Pathophysiology of obesity and its associated diseases

Abstract

The occurrence of obesity has increased across the whole world. Many epidemiological studies have indicated that obesity strongly contributes to the development of cancer, cardiovascular diseases, type 2 diabetes, liver diseases and other disorders, accounting for a heavy burden on the public and on health-care systems every year. Excess energy uptake induces adipocyte hypertrophy, hyperplasia and formation of visceral fat in other non-adipose tissues to evoke cardiovascular disease, liver diseases. Adipose tissue can also secrete adipokines and inflammatory cytokines to affect the local microenvironment, induce insulin resistance, hyperglycemia, and activate associated inflammatory signaling pathways. This further exacerbates the development and progression of obesity-associated diseases. Although some progress in the treatment of obesity has been achieved in preclinical and clinical studies, the progression and pathogenesis of obesity-induced diseases are complex and unclear. We still need to understand their links to better guide the treatment of obesity and associated diseases. In this review, we review the links between obesity and other diseases, with a view to improve the future management and treatment of obesity and its co-morbidities.

Keywords: Adipokines; Cardiovascular disease; Inflammation; Insulin resistance; Lipid accumulation; Liver disease; MNK; Obesity.

Graphical abstract

Figure 1

Overview of the obesity epidemic, obesity definition and obesity-associated diseases.

Figure 2

Cellular mechanisms linking obesity and cancer. Adipose tissue is enlarged by excess fat and secretes adipokines, such as leptin and insulin that activate the RAS/Erk and PI3K/AKT/mTOR signaling pathways. Adipose tissue also produces proinflammatory cytokines which induce oxidative stress and mitochondrial dysfunction, triggering the p38/MAPK signaling pathway. All these changes promote cancer cell proliferation and cell division and inhibit cell apoptosis.

Figure 3

Schematic representation of the role of obesity in the promotion of cardiovascular diseases. Adipose tissue hypertrophy and ectopic deposition around the heart and coronary arteries impair angiogenesis, promote local tissue hypoxia and necrosis, and induce left ventricular hypertrophy and remodeling, which contribute to heart failure. Adipokines, free fatty acids (FFAs) and superoxides secreted by adipose tissue activate sympathetic nerve activity to induce hypertension and then increase left ventricular mass, stroke volume and cardiac output. Triglycerides (TG) in ectopic fat is transported by very low-density lipoprotein (VLDL) into the circulation. Low-density lipoprotein (LDL) undergoes oxidation and other modifications to combine with macrophages, forming foam cells, a hallmark of early atherosclerosis (AS) lesions.

Figure 4

Schematic representation of the links between obesity and insulin resistance and their internal mechanisms associated with T2DM. Free fatty acids (FFAs) and their metabolites activate protein kinase C and promote Ser/Thr phosphorylation of insulin receptor substrates 1 (IRS-1), in turn reducing normal Tyr phosphorylation of IRS-1 and impairing the control of the glucose transporter GLUT4, inducing insulin resistance and thus poor glucose tolerance. Proinflammatory cytokines secreted by adipose tissue activate the JNK signaling pathway and indirectly inhibit the translocation of GLUT4 to promote insulin resistance. Elevated leptin and low adiponectin levels, along with insulin resistance, impair β-cell function, suppressing insulin secretion and leading to T2DM. The black line indicates the normal mechanism underlying the insulin-stimulated uptake of glucose involving translocation of the glucose transporter GLUT4 to the plasma membrane. The purple line indicates the defective process(es) in obese individuals.

Figure 5

Schematic representation of the links between obesity and liver diseases. Free fatty acids (FFAs) and glucose from the circulation accumulate in the liver and support de novo lipogenesis (DNL) of FAs to form triglycerides (TG), which causes fatty liver. Under the ‘second hit’ of inflammation induced by oxidative stress, ER stress and reactive oxygen species (ROS) cause adipocyte apoptosis, which eventually leads to NASH and sometimes to HCC.