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

Human SHORT syndrome is caused by dominant negative human <i>PIK3R1</i> 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 dyslipidemia. <i>Pik3r1^Y657*^/WT</i> (<i>Pik3r1^Y657*</i>) mice metabolically phenocopy humans, moreover exhibiting increased energy expenditure on high-fat feeding. We have hypothesized 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 set out to determine whether increased Ucp1-dependent thermogenesis explains the increased energy expenditure in <i>Pik3r1</i>-related IR. Male and female <i>Pik3r1^Y657*</i> mice challenged with a 45% fat diet for 3 wk at 21°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°C did not alter the metabolic phenotype of male <i>Pik3r1^Y657*</i> mice but led to lowered physical activity in female <i>Pik3r1^Y657*</i> mice compared with controls. Nevertheless, these mice still exhibited increased energy expenditure. Ucp1-dependent thermogenic capacity at 30°C was similar in <i>Pik3r1^Y657*</i> and WT mice. We conclude that the likely metabolically protective "energy leak" in Pik3r1-related IR is not caused by Ucp1-mediated brown adipose tissue (BAT) hyperactivation, nor impaired thermal insulation. Further metabolic studies are required to seek alternative explanations such as non-Ucp1-mediated futile cycling.<b>NEW & NOTEWORTHY</b> Understanding how <i>Pik3r1^Y657*</i> mice and humans are protected from lipotoxicity despite insulin resistance may suggest new ways to mitigate metabolic syndrome. We find reduced metabolic efficiency in <i>Pik3r1^Y657*</i> mice but no differences in locomotion, thermoregulation, or Ucp1-dependent thermogenesis. The protective higher energy expenditure in Pik3r1-related insulin resistance has an alternative, likely metabolic, explanation.