In male C57BL/6 mice, a high-fructose diet induces visceral obesity, insulin resistance, proinflammatory adipokine production, macrophage infiltration, endoplasmic reticulum stress, and reduced high-molecular-weight adiponectin signaling, and these metabolic dysfunctions are entirely prevented in mice genetically deficient in ketohexokinase (KHK), demonstrating that fructose metabolism via KHK is necessary for these effects.

When fructose is processed by the enzyme ketohexokinase in fat tissue, it drains energy from cells, creates harmful byproducts, and stresses the cell's internal machinery. This stress causes the fat cells to release inflammatory signals, attract immune cells, and stop producing a key hormone that keeps metabolism healthy. Without this hormone, the body cannot properly use insulin or burn fat, leading to fat buildup around organs and high blood sugar.