Caloric excess alone cannot explain the current epidemics of obesity and diabetes, and the obese patient cannot be solely accountable for their obesity. These metabolic diseases represent a failure in overall metabolic regulation, and an inability of the scientific community to solve this major problem. Treating obesity as a disease will help lead to improvement in the health of our population and the development of useful drugs for the prevention or treatment of obesity.
However, excess weight does not afflict all individuals. In a Swedish study, documenting an increased incidence of obesity from 9.4% in 1990 to 17.5% in 2004, thirty five percent (5242) of the adults were found to be non-gainers (1
). The chances of not gaining weight in this population correlated with older age, being female, diagnosis of diabetes, and lack of snuff use. A recent study in the US also found that although overweight and obesity continue to increase, there are still more than 30% of adults on average that are not overweight (2
). In the National Health and Nutrition Examination Survey (NHANES) cohort, race/ethnicity, being female and older age correlated with not being overweight. The continued presence of subjects with apparently normal body weight regulation is useful in our quest to identify potential causes of disorders of metabolic regulation. Comparing individuals who gain weight with those who do not could help to validate or refute our hypothesis.
Dynamic changes occur in the body in response to food (3
), discussed below, sleep, exercise (4
), diabetes and normal living that influence energy requirements, energy expenditure and choice of fuel (6
). Our metabolism responds by using fuels and fuel stores to provide exactly enough ATP for all of the work of each tissue, and not any more
, via a highly sensitive, regulated and responsive process that is mainly mitochondrial (8
). To achieve the goal of providing exactly the needed amount of ATP under all circumstances, adequate fuel reserves are needed, in the form of glycogen and fat, although determinants of the size of these reserves is not fully understood (9
). Nevertheless, glycogen stores and protein pools are fixed and limited, while fat stores are expandable but tend to remain stable over long periods of time, and to return to previously defended levels following either decreases or increases in their mass. In general, excursions in the reserve pool sizes occur continuously during each day, within fixed limits that vary little. Thus, depletion in glycogen and lipid stores occurs with exercise and between meals (10
). Although it is possible to experience great alterations in these pools, during starvation or periods of excess consumption, this only occurs rarely. Abundant evidence exists to indicate that periods of over- or under-consumption are followed by periods of restoration of the previous status quo
, hence the difficulty in long term maintenance of weight loss following successful diets (11
). In the Vermont prison study (13
) where lean individuals were recruited to increase their body weight by 20%, not all volunteers were able to gain weight. However, the lean volunteers that gained weight required an average of nearly 7000 calories/day and most rapidly returned to their original weight upon termination of the study.
An important contributor to energy balance is clearly food intake. In mammals, hunger initiates food-seeking behavior followed by eating that is terminated in response to satiety signals (14
). Recent research has begun to clarify the mechanisms involved in regulating hunger, food seeking and satiety. Even without knowledge of the molecular mechanisms involved, normal body weight has been maintained in most individuals, through most of human history. Likewise, obesity among animals is rare. The contribution of this important component of the energy balance equation has been less explored, whereas, energy intake and physical activity are readily determined and almost exclusively considered (16
The notion that personal self-discipline is the key to body weight regulation, is not supported by compelling evidence, and is inconsistent with regulation of other major systems such as blood sugar (not usually dependent on controlling sugar intake) (18
), body temperature (responsive to, but rarely regulated by, ambient temperature) (19
) or electrolyte balance (responsive to but not normally controlled by salt or water intake) (20
) although rare extremes can override each regulated system such as massive glucose loading, salt or water intake or prolonged exposure to extreme temperatures.
In this article, a model will be presented, based on changes in circulating redox, to provide an explanation for food or environment-induced alterations in body weight, through modifications in the regulation of energy efficiency, appetite or satiety. This model does not violate the laws of thermodynamics, but focuses rather on the non-volitional aspects of body weight regulation. Volitional behaviors are caused by information that has been processed by the central nervous system (such as choice of food), whereas non-volitional behaviors are mainly determined by chemical information and information in the nervous system, that is not adjusted (such as hunger).