Earlier human studies have shown that chronic, continuous exposure to CO2 at 0.5-3% inspired concentrations for more than one month alters pH homeostasis and raises body CO2 storage [15,16,17], as does higher atmospheric CO2 concentration in the terrestrial biosphere. Mostly during CO2 exposure, ion profile changes in red blood cells (RBCs); hemoglobin-O2(HbO2) affinity increases with RBCs oxidation; the adrenal cortical response is activated, as measured by increased blood corticosteroid level and lymphopenia; and the partial pressure of CO2 in the arterial blood (PaCO2) rises as CO2 is stored as HCO3- in the extracellular fluid (ECF), and as CO3-2 in bone, at the expense of buffer protein and phosphate in the lean body mass (LBM) [15,16,17]. Continuous CO2 inhalation is commonly thought to be tolerated at 3% inspired concentrations for at least one month, and 4% inspired concentrations for over a week. The effects produced seem reversible, decrements in performance or in normal physical activity may not happen at these concentrations .
Thus, it should be noted not only that CO2 levels in poorly ventilated spaces can be found even higher than this range of 3-4%, but also that humans may be chronically exposed to intermittent, not continuous CO2 inhalation, a condition that by inducing mildly increased endogenous CO2 may cause pathological adaptations. In fact, studies show that because of the greater concentration of buffer base, acclimatization to CO2 results in desensitization of dyspnea and in changes of set point for central respiratory controllers such that, on return to “outdoor” air breathing, ventilation may decline below control values even in individuals intermittently exposed to CO2 increase for 13 hours per day [15,19]. Furthermore, chronic exposure to intermittent, mild ambient CO2 increase results also in changes of set point for central feeding controllers which may lead to obesity. In fact, it has been shown that during chronic inhalation of CO2 at 1.5% inspired concentration for more than one month, food intake decreases significantly, by ~30%, but body weight does not change . On return to “normal” air breathing, food intake rises and body weight is gained . Actually, stress is a well known inducing factor of both transient and chronic loss of appetite or overeating .
Inhaled CO2 induces the same physiological effects as does metabolically produced CO2, the key chemical messenger gas in the linking of respiration, systemic circulation, and local vascular response, to body’metabolic demands both at rest and exercise . Increased CO2 needs to be removed as quickly as possible because its lowering of blood pH can denature enzymes. A major portion of the physicochemical defenses of neutrality by the buffer systems of the whole body takes place in muscle and bone . Protein from muscle can be released to bind with acids in the blood. This can contribute to LBM loss. Calcium and phosphorus in bones can bind to acidic substances to neutralize them, thereby contributing to bone mineral loss. Suggestively, greater CO2 stores matching reduced bone mineralization characterizes Osteoporosis, a major public health problem whose risks for osteopenia, and non-spine fractures have been shown to be significantly higher for people with higher percentage of body fat . Increased CO2 storage is present also in obstructive sleep apnea (OSA), a prevalent disorder characterized by gradual PaCO2 elevations, associated with major nocturnal hemoglobin desaturation, higher HbO2 affinity, and repetitive episodes of partial or complete upper airway obstruction . Most individuals with OSA have metabolic syndrome (MetS), a common, condition consisting of a constellation of metabolic risk factors for atherosclerosis and cardiovascular disease (ACVD) associated with abdominal obesity, namely, increased plasma glucose values, higher blood pressure levels, higher triglycerides levels, and lower high-density lipoprotein cholesterol (HDL-C) levels . The MetS presents abnormal intracellular ion profile in RBCs, and sustained cortisol levels [28,29] as does exposure to CO2 at 1.5% inspired concentrations for more than one month [17,30].
As stated, CO2 acclimatization to chronic exposure to CO2 at 1.5% inspired concentration results in greater concentrations of buffer base, with the consequent reduction of minute volume ventilation, forced vital capacity, and PaO2 . Beyond that, food intake rises, and body weight is gained, on return to “normal” air breathing , as compared to exposure to moderately increased ambient CO2 in which lower (~30%) food intake, without body weight changes, matches increased ventilation . Accordingly, adaptations to chronic exposure to intermittent, mildly increased ambient CO2 may result in lower O2 uptake, reduced metabolic rate, and excess feeding, as it occurs in MetS. Food intake may rise because mildly increased endogenous CO2 enhances the expression of TNF-α and IL-6, which further glucocorticoids release, with consequent higher expression of the oroxigenic NPY. Hence, CO2 does not only determine the need for alveolar ventilation, but it is also the “stress” ruler of both transient and chronic overeating or loss of appetite , to normalize/oppose pH changes.
