Abstract

In a recent pilot study, joint administration of pyruvate, hydroxycitrate (HCA), and carnitine to obese subjects was associated with a remarkable rate of body-fat loss and thermogenesis, strongly suggestive of uncoupled fatty-acid oxidation. Hepatocytes possess an uncoupling mechanism – reverse electron transport – that enables fasting ketogenesis to proceed independent of respiratory control. Electrons entering the respiratory chain at the coenzyme Q10 (CoQ) level via FAD-dependent acyl coA dehydrogenase, can be driven `up' the chain by the electrochemical proton gradient to reduce NAD⁺; if these electrons are then shuttled to the cytoplasm, returning to the respiratory chain at the CoQ level, the net result is heat generation at the expense of the proton gradient, enabling the uncoupled flow of electrons to oxygen. Pyruvate's bariatric utility may stem from its ability to catalyze the rapid transport of high-energy electrons from mitochondria to the cytoplasm, thus stimulating electron shuttle mechanisms. By enabling rapid mitochondrial uptake of fatty acids and thus disinhibiting hepatocyte ketogenesis, HCA/carnitine should initiate reverse electron transport: concurrent amplification of electron shuttle mechanisms by pyruvate can be expected to accelerate this reverse electron transport, thereby decreasing the electrochemical proton gradient. As a result, hepatocytes may be able to convert fatty acids to CO₂and heat with little net generation of ATP. These considerations suggest that it may be feasible to render hepatocytes functionally equivalent to activated brown fat, such that stored fat can be selectively oxidized in the absence of caloric restriction. Other measures which enhance the efficiency of hepatocyte electron shuttle mechanisms may increase the efficacy of this strategy.

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