TY - JOUR
T1 - Pirt deficiency has subtle female-specific effects on energy and glucose metabolism in mice
AU - Jall, Sigrid
AU - Finan, Brian
AU - Collden, Gustav
AU - Fischer, Katrin
AU - Dong, Xinzhong
AU - Tschöp, Matthias H.
AU - Müller, Timo D.
AU - Clemmensen, Christoffer
N1 - Funding Information:
We thank Heidi Hofmann, Emilija Malogajski, Luisa Müller, Laura Sehrer, and Jakob Langer for assistance with in vivo and in vitro experiments. This work was supported by: The Alfred Benzon Foundation, The Lundbeck Foundation Fellowship: R238-2016-2859, The Novo Nordisk Foundation (Grant number NNF17OC0026114), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program under grant agreement No 694968 (PREMSOT), the Alexander von Humboldt Foundation, the Helmholtz Alliance ICEMED & the Initiative and Networking Fund of the Helmholtz Association, the Helmholtz initiative on Personalized Medicine iMed, the Helmholtz cross-program “Metabolic Dysfunction”, German Research Foundation DFG-TRR152-TP23. Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center, based at the University of Copenhagen, Denmark and partially funded by an unconditional donation from the Novo Nordisk Foundation (Grant number NNF18CC0034900.)
Funding Information:
This work was supported by: The Alfred Benzon Foundation , The Lundbeck Foundation Fellowship : R238-2016-2859 , The Novo Nordisk Foundation (Grant number NNF17OC0026114 ), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program under grant agreement No 694968 (PREMSOT), the Alexander von Humboldt Foundation , the Helmholtz Alliance ICEMED & the Initiative and Networking Fund of the Helmholtz Association , the Helmholtz initiative on Personalized Medicine iMed , the Helmholtz cross-program “Metabolic Dysfunction”, German Research Foundation DFG-TRR152-TP23 . Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center, based at the University of Copenhagen, Denmark and partially funded by an unconditional donation from the Novo Nordisk Foundation (Grant number NNF18CC0034900 .)
Publisher Copyright:
© 2019 The Authors
PY - 2019/5
Y1 - 2019/5
N2 - Objective: The contribution of brown adipose tissue (BAT) to adult human metabolic control is a topic of ongoing investigation. In context, understanding the cellular events leading to BAT uncoupling, heat production, and energy expenditure is anticipated to produce significant insight into this endeavor. The phosphoinositide interacting regulator of transient receptor potentials (Pirt) was recently put forward as a key protein regulating cold sensing downstream of the transient receptor potential melastatin 8 (TRPM8). Notably, TRPM8 has been identified as a non-canonical regulator of BAT thermogenesis. The aim of this investigation was to delineate the role of Pirt in energy homeostasis and glucose metabolism - and the possible involvement of Pirt in TRPM8-elicited energy expenditure. Methods: To this end, we metabolically phenotyped male and female Pirt deficient (Pirt−/−) mice exposed to a low-fat chow diet or to a high-fat, high-sugar (HFHS) diet. Results: We identified that chow-fed female Pirt−/− mice have an increased susceptibility to develop obesity and glucose intolerance. This effect is abrogated when the mice are exposed to a HFHS diet. Conversely, Pirt−/− male mice display no metabolic phenotype on either diet relative to wild-type (WT) control mice. Finally, we observed that Pirt is dispensable for TRPM8-evoked energy expenditure. Conclusion: We here report subtle metabolic abnormalities in female, but not male, Pirt−/− mice. Future studies are required to tease out if metabolic stressors beyond dietary interventions, e.g. temperature fluctuations, are interacting with Pirt-signaling and metabolic control in a sex-specific fashion.
AB - Objective: The contribution of brown adipose tissue (BAT) to adult human metabolic control is a topic of ongoing investigation. In context, understanding the cellular events leading to BAT uncoupling, heat production, and energy expenditure is anticipated to produce significant insight into this endeavor. The phosphoinositide interacting regulator of transient receptor potentials (Pirt) was recently put forward as a key protein regulating cold sensing downstream of the transient receptor potential melastatin 8 (TRPM8). Notably, TRPM8 has been identified as a non-canonical regulator of BAT thermogenesis. The aim of this investigation was to delineate the role of Pirt in energy homeostasis and glucose metabolism - and the possible involvement of Pirt in TRPM8-elicited energy expenditure. Methods: To this end, we metabolically phenotyped male and female Pirt deficient (Pirt−/−) mice exposed to a low-fat chow diet or to a high-fat, high-sugar (HFHS) diet. Results: We identified that chow-fed female Pirt−/− mice have an increased susceptibility to develop obesity and glucose intolerance. This effect is abrogated when the mice are exposed to a HFHS diet. Conversely, Pirt−/− male mice display no metabolic phenotype on either diet relative to wild-type (WT) control mice. Finally, we observed that Pirt is dispensable for TRPM8-evoked energy expenditure. Conclusion: We here report subtle metabolic abnormalities in female, but not male, Pirt−/− mice. Future studies are required to tease out if metabolic stressors beyond dietary interventions, e.g. temperature fluctuations, are interacting with Pirt-signaling and metabolic control in a sex-specific fashion.
KW - Body weight
KW - Brown adipose tissue
KW - Energy metabolism
KW - Sex differences
KW - Signaling molecule
KW - TRPM8
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U2 - 10.1016/j.molmet.2019.02.011
DO - 10.1016/j.molmet.2019.02.011
M3 - Article
C2 - 30902502
AN - SCOPUS:85063046541
SN - 2212-8778
VL - 23
SP - 75
EP - 81
JO - Molecular Metabolism
JF - Molecular Metabolism
ER -