Mitochondrial uncoupler SHC517 reverses obesity in mice without affecting food intake.

Affiliation

Chen SY(1), Beretta M(1), Alexopoulos SJ(1), Shah DP(1), Olzomer EM(1), Hargett SR(2), Childress ES(3), Salamoun JM(3), Aleksovska I(1), Roseblade A(4), Cranfield C(5), Rawling T(4), Quinlan KGR(1), Morris MJ(6), Tucker SP(7), Santos WL(8), Hoehn KL(9).
Author information:
(1)School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
(2)Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
(3)Department of Chemistry and Virginia Tech Centre for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
(4)School of Mathematical and Physical Sciences, University of Technology, Sydney, NSW 2007, Australia.
(5)School of Life Sciences, University of Technology, Sydney, NSW 2007, Australia.
(6)School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
(7)Continuum Biosciences Pty Ltd., Sydney, NSW, 2035, Australia.
(8)Department of Chemistry and Virginia Tech Centre for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA; Continuum Biosciences Pty Ltd., Sydney, NSW, 2035, Australia. Electronic address: [Email]
(9)School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.; Continuum Biosciences Pty Ltd., Sydney, NSW, 2035, Australia. Electronic address: [Email]

Abstract

AIMS: Mitochondrial uncouplers decrease caloric efficiency and have potential therapeutic benefits for the treatment of obesity and related metabolic disorders. Herein we investigate the metabolic and physiologic effects of a recently identified small molecule mitochondrial uncoupler named SHC517 in a mouse model of diet-induced obesity. METHODS: SHC517 was administered as an admixture in food. The effect of SHC517 on in vivo energy expenditure and respiratory quotient was determined by indirect calorimetry. A dose-finding obesity prevention study was performed by starting SHC517 treatment concomitant with high fat diet for a period of 12 days. An obesity reversal study was performed by feeding mice western diet for 4 weeks prior to SHC517 treatment for 7 weeks. Biochemical assays were used to determine changes in glucose, insulin, triglycerides, and cholesterol. SHC517 concentrations were determined by mass spectrometry. RESULTS: SHC517 increased lipid oxidation without affecting body temperature. SHC517 prevented diet-induced obesity when administered at 0.05% and 0.1% w/w in high fat diet and reversed established obesity when tested at the 0.05% dose. In the obesity reversal model, SHC517 restored adiposity to levels similar to chow-fed control mice without affecting food intake or lean body mass. SHC517 improved glucose tolerance and fasting glucose levels when administered in both the obesity prevention and obesity reversal modes. CONCLUSIONS: SHC517 is a mitochondrial uncoupler with potent anti-obesity and insulin sensitizing effects in mice. SHC517 reversed obesity without altering food intake or compromising lean mass, effects that are highly sought-after in anti-obesity therapeutics.