Abstract

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 21C 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 30C 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 30C 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.

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

Footnotes

* 1. Abstract reformatted 2. Various figure elements replaced or added, removing some lean mass normalisation and replacing with ANCOVA where appropriate

Details

Title
The metabolically protective energy expenditure increase of Pik3r1-related insulin resistance is not explained by Ucp1-mediated thermogenesis
Author
Luijten, Ineke; Onishi, Ami; Mckay, Eleanor J; Bengtsson, Tore; Semple, Robert
University/institution
Cold Spring Harbor Laboratory Press
Section
New Results
Publication year
2024
Publication date
Nov 4, 2024
Publisher
Cold Spring Harbor Laboratory Press
ISSN
2692-8205
Source type
Working Paper
Language of publication
English
ProQuest document ID
2925283641
Copyright
© 2024. This article is published under http://creativecommons.org/licenses/by/4.0/ (“the License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.