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Mfn2 deletion in brown adipose tissue protects from insulin resistance and impairs thermogenesis
Author(s) -
Mahdaviani Kiana,
Benador Ilan Y,
Su Shi,
Gharakhanian Raffi A,
Stiles Linsey,
Trudeau Kyle M,
Cardamone Maria,
EnríquezZarralanga Violeta,
Ritou Eleni,
Aprahamian Tamar,
Oliveira Marcus F,
Corkey Barbara E,
Perissi Valentina,
Liesa Marc,
Shirihai Orian S
Publication year - 2017
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201643827
Subject(s) - thermogenesis , mfn2 , insulin resistance , brown adipose tissue , endocrinology , medicine , biology , mitochondrial fusion , insulin , mitochondrion , thermogenin , adipose tissue , microbiology and biotechnology , genetics , mitochondrial dna , gene
BAT ‐controlled thermogenic activity is thought to be required for its capacity to prevent the development of insulin resistance. This hypothesis predicts that mediators of thermogenesis may help prevent diet‐induced insulin resistance. We report that the mitochondrial fusion protein Mitofusin 2 (Mfn2) in BAT is essential for cold‐stimulated thermogenesis, but promotes insulin resistance in obese mice. Mfn2 deletion in mice through Ucp1‐cre ( BAT ‐Mfn2‐ KO ) causes BAT lipohypertrophy and cold intolerance. Surprisingly however, deletion of Mfn2 in mice fed a high fat diet ( HFD ) results in improved insulin sensitivity and resistance to obesity, while impaired cold‐stimulated thermogenesis is maintained. Improvement in insulin sensitivity is associated with a gender‐specific remodeling of BAT mitochondrial function. In females, BAT mitochondria increase their efficiency for ATP ‐synthesizing fat oxidation, whereas in BAT from males, complex I‐driven respiration is decreased and glycolytic capacity is increased. Thus, BAT adaptation to obesity is regulated by Mfn2 and with BAT ‐Mfn2 absent, BAT contribution to prevention of insulin resistance is independent and inversely correlated to whole‐body cold‐stimulated thermogenesis.