External Body Weight Effects on Body Weight in Adults With Grade II and III Obesity

BACKGROUND Obesity is one of the most prevalent and booming health and social problems in recent decades in industrialized societies. Obesity rates in European countries such as the United Kingdom, Germany, France and Spain fluctuate between 23 and 29% in the adult population, according to the World Health Organization (WHO). These values increase to 42.4%, 27% and 31% in the United States, Canada and Australia, respectively, considering data from the last 5 years from the main health agencies of these countries, making it a social and public health problem.

The etiopathogenesis of this condition is multifactorial; the obesogenic characteristics of the environment can influence gene expression conditioning the development of obesity. Increased caloric intake, influenced by high-fat diets (Westerns\' diet), the absence or insufficiency of physical activity and alterations in energy metabolism seem to be the three fundamental factors contributing to the development of obesity. Moreover, these factors seem to play a major role in the development of other metabolic entities such as hypertension, dyslipidemia and insulin resistance or type II diabetes, which, together with central obesity, make up the metabolic syndrome. This clinical entity doubles the risk of coronary and cerebrovascular disease, increases the risk of diabetes fivefold, and increases all-cause mortality by 50%. In parallel to the risk factors listed above, some studies highlight the role of a sedentary lifestyle as a factor independent of physical activity in contributing to the development of metabolic pathology. Not only the absence of low, moderate or high intensity physical activity has been correlated with the development of metabolic syndrome, but also the increase in time spent in sedentary activities, with an odds ratio of 2.38.

These intrinsic and extrinsic factors seem to interact and condition each other, altering homeostatic and physiological processes in obese individuals.

Since its discovery and description in the 1990s by Friedman leptin has been the most important hormonal factor in the regulation and control of caloric intake and metabolism, and consequently of body weight and composition. Its peripheral production at the level of white fat tissue and its hypothalamic effects (decrease in orexic neuronal activity and conditioning of dopaminergic reward circuits) condition the individual\'s response to food, regulating satiety and intake.

Evidence shows that this mechanism is altered in people with obesity where excessive leptin production, due to increased concentrations of fat tissue, and consequently high serum concentrations, condition central and peripheral sensitivity to this hormone, generating, in the long run, lower response efficiency, giving rise to the term "leptin resistance ". This resistance seems to modify the hypothalamic satiety signal, as well as the dopaminergic circuits associated with food intake,predisposing to the appearance or increase of metabolic pathology, especially obesity. This dysregulation in caloric intake appears without alterations in the production and function of ghrelin, a hormone produced in the stomach associated with hunger.

Recent research has proposed a second system of body weight homeostasis associated with the mechanical stimulus of standing upright, coined the term "gravitostat ".

Studies in mice and in humans show promising results in the regulation of body weight and fat percentage by this mechanical system. These investigations have shown significant reductions in both parameters when external weight is added to the study subjects, generating modifications in food intake and caloric expenditure. These adaptations have been tested independently of leptin resistance or the lack of leptin receptors, thus demonstrating the existence of an independent homeostatic regulation pathway. These changes have been shown to be significant only in obese subjects, whereas in normopese subjects, who show greater sensitivity to leptin, the changes produced by the increased load do not appear to be significant. Regarding body recomposition, these studies seem to indicate a maintenance of muscle mass, without experiencing significant losses, as in other contexts of caloric deficit thus prioritizing the loss of white fat tissue (especially visceral) as a mechanism of weight regulation.

Some studies justify this action by the production of fibroblast growth factors (FGF) produced by the osteocytes, specifically, the factor FGF21 associated with the hypothalamic receptor FGFR1c. The triplication in the serum quantities of FGF21 factor, by hepatic expression, in subjects exposed to body weight, seems to justify the increase in fat mobilization and oxidation, as well as the loss of body weight, which, despite the catabolic context, does not affect muscle mass. In any case, the results do not yet seem to be conclusive, since at supraphysiological loads of FGF21 the action of weight loss is mitigated, probably indicating a regulation by the FGFR1c receptor mediated, in part, by one or more other factors. This could be a key factor in the lack of effectiveness in normopese individuals.

Some stuides show how the increased load during the prepubertal period in rats reduces the expression of hormones associated with growth (IGF-1 and GHGH) as a homeostatic mechanism to control sudden weight gain. Similarly, down-regulation of ghrelin receptors at the hypothalamic level is observed, leading to a decrease in caloric intake. Other adaptations that could explain the physiological mechanism of body homeostasis, in this case, during growth.

With respect to analytical parameters, the only clinical trial carried out in humans only shows significant reductions in LDL and leptin; the results are inconclusive for the other parameters studied.

Taking this into consideration, some evidence observed a bidirectional regulation, with increases in body weight and fat mass in subjects with the sudden decrease in load. The lack of follow-up in human studies4 does not allow extrapolation of these results. At the clinical level, this regulation could justify weight and, essentially, fat gain after liposuction interventions6 or other contexts of abrupt weight loss or dietary patterns with aggressive caloric restriction. In this case, both homeostatic systems would influence, on the one hand, the gravitostat would increase food intake and the decrease in adipose tissue and the conditioned reduction in leptin production would decrease anorexic signals, predisposing the subjects to have more frequent and calorically dense intakes.

The results presented by some reserchers are promising in the development of new tools to help patients with obesity, despite this, the short duration of the intervention and the lack of follow-up of the patients, the lack of consistent changes in the analytical analysis, the performance only in young and moderately obese patients, as well as the high demand of the intervention protocol and the sudden gain in body weight after the intervention (in basic studies) make further research necessary to prove the applicability, usefulness and effectiveness of the gravitostat as a therapeutic tool, as well as the high demands of the intervention protocol and the sudden gain of body weight after the intervention (in basic studies) make it necessary to carry out further research to prove the applicability, usefulness and effectiveness of the gravitostat as a therapeutic tool in patients with obesity.

For this reason, the present doctoral thesis proposes an intrasubject controlled study for a period of 12 weeks (4 control, 4 intervention and 4 follow-up) in patients with grade II and III obesity. During the intervention period, the participants will be exposed to an external load, by means of a weighted vest of 10% of their body weight, for a minimum of 8 hours per day for 4 weeks. In the first phase of the study, participants will be followed without changes in their lifestyle as a control. During the intervention, they will be instructed to perform their usual activities with the vest, without further alterations in their lifestyle.

For this study, accepting an alpha risk of 0.05 and a beta risk of less than 0.2 in a unilateral contrast, 24 patients are required to detect a difference equal to or greater than 0.15 unit. A common standard deviation of 1.4 and a correlation between the first and second measurement of 0.99 (according to literature) is assumed. A loss rate of 10% is assumed. Patients will be recruited from the endocrinology service of the Hospital Universitario Parc Taulí.