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Insulin alters brain lipid profile and mitochondrial function
Author(s) -
Carr Sheryl,
Trumbull Annie,
Hutchinson BreAnna,
Dallon Blake,
Harrison Mitchell,
Gray Harrison,
Gibbs Jonathan,
Eskildsen Dane,
Kudlacek Jess,
Heldt Brett,
Clayton Craig,
Wisco Jonathan J.,
Bikman Benjamin T.
Publication year - 2017
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.31.1_supplement.976.9
Subject(s) - hyperinsulinemia , ceramide , insulin resistance , insulin , medicine , endocrinology , sphingolipid , biology , insulin receptor , mitochondrion , downregulation and upregulation , microbiology and biotechnology , biochemistry , apoptosis , gene
Alzheimer's disease (AD), the most common neurodegenerative disorder worldwide, is characterized by increased levels of neurofibrillary tangles and amyloid‐beta plaques. Evidence has previously implicated the potent role that insulin resistance plays in the development and progression of AD, suggesting to some that AD represents a distinct type of diabetes. Additionally, disparate lines of evidence find a role for alterations in brain mitochondrial function in AD etiology. We sought to test a unifying hypothesis—namely, that hyperinsulinemia promotes accrual of the sphingolipid ceramide, which, as we've previously found, pathologically alters mitochondrial function. Via daily insulin injections, we induced hyperinsulinemia in ApoE4 mice. In addition to insulin, one group received myriocin injections to inhibit ceramide biosynthesis. We observed significant increases in brain ceramides in the insulin‐treated group, which correlated with disrupted brain mitochondrial function. However, the group receiving myriocin alone, or, importantly, myriocin with insulin had normal lipid profiles and apparently normal mitochondrial bioenergetics. Altogether, our findings suggest a causative role for insulin in AD etiology via an insulin‐induced upregulation of ceramide biosynthesis and accrual in the brain.