Smoking, weight loss, obesity and type 2 diabetes
Have the effects of passive or active smoking been standarised for
their effects upon weight and potentially upon the complications of
obesity and type 2 diabetes? Might the agggressive anti-smoking lobby have
contributed to the costly epidemic in obesity and type 2 diabtes that
Professor Sir George Alberti have warned us about? More importantly do the
effects of smoking on weight provide any clues to how we might manage
obesity and prevent type 2 diabetes more effectively.
In his recent review on obesity Professor Steven Bloom observed that
obesity may be treated by decreasing intake, decreasing absorption of
nutirents or by increasing the basal metabolic rate by exercise or with
thyroxine. Investigators and pharmaceutical companies have concentrated
upon the first two but neglected the third. Professor Bloom considers
increasing basal metabolic rate with thyroxine dangerous because of its
potential to cause thyrotoxicosis. He does not consider other ways in
which the metabolic or rather catabolic rate of of adipose tissue might be
increased. There appear to be several very simple ways in which this might
be accomplished. The first is exercise and the second is smoking. There
may, however, be other simpler, safer and more effective ways of
increasing catabolic rate and inducing controllable weight loss.
The onset of strenuous exercise has been estimated to increase
glycolytic rate as much as 1000 fold (1). ATP and creatine phosphate pools
are depleted within seconds and the resynthesis of ATP depends first upon
the adenylate kinase reaction and then upon glycolysis. Contrary to
popular perceptions glycolysis alone is the preferred means of
replenishing ATP in dynamic cellular circumstances such as those existing
in glial cells, healing wounds, embryos and neoplasms. This is presumably
because far fewer metabolic steps are required to resynthesise ATP by
anaerobic than by aerobic means. Indeed the generation of lactate buys
time by shifting the metabolic burden from muscles to other tissues,
notably liver, heart, brain and kidney. The continued generation of
significant amounts of ATP by glycolysis alone is, however, possible only
so long as the transport of oxygen and nutrient to these other organs
allows oxidative phosphorylation in them to proceed. The Cori, alanine and
ornithine cycles are intimately involved in the shifting of the metabolic
burden from exercising muscles.
The principle difference between ATP resynthesis by glycolysis alone
and that by glyoclysis and oxidative phosphorylation is that it requires
some 19 times more nutrient to resynthesize one mole ATP by glycolysis
alone than by glycolysis and oxidative phosphorylation. This increased
need for nutrient is provided by muscle glycogen stores intially and then
by fatty acids released by the lipolysis of adipose stores to form fatty
acids and glycerol. Beta oxidation of the fatty acids and metabolism of
the glycerol in the glycolytic pathway causes the weight loss in
exercising subjects. In other words the rate of adipose tissue catabolism
appears to be increased by depriving muscles of their ability to
resynthesise ATP by oxidative phosphorylation. It is, therefore, not just
the increase in workload but also the shift in ATP resynthesis from
dependence upon glycolysis and oxidative phosphorylation to dependence
upon glyocolysis alone that accounts for the weight loss.
It is common knowledge that people who smoke are likely to gain
weight when they stop smoking. The weight gain is not caused by a decrease
in exercise. Tobacco smoking is also known to reduce appetite and body
weight. Cessation of smoking leads to hyperphagia and weight gain (2). An
intravenous infusion of nicotine causes hypophagia in rats, that is a
significant decrease in the number of meals and a smaller decrease in the
size of meals. These changes are accompanied by a reduction in weight.
Stopping the nicotine infusion results in hyperphagia by a significant
increase in meal sizes. Body weight normalized.
Nictotine has also been shown to cause a dose-dependent decrease in
oxygen consumption in the brain (3). Nicotine does this by binding to
complex I of the respiratory chain and inhibiting the NADH-Ubiquinone
reductase activity. The nicotine and NADH are competitive on complex I. In
decreasing oxygen consumption by its action on complex I nicotine also
decreases free radical generation. In other words nicotine appears to do
in animals what exercise does in man without the need for an increase in
Smoking also exposes subjects to carbon monoxide. In carbon monoxide
(CO) poisoning, the mortality and morbidity risk do not always correlate
with the level of carboxyhemoglobin (COHb)(4). Recent studies have
established that the mitochondrial cytochrome portion of the respiratory
chain is susceptible to CO toxicity at concentrations traditionally
considered nontoxic. These laboratory findings correlate with subtle
neurologic symptoms detected by psychometric studies in individuals many
days from the time of acute intoxication.
