Homeothermic vertebrates (birds and mammals) have two mechanisms for direct thermogenesis at the cellular level.

The first mechanisms begins with the release of two substances in response to chilling, the thyroid hormone thyroxine and the neurotransmitter norepinephrine, which open channels for the facilitated diffusion of Na+ ions into the cell. The Na+ ions are then returned by active transport to the extracellular space. The movement of sodium ions from inside the cell to outside the cell stores free energy (the movement is against both against a concentration gradient and positive electrical potential). The return of the Na+ ions represents a free energy decrease, and also an enthalpy decrease, meaning that the system generates heat as it cycles.

The second mechanism involves the production of heat in brown fat. Brown fat contains large numbers of mitochondria. In brown fat, chemiosmosis can be decoupled from ATP synthesis, so the free energy decrease involved as protons diffuse from the intermembranous space into the matrix evolves heat rather than leads to substrate level phosphorylation.