Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice

Stephanie J. Alexopoulos, Sing-Young Chen, Amanda E. Brandon, Joseph M. Salamoun, Frances L. Byrne, Christopher J. Garcia, Martina Beretta, Ellen M. Olzomer, Divya P. Shah, Ashleigh M. Philp, Stefan R. Hargett, Robert T. Lawrence, Brendan Lee, James Sligar, Pascal Carrive, Simon P. Tucker, Andrew Philp, Carolin Lackner, Nigel Turner, Gregory J. Cooney, Webster L. Santos () and Kyle L. Hoehn ()
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Stephanie J. Alexopoulos: University of New South Wales
Sing-Young Chen: University of New South Wales
Amanda E. Brandon: University of Sydney
Joseph M. Salamoun: Virginia Tech
Frances L. Byrne: University of New South Wales
Christopher J. Garcia: Virginia Tech
Martina Beretta: University of New South Wales
Ellen M. Olzomer: University of New South Wales
Divya P. Shah: University of New South Wales
Ashleigh M. Philp: Garvan Institute of Medical Research
Stefan R. Hargett: University of Virginia
Robert T. Lawrence: University of Virginia
Brendan Lee: University of New South Wales
James Sligar: Garvan Institute of Medical Research
Pascal Carrive: University of New South Wales
Simon P. Tucker: Continuum Biosciences Pty Ltd.
Andrew Philp: Garvan Institute of Medical Research
Carolin Lackner: Medical University of Graz
Nigel Turner: University of New South Wales
Gregory J. Cooney: University of Sydney
Webster L. Santos: Virginia Tech
Kyle L. Hoehn: University of New South Wales

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.

Date: 2020
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DOI: 10.1038/s41467-020-16298-2

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