Smoking for weight control is prevalent across many race/ethnic
groups and both genders among adolescents (5). The increase in weight
after the cessation of smoking may, therefore, be due to los of the
inhibition of oxidative phoshorylation by nicotine and/or the carbon
monoxide in inhaled smoke. Conversely the loss of weight apparently caused
by taking up smoking might be due to these effects.
Weight loss also occurs at high altitude and in patients with
obstructive lung disease(6,7). The pathophysiology behind changes in body
composition at extreme altitude is still not fully understood. Proper
acclimatization to altitude and high caloric intake minimizes, but cannot
completely prevent significant weight loss under the influence of
Intermittent hypoxic training has evoked considerable investigative
interest. There are two different strategies: (1) providing hypoxia at
rest with the primary goal being to stimulate altitude acclimatization and
(2) providing hypoxia during exercise, with the primary goal being to
enhance the training stimulus. Each approach has many different possible
application strategies, with the essential variable among them being the
"dose" of hypoxia necessary to achieve the desired effect.
One approach, called living high-training low, has been shown to
improve sea-level endurance performance (8). This strategy combines
altitude acclimatization (2500 m) with low altitude training to ensure
high-quality training. The opposite strategy, living low-training high,
has also been proposed by some investigators. Rather than intensifying the
training stimulus, training at altitude or under hypoxia leads to the
opposite effect and is unlikely to provide any advantage for a well-
trained athlete"(8). But living high (also causes a significant decrease
in food and water intake, and body weight(9). Carbohydrate supplements do
not ameliorate this loss in body weight. The implication is that if living
high-training low can cause weight loss it may do so despite consuming
Although the effects of hypoxia and smoking upon weight loss have
been attributed to a loss of appetite and decreased intake the mechanism
might be the same as that causing pyloric reflux the volume of which
increases as the number of cigarettes smoked each day increases (10).
Excessive amounts of pyloric reflux may in occasions, in our experience,
cause nausea and vomiting(11). Loss of appetite, heart burn from gastro-
oesophageal reflux [which often accompanies large amounts of pyloric
reflux], nausea and vomiting are the sequential symptoms and signs of
obstructed gut or retrograde gastroduodenal peristaltic activity. It has
been proposed, therefore, that the reflux might be due to motor
disturbances caused by the unreversed ATP hydrolysis and its accompanying
fall in pH and rise in [Ca++] in smooth muscle cells, changes that occur
in hypoxic tissues (12).
Might the smoking of cigarettes, possibly enhanced to yield higher
doses of nicotine and carbon monoxide, be used to prevent weight gain or
manage obesity and type 2 diabetes? What then of the increased risk of
cancers and other diseases? The manner in which smoking causes cancer and
these other diseases is not known. One possibility is that smoking might
cause these diseases by precipitating intermittent episodes in which there
is an anaerobic or glyoclytic shift in ATP resynthesis. Weight loss is a
common feature of carcinoma of the lung and often precedes the development
of any clinical evidence of malignant diseases (13). Indeed cachexia, as
the profound weight loss in malignant dieases is called, often develops
before there has been any loss in nutrient intake and before there is
significant tumour burden. It has been proposed, therefore, that whatever
it is that causes cachexia might also be the cause of the cancers(14).
If indeed inhibiting oxidative phosphorylation intermittently
increases the rate of lipolysis and fatty acid catabolism and induces
weight loss, as these data suggest, then smoking enhanced cigarettes and
especially intermittent hypobaric hypoxia are appealing strategies for
controlling weight, preventing type 2 diabetes without increasing
unacceptably the risk of other diseases. Pharmocological means of
achieving the same objectives are not as appealing because the therapeutic
effect could be much more difficult to manage and especially to reverse.
is more difficult to control. Careful monitoring of the subjects during
their hypoxic stress would, however, be advisable to limit the risk of
acute cardiovascular events as it is for exercise. It would, however, be
much easier to manage the risks with hypobaric hypoxia than with exercise
unless conducted in an hypobaric chanmer.
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12. Richard G Fiddian-Green<br>Oesophageal reflux: also a metabolic
disorder?http://bmj.com/cgi/eletters/325/7370/945#26621, 30 Oct 2002
13. Richard G Fiddian-Green Omega-3 fatty acids and brown
fat.http://bmj.com/cgi/eletters/326/7404/1419#35863, 19 Aug 2003
14. Richard G Fiddian-Green A common denominator in cancer and
thromboembolism?Pathophysiological considerations in
http://bmj.com/cgi/eletters/326/7379/37#29394, 4 Feb 2003
Competing interests: No competing interests