Suppression of superoxide/hydrogen peroxide production at mitochondrial site I decreases fat accumulation, improves glucose tolerance and normalizes fasting insulin concentration in mice fed a high-fat diet.

We developed S1QEL1.719, a novel bioavailable S1QEL (suppressor of site I electron leak). S1QEL1.719 prevented superoxide/hydrogen peroxide production at site I of mitochondrial complex I in vitro. The free concentration giving half-maximal suppression (IC) was 52 nM. Even at 50-fold higher concentrations S1QEL1.719 did not inhibit superoxide/hydrogen peroxide production from other sites. The IC for inhibition of complex I electron flow was 500-fold higher than the IC for suppression of superoxide/hydrogen peroxide production from site I. S1QEL1.719 was used to test the metabolic effects of suppressing superoxide/hydrogen peroxide production from site Iin vivo. C57BL/6J male mice fed a high-fat chow for one, two or eight weeks had increased body fat, decreased glucose tolerance, and increased fasting insulin concentrations, classic symptoms of metabolic syndrome. Daily prophylactic or therapeutic oral treatment of high-fat-fed animals with S1QEL1.719 decreased fat accumulation, strongly protected against decreased glucose tolerance and prevented or reversed the increase in fasting insulin level. Free exposures in plasma and liver at C were 1-4 fold the IC for suppression of superoxide/hydrogen peroxide production at site I and substantially below levels that inhibit electron flow through complex I. These results show that the production of superoxide/hydrogen peroxide from mitochondrial site Iin vivo is necessary for the induction and maintenance of glucose intolerance caused by a high-fat diet in mice. They raise the possibility that oral administration of S1QELs may be beneficial in metabolic syndrome.