The efficacy of reverse-electron-transport
therapy of
obesity should be promoted by agents which up-regulate hepatocyte
enzymes that are potentially rate-limiting for mitochondrial
fatty acid oxidation and electron shuttles. Peroxisome proliferator drugs, including the
fibrates used to treat
hyperlipidemia, may be useful in this regard, as they induce malic
enzyme, the mitochondrial
glycerol-3-phosphate dehydrogenase, and
carnitine palmitoyl
transferase I in rodent hepatocytes. An agent of this class,
MEDICA 16, has the additional property of potently inhibiting both
citrate lyase and
acetyl-CoA carboxylase. As a result, methyl-substituted diacarboxylic
acids (
MEDICA) 16 can be expected to disinhibit hepatic
fatty acid oxidation while up-regulating electron shuttle mechanisms, and thus should stimulate reverse electron transport. This may explain the remarkable 40% increase in basal metabolic rate observed in normal rats ingesting MEDICA 16--an effect not associated with any compensatory increase in food intake. Relative to controls, the MEDICA 16-treated rats achieved a 50% reduction in body fat and a modest increase in lean mass, such that weight and growth were not changed. In other rodent strains,
MEDICA 16 has prevented
obesity diabetes and
atherogenesis. However, whether
MEDICA 16 and other peroxisome proliferator drugs will have clinical utility in reverse-electron-transport
therapy may hinge on their ability to induce key
enzymes in human hepatocytes; cell culture studies to evaluate this are required.