Natural Human Genetic Variation Determines Basal and Inducible Expression of PM20D1, an Obesity-Associated Gene.

Significance Generation of heat by brown and beige fat cells is a potential avenue to increased energy expenditure, and thus management of obesity and metabolic syndrome. PM20D1 plays a role in thermogenesis based on mouse studies, but its expression had not been investigated in human adipocytes. Here we show that human PM20D1 expression is genetically variable at 2 levels. Genotype at certain distant variants correlates with overall PM20D1 expression levels across all human tissues (an “on/off switch”), while a different variant near the gene determines its regulation specifically in adipocytes by the PPARγ receptor and the antidiabetic drugs that target it (a “rheostat”). Human regulatory genetic variation in PM20D1 expression is associated with obesity and may ultimately inform individualized medicine approaches.