Surplus fat rapidly increases fat oxidation and insulin resistance in lipodystrophic mice.

•In contrast to wild type mice, lipodystrophic Azip mice manifest striking metabolic inflexibility.•Wild type mice respond to excess dietary fat by storing the surplus energy and thus gain weight.•In contrast, Azip mice increase fat oxidation and energy expenditure in response to surplus energy intake.•Unfortunately this apparently ‘helpful’ adaptation also results in substrate competition and worsening insulin resistance.