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The Mitochondrial Permeability Transition Pore Regulator Cyclophilin D Exhibits Tissue‐Specific Control of Metabolic Homeostasis
Author(s) -
Laker Rhianna,
Taddeo Evan,
Zhang Mei,
Hoehn Kyle,
Yan Zhen
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1036.14
Subject(s) - mptp , mitochondrial permeability transition pore , homeostasis , regulator , mitochondrion , steatosis , endocrinology , medicine , adipose tissue , biology , energy homeostasis , glucose homeostasis , chemistry , microbiology and biotechnology , biochemistry , insulin resistance , diabetes mellitus , obesity , dopamine , apoptosis , programmed cell death , gene , dopaminergic
The mitochondrial permeability transition pore (mPTP) is a key regulator of mitochondrial health, and the mPTP has been implicated in the pathogenesis of metabolic disease. Cyclophilin D (CypD) is a critical regulator that directly binds to mPTP constituents to facilitate pore opening. Mice lacking CypD in all tissues are protected from diet‐induced glucose intolerance; however, the tissue‐specific function of CypD and mPTP have not been ascertained. To determine the functional role of CypD in metabolic tissues that control glucose homeostasis, we generated liver‐specific and muscle‐specific CypD knockout mice (LKO and MKO, respectively; n=9‐11/gp). These mice were fed either normal chow (NC) or 45% high fat diet (HFD) and evaluated for metabolic phenotypes. We observed that MKO mice were statistically identical to floxed controls with respect to body weight gain or glucose tolerance when fed either diet. However, LKO mice fed HFD developed greater hepatic steatosis, adipose mass, glucose intolerance and pyruvate intolerance compared with flox control mice. These findings demonstrate that CypD has tissue‐specific roles in the context of metabolic physiology, and the loss of CypD in liver is sufficient to exacerbate whole‐body metabolic dysfunction with high fat feeding. Supported by NIH grant R01AR050429