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

Objective The human PIK3R1 Y657* mutation impairs phosphoinositide 3-kiase (PI3K) activation, producing insulin resistance (IR) and reduced adiposity but, surprisingly, no fatty liver or dyslipidaemia. Mice heterozygous for Pik3r1 Y657* metabolically phenocopy humans, moreover exhibiting increased energy expenditure. We suggest that this protects from lipotoxicity despite IR, and here investigate its cause. Methods Pik3r1Y657*/WT (Pik3r1Y657*) mice and wild-type (WT) littermates single-caged at 21 or 30°C were fed a 45% high-fat diet for 3 weeks. Body composition, food intake, metabolic efficiency, energy expenditure and physical activity were determined. Body temperature and tail heat loss were assessed by infrared imaging, thermal insulation by a modified Scholander experiment, and total Uncoupling Protein 1 (Ucp1)-dependent thermogenic capacity by determining peak norepinephrine-induced oxygen consumption. Results Pik3r1Y657* mice at 21°C showed higher energy expenditure than WT mice that was not fully explained by concomitant increase in food intake, nor by changes in physical activity, all as previously reported. No changes were seen in body temperature, tail vein heat dissipation, nor thermal insulation. Moreover, Ucp1-dependent thermogenesis was unaltered. Housing at 30°C did not alter the metabolic phenotype of male Pik3r1Y657* mice, but lowered physical activity and energy expenditure in females. Ucp1-dependent thermogenic capacity at 30°C was unchanged in Pik3r1Y657* mice compared to WT. Conclusions The ‘energy leak’ that we suggest is metabolically protective in Pik3r1-related IR in mice and humans is not caused by Ucp1-mediated BAT hyperactivation, nor by impaired thermal insulation. Further metabolic studies are now required to seek alternative explanations such as non Ucp1-mediated futile cycling within or among metabolically important tissues. ### Competing Interest Statement RS has received consulting fees from Novartis, Astra Zeneca, and Alnylam, research contribution in kind from Pfizer, and speaking fees from Novo Nordisk, Eli Lilly, and Amryt