Colditz1 reported an inverse association between alcohol consumption and body mass index (BMI) in women, despite an increase in energy intake due to the alcohol. In response to this study, Lands and Zakhari2 put forward a hypothesis to explain the apparent contradiction. It appears, at least in women, that carbon energy from alcohol plays no apparent contribution towards body weight accumulation, presumably because the energy is inefficiently utilised. This would suggest that alcohol could remain outside of the regulatory mechanisms that attempt to match energy intake to energy output and maintain body weight within narrow physical limits. In fact studies have shown a lack of weight gain when subjects have been fed alcohol in studies looking at the effects of alcohol on other physiological parameters such as blood lipids and the toxic effects of ethanol. A closer look at the metabolism of alcohol would therefore be justified in order to better elucidate the possible reason for anti-obesogenic effects.
Ethanol can be metabolised by three different enzyme systems. The cytosolic route for the metabolism of ethanol is via conversion to acetaldehyde using the enzyme alcohol dehydrogenase. This step causes the generation of 3 ATP in the form of NADH. The acetaldehyde is then metabolised to acetate using the enzyme aldehyde dehydrogenase and finally to carbon dioxide via the citric acid cycle. This is the normal metabolic route for ethanol and yields roughly 16 ATP per mol of ethanol. However, other metabolic routes exist. For example ethanol can be oxidised to acetaldehyde in the in the endoplasmic reticulum in a reaction catalysed by cytochrome P450-II-eI or in the peroxisome in a reaction catalysed by peroxisomal catalase. Both of these pathways represent a loss of reducing equivalents (rather than a gain as seen with cytosolic alcohol dehydrogenase) and as a result the first step consumes an equivalent of 3 ATP rather than producing 3 ATP
One suggestion by Lands and Zakhari was that ethanol may participate in futile cycling, which may occur at a faster rate in women than men. Rather than the energy from the ethanol being utilised for the production of ATP, futile cycles can consume ATP with the dissipation of the energy as heat. One such cycle could be the oxidation of ethanol to acetaldehyde that requires the input of 3 ATP (such as in the peroxisome or endoplasmic reticulum), followed by the reduction of acetaldehyde back to alcohol which requires an input of 3 ATP. Such a futile cycle could therefore result in the net loss of 6 ATP, and a few turns of the cycle could therefore negate the extra caloric intake of the alcohol. Correcting for body size, the area under the curve for the blood alcohol in women is greater than for men, which might suggest futile cycling occurs at a higher rate in women than men. However, there is another explanation that is perhaps more simple in its reasoning.
The inverse association between alcohol consumption and body mass index did increase total calorie intake from a mean intake of 1500 to 1682 kcal per day with an increase from 25.0 to 49.9 grams per day alcohol, and further to 2011 kcal per day with ≥50 grams per day alcohol. However some of this additional intake was offset by a reduction in carbohydrates, particularly sucrose. Sucrose is a disaccharide consisting of one molecule of glucose and one molecule of fructose, the latter being strongly implicated in the development of insulin resistance. Reducing sucrose intake may therefore have beneficial effects on insulin sensitivity in these individuals and protect them from body weight gain by ensuring the glucose disposal in skeletal muscle is not reduced in efficiency. Efficient storage of glucose in skeletal muscle would then allow glycogen replenishment, which would facilitate physical activity and allow the oxidation of energy without the need for excessive partitioning to adipose tissue.
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