TY - JOUR
T1 - Perilipin 5 links mitochondrial uncoupled respiration in brown fat to healthy white fat remodeling and systemic glucose tolerance
AU - Gallardo-Montejano, Violeta I.
AU - Yang, Chaofeng
AU - Hahner, Lisa
AU - McAfee, John L.
AU - Johnson, Joshua A.
AU - Holland, William L.
AU - Fernandez-Valdivia, Rodrigo
AU - Bickel, Perry E.
N1 - Funding Information:
We dedicate this manuscript to the late Lisa Hahner, who contributed so much her great skill and effort to this project. We thank Philipp Scherer and UT Southwestern Touchstone Diabetes Center for the UCP1rtTA mouse, and his help designing the TRE-Plin 5 transgene. We thank the UT Southwestern Metabolic Phenotyping Core (Ruth Gordillo and Syann Lee), Electron Microscopy Core (Kate Luby-Phelps and Anza Dar-ehshouri), Histo Pathology Core (Bret M. Evers and John M. Shelton), and Transgenic Core (Robert E. Hammer). This study was supported by NIH R01DK115875 for P.E.B., NIH R01DK112826 and R01DK108833 for W.L.H., and Wayne State University Startup funds for R.F.-V.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Exposure of mice or humans to cold promotes significant changes in brown adipose tissue (BAT) with respect to histology, lipid content, gene expression, and mitochondrial mass and function. Herein we report that the lipid droplet coat protein Perilipin 5 (PLIN5) increases markedly in BAT during exposure of mice to cold. To understand the functional significance of cold-induced PLIN5, we created and characterized gain- and loss-of-function mouse models. Enforcing PLIN5 expression in mouse BAT mimics the effects of cold with respect to mitochondrial cristae packing and uncoupled substrate-driven respiration. PLIN5 is necessary for the maintenance of mitochondrial cristae structure and respiratory function during cold stress. We further show that promoting PLIN5 function in BAT is associated with healthy remodeling of subcutaneous white adipose tissue and improvements in systemic glucose tolerance and diet-induced hepatic steatosis. These observations will inform future strategies that seek to exploit thermogenic adipose tissue as a therapeutic target for type 2 diabetes, obesity, and nonalcoholic fatty liver disease.
AB - Exposure of mice or humans to cold promotes significant changes in brown adipose tissue (BAT) with respect to histology, lipid content, gene expression, and mitochondrial mass and function. Herein we report that the lipid droplet coat protein Perilipin 5 (PLIN5) increases markedly in BAT during exposure of mice to cold. To understand the functional significance of cold-induced PLIN5, we created and characterized gain- and loss-of-function mouse models. Enforcing PLIN5 expression in mouse BAT mimics the effects of cold with respect to mitochondrial cristae packing and uncoupled substrate-driven respiration. PLIN5 is necessary for the maintenance of mitochondrial cristae structure and respiratory function during cold stress. We further show that promoting PLIN5 function in BAT is associated with healthy remodeling of subcutaneous white adipose tissue and improvements in systemic glucose tolerance and diet-induced hepatic steatosis. These observations will inform future strategies that seek to exploit thermogenic adipose tissue as a therapeutic target for type 2 diabetes, obesity, and nonalcoholic fatty liver disease.
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U2 - 10.1038/s41467-021-23601-2
DO - 10.1038/s41467-021-23601-2
M3 - Article
C2 - 34083525
AN - SCOPUS:85107347926
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3320
ER -