hyperplasia). Recent studies suggest that these two mechanisms coexist in adult adipose tissue, even though previous observations indicated that adipocyte number stabilized between childhood and early adulthood. Specific population studies of adult adipose tissue have shown a positive correlation between adipocyte size and hyperinsulinemia and impaired glucose tolerance. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in non-diabetic individuals have smaller adipocytes compared to obese diabetic patients. Compared to SAT, VAT exhibits limited tissue plasticity potential, primarily through hypertrophic growth. Visceral fat accumulation in obese subjects is associated with ectopic lipid deposition, likely mediated by excess cellular storage capacity and impaired cell growth. This ectopic deposition primarily occurs in the liver and skeletal muscle and is associated with insulin resistance (IR) and diabetes, as well as other obesity-related diseases. Furthermore, it may involve the myocardium, pericardium, pancreas, brain, and several peripheral organs, mediating the toxic effects of fat on target cells, such as cell dysfunction and cell death. The increased risk of cardiovascular disease observed in obese individuals stems not only from the indirect effects of metabolic diseases but also from localized, direct fatty diseases and atherosclerotic mechanisms.

The occurrence of obesity and excessive fat accumulation are also related to the defects or dysfunction of various enzymes in local tissues such as adipose tissue, liver, and skeletal muscle. Several enzymes in adipocytes have been confirmed to directly participate in the local tissue fat metabolism process: lipoprotein lipase (LPL) controls and regulates the entry of exogenous fatty acids into adipocytes; fatty acid synthase and benzoyldiphenyl esterase catalyze the synthesis of fatty acids from acetyl-CoA. Skeletal muscle is the main site for the oxidation and utilization of lipids and glucose in the human body. In normal individuals, 80% of the energy required by skeletal muscle in a fasting state comes from the oxidation of fatty acids, mainly regulated by lipoprotein lipase. In obese individuals, the activity of this enzyme in skeletal muscle is low, resulting in reduced fatty acid oxidation and the transfer and storage of large amounts of fat into adipose tissue. In addition, obese individuals also have a genetic defect in carnitine palmitoyltransferase, which, as the rate-limiting enzyme for the esterification and transfer of long-chain acetyl-CoA to mitochondria, promotes the uptake and utilization of fatty acids by skeletal muscle. Therefore, obesity reduces the uptake and utilization of fatty acids, leading to increased endogenous fat synthesis and consequently fat accumulation. Elevated plasma triglyceride (TG) levels in obesity are related not only to increased exogenous fat intake but also to the individual's genetic susceptibility. Plasma lipoprotein lipase (LPL) is a key enzyme in TG hydrolysis. In obese individuals, the gene for this enzyme exhibits polymorphism, and the level of its activator is low. These two factors reduce LPL activity, ultimately slowing TG hydrolysis. Furthermore, increased endogenous TG synthesis in the liver and the inability of LPL to be properly activated in postprandial adipose tissue cells, leading to impaired clearance of TG-rich lipoproteins, also contribute to the development of hypertriglyceridemia.