Sarcolipin

Sarcolipin binds SERCA pumps and uncouples ATP hydrolysis from calcium transport. This futile cycling of the pump hydrolyzes ATP and generates heat without net calcium transport, contributing to non-shivering thermogenesis. This mechanism is particularly important during cold acclimation when brown adipose tissue UCP1-based thermogenesis is insufficient.

When sarcolipin reduces SERCA efficiency, calcium clearance from the cytoplasm is slowed, altering the calcium transient during muscle contraction. In the cardiac atria, sarcolipin expression modulates atrial contractility and conduction properties. Sarcolipin-knockout mice have increased atrial contractility and reduced thermogenic capacity.

SLN-knockout mice have severely impaired ability to maintain body temperature during acute cold exposure compared to wild-type mice, even with functional brown adipose tissue. Overexpression of sarcolipin in skeletal muscle increases thermogenesis and protects against diet-induced obesity and glucose intolerance, establishing SLN as a key thermogenic mediator.

Sarcolipin-overexpressing mice are resistant to high-fat diet-induced obesity due to increased caloric expenditure through SERCA uncoupling. Sarcolipin expression is regulated by thyroid hormone and beta-adrenergic signaling. These findings position sarcolipin as a potential target for enhancing thermogenic capacity in metabolic disease.