The metabolically protective energy expenditure increase of Pik3r1-related insulin resistance is not explained by Ucp1-mediated thermogenesis

Human SHORT syndrome is caused by dominant negative human PIK3R1 mutations that impair insulin-stimulated phosphoinositide 3-kinase (PI3K) activity. This produces severe insulin resistance (IR) and often reduced adiposity, commonly described as lipodystrophy. However unlike human primary lipodystrophies, SHORT syndrome does not feature fatty liver or dyslipidaemia. Pik3r1Y657*/WT (Pik3r1Y657*) mice metabolically phenocopy humans, moreover exhibiting increased energy expenditure. We have hypothesised that this increased energy expenditure explains protection from lipotoxicity, and suggested that understanding its mechanism may offer novel approaches to mitigating the metabolic syndrome. We thus set out to determine whether increased Ucp1-dependent thermogenesis explains the increased energy expenditure in Pik3r1-related IR. Male and female Pik3r1Y657* mice challenged with a 45% fat diet for 3 weeks at 21{degrees}C showed reduced metabolic efficiency not explained by changes in food intake or physical activity. No changes were seen in thermoregulation, assessed by thermal imaging and a modified Scholander protocol. Ucp1-dependent thermogenesis, assessed by norepinephrine-induced oxygen consumption, was also unaltered. Housing at 30{degrees}C did not alter the metabolic phenotype of male Pik3r1Y657* mice, but led to lowered physical activity in female Pik3r1Y657* mice compared to controls. Nevertheless these mice still exhibited increased energy expenditure. Ucp1-dependent thermogenic capacity at 30{degrees}C was similar in Pik3r1Y657* and WT mice. We conclude that the likely metabolically protective energy leak in Pik3r1-related IR is not caused by Ucp1-mediated BAT hyperactivation, nor impaired thermal insulation. Further metabolic studies are required to seek alternative explanations such as non Ucp1-mediated futile cycling. New and NoteworthyUnderstanding how Pik3r1Y657* mice and humans are protected from lipotoxicity despite insulin resistance may suggest new ways to mitigate metabolic syndrome. We find reduced metabolic efficiency and increased energy expenditure in Pik3r1Y657* mice but no differences in locomotion, thermoregulation or Ucp1-dependent thermogenesis. Protective energy expenditure in Pik3r1-related insulin resistance has an alternative, likely metabolic, explanation