With moderately increased endogenous CO2, as soon as RBCs oxidation threatens pH homeostasis, TNF-α may induce the coincident appearance of MetS ACVD risk factors  to restore the lost balance. In essence, TNF-α inhibits auto-phosphorylation of tyrosine residues of insulin receptors and promotes serine phosphorylation of insulin receptor substrate-1; this, in turn, triggers serine phosphorylation of insulin receptors in adipocytes, prevents the normal tyrosine phosphorylation, and interferes with transduction of the insulin signal. Hence, insulin resistance results in Akt (protein-kinase-B) inhibition and subsequent
inhibition of NO-synthase (NOS) . Accordingly, TNF-α promotes adaptations such as insulin resistance-hyperglycemia, NOS inhibition, reoccurrence of glycolysis, and decreased O2 uptake whose joined effects overall reduce RBCs oxidation and maintain blood O2 release. Inflammation is, indeed, a fundamental survival mechanism but it is dangerous when its transient, physiological adaptations are converted to a long-lasting, pathological state. Potential causes for steady CRH activation and glucocorticoids release include environmental stresses, which as explained, result in higher HbO2 affinity and mildly increased endogenous CO2 . Ominously, as atmospheric CO2 increases, Global Warming may threaten human health. Thus, the following reviews the mechanism through which intermittent exposure to mildly increased ambient CO2 may lead to MetS and/or osteoporosis.
Overall, during exposure to mildly raised ambient CO2 levels, slow adaptive processes in electrolyte exchange and pH regulation results in higher PaCO2 due to reduction in forced vital capacity. Presumably, food intake decreases much to reduce PaCO2, and body weight does not change  due to the water retention required to hydrate and store the inhaled CO2 as ECF HCO3-, and as bone CO3-2. Basically, with CO2 acclimatization, compensatory processes for respiratory acidosis result in metabolic alkalosis  which, on return to “normal” air breathing, constantly triggers glucocorticoids release. In fact, with abdominal accumulation, a lower compliance of the respiratory system causes the decline of forced vital capacity, minute volume ventilation, and PaO2 , with ensuing chronic lactate accumulation. This, by raising HbO2 affinity, results in higher PaCO2, and RBCs oxidation with TNF-α and IL-6 release from phagocytic cells. Besides, the relentless LBM loss coupled to the body fat gain arisen during exposure to CO2 implies not only that HbO2 affinity rises, and O2 release falls because the loss of body phosphate impairs 2-3DPG synthesis , but also that adipocytes release TNF-α and IL-6. Presumably, on return to normal air breathing, food intake rises, and insulin resistance persists until an ampler number of adipocytes release enough leptin which lowers bone formation and food intake without respiratory depression. In few words, with chronic exposure to intermittent, mildly increased CO2, body buffers loss sets a vicious cycle in which the more CO2 is inhaled and stored, the more food is eaten to raise PaCO2, foster ventilation, and save pH homeostasis.
With time, however, steady activation of the stress response leads to the loss of bone and muscle which, due to parallel abdominal fat accumulation, causes shallow, rapid breathing (not conscious tachypnea), turns up the set point for central feeding controllers, and induces overeating with its chronic pathological consequences, namely, MetS and osteoporosis.
Chronic exposure to CO2 at 0.5-3% inspired concentrations alters pH homeostasis and fosters body CO2 storage in humans [15,16, 17], as does increased atmospheric CO2 in the terrestrial biosphere. Increased CO2 stores in bone are present in osteoporosis, whose risks for osteopenia, and non-spine fractures have been shown to be significantly higher for subjects with higher percentage body fat, independent of body weight . Fat accumulation and increased CO2 stores characterize also MetS which, despite lifestyle changes and the use of pharmacologic approaches to lower plasma cholesterol levels, continues to be, and it is expected to become the major cause of disability and death in the world by 2020 . So far, it seems undeniable that pH homeostasis, the linkage between breathing and feeding via CO2 economy, discloses the stress of Global Warming on human health.