Body fat distribution patterns in humans are heterogeneous and result from regional differences in intrinsic properties of adipose cells as well as local hormonal effects. Under chronic overfeeding conditions, adipose tissue expansion in a given compartment occurs by adipocyte hypertrophy (enlargement of existing adipocytes through triglyceride synthesis), and/or adipocyte hyperplasia (generation of new adipocytes through differentiation of preadipocytes). Visceral adipocytes (e.g. omental fat cells) are efficient for hypertrophy through lipid storage and show high lipolytic responsiveness, whereas subcutaneous cells have a higher capacity for hyperplasia. Our results demonstrate that visceral adipocyte hypertrophy and high diacylglycerol acyltransferase activity are independently related to hypertriglyceridemia and triglyceride enrichment of circulating lipoproteins. Moreover, low capacity for adipogenic differentiation of preadipocytes in the subcutaneous fat compartment is a significant predictor of excess visceral adipose tissue accumulation, visceral adipocyte hypertrophy, triglyceride enrichment of lipoproteins and fasting hyperglycemia. Adipose tissue-derived cytokines and immune cells infiltrating adipose tissues also mediate the link between visceral obesity and cardiometabolic alterations increasing type 2 diabetes and cardiovascular disease risk. These inflammatory phenotypes are also observed in patients with visceral adipocyte hypertrophy when compared to those who predominantly exhibit hyperplasic adipose tissue expansion. Overall, in individuals with elevated cardiometabolic risk, adipose tissue function impairments include adipocyte hypertrophy, impaired adipogenesis, low free fatty acid uptake, reduced triglyceride synthesis, resistance to the inhibitory effect of insulin on lipolysis, immune cell infiltration and inflammatory cytokine secretion. These alterations collectively reflect reduced storage capacity of fat tissues and contribute to systemic metabolic perturbation.