Fat utilization and arterial hypertension in overweight/obese subjects

According to the current demographic projections it is expected an increase in the cardiovascular diseases (CVDs) incidence; therefore more sensitive predictors of the risk of the CVDs are needed. In this regard, the Respiratory Quotient (RQ), the ratio between carbon dioxide production and oxygen consumption, reflecting the utilization of the nutrients in a subject [1] may have an important role. In fact, it is well known that after an overnight fast, a subject receiving a balanced diet, that meets the energy requirements for the weight maintenance, burns fat as main substrate; as consequence the value of RQ, usually, results close to 0.85 [1, 2]. It has been also shown that subjects tending to burn more glucose, but less fat, have an increased value of RQ [3, 4]. Moreover an high RQ is associated with an high rate of subsequent weight gain [2] and with an increased Carotid Intima-Media Thickness (CIMT), a well known predictor of cardiovascular events [5], in overweight/obese individuals of both sexes [6].

At this time, whether RQ is also associated with the cardiovascular risk factors is not fully clarified, therefore aim of this study was to investigate on the relationship between the RQ and the cardiovascular isk factors in individuals of both sexes.

In our cross-sectional study, we consecutively enrolled 223 individuals among a total of 250 evaluated from January 2011 to September 2012, all undergoing the nutritional screening tests including an Indirect Calorimetry for the RQ and Resting Metabolic Rate (RMR) measurement, at our Clinical Nutrition Unit. The population included both gender, having more than 45 years, with a wide range of body mass index (BMI), and participating in the study on the adherence to Mediterranean Diet and body composition (approved by local ethical committee, projects codes 2011.4; 2013-1/CE ). We enrolled subjects who were weight stable in the four weeks preceding the screening tests, who were following a nutritionally balanced diet meeting energy requirements (i.e.: a solid-food diet that supplied 50% of the calories as carbohydrate, 30% as fat, and 20% as protein), as resulted from the nutritional intake assessment.

According to the medical history, physical examination and blood screening tests, we enrolled apparently healthy individuals. We excluded individuals having clinical evidence of debilitating diseases, (cancer, severe renal failure, sever liver insufficiency, chronic obstructive pulmonary disease), thyroid dysfunction, and cardiovascular disease (myocardial infarction, stroke). We excluded also subjects taking antiobesity medications, psychotropic drugs and chronotropic agents. Furthermore, we excluded individuals following who practiced a regular physical exercise program, who had recently changed the use of tobacco (in the previous four months) and smokers. To avoid the presence of individuals with alterations of the pulmonary ventilation we excluded from the statistical analysis, those having an RQ value over 1.00 or under 0.70 (normal range of RQ: 1.00 to 0.70) [7‐9]. The following criteria were used to define the distinct cardiovascular risk factors; diabetes: fasting blood glucose ≥126 mg/dl or antidiabetic treatment; hyperlipidemia: total cholesterol >200 mg/dl and/or triglycerides >200 mg/dl or lipid lowering drugs use; hyperuricemia: serum urate concentration > 7 mg/dl or urate lowering drugs use; hypertension: systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg or antihypertensive treatment; overweight: BMI ≥ 25 <30 Kg/m²; obesity: body mass index ≥30 kg/m²; smoking: current smokers or past smokers (at least before the previous four months) [10, 11]. Furthermore, if at least 3 of the NCEP criteria were present [12], the subjects were identified as having the Metabolic Syndrome (MetS).

All tests were performed after a 12 h overnight fasting. Before tests, we gave no particular suggestions on the menu for the meal, but we requested that the dinner before the experiments would have to include types of foods and drinks usually consumed. Indeed they have no caffeinated beverages between their evening meal and the conclusion of the tests on the examination’s morning. Written informed consent was obtained. The investigation conforms to the principles outlined in the Declaration of Helsinki.

In this study we enrolled 133 female and 90 male with a mean age of 53 ± 12 ys with complete data. There were no differences in RQ value between gender (p= 0,26), therefore all the analyses were performed in the overall population. At univariate analysis we found a positive relation (with a p < 0,1) between RQ and RMR, glucose, triglyceride, SBP and DBP (Table 1). The multivariate regression analysis confirmed that SBP only was correlated to RQ (Table 2, model I). This correlation was confirmed after the presence of the MetS was included in this analysis (Table 2, model II, data not shown). Table 3 shows the characteristics of the population according to RQ quartiles. A significant difference in the prevalence of hypertension was showed between groups, with the highest prevalence in the IV quartile (Figure 1; Table 3). The ANOVA test confirmed that SBP was the only factors significatively different between quartiles (I vs IV ; II vs IV quartile) (Table 3).

The main finding of this study was the direct correlation between RQ and SBP and RMR (Table 1) and the high prevalence of hypertension among individuals with the highest RQ (Table 3, Figure 1). After the adjustments for the confounding factors, the RQ remains correlated to SBP.

In particular, subjects with an RQ higher than 0,90 (IV RQ quartile) had an high prevalence of hypertension (47%) unless their metabolic risk profile was similar to that of the other quartiles (i.e. 40% male, mean age ~ 53 ys and mean BMI ~ 32 Kg/m²; tab 3).

This is a novel finding, never investigated to date and very intriguing. It is well known that RQ is associated with a high rate of subsequent weight gain [2, 17]. Indeed the obesity rarely exists as an isolated condition, but it is frequently associated with hypertension [18]. Therefore one possible explanation of the link between the high RQ and hypertension may be a high BMI among the subjects with high RQ, [2, 19], but in our study the similar BMI among quartiles would reject this explanation. Thus, we infer the presence of other mechanisms like the activation of the Renin Angiotensin System (RAS)[19‐27], that results to be associated to the mechanisms of lipid oxidation. Several experiments on mice lacking the Angiotensin II receptor showed, in fact, an increase in the fat utilization and a parallel reduction of the fat mass [28], corroborating the association between hypertension and the index of low fat utilization in our investigation. In addition, a study has shown that in mice with myocardial hypertrophy, the genes associated with the transport and breaking down of the fatty acids are less active than in normal mice [29]. Thus, it is possible to theorize that the failure in the fat utilization may be a predictor of the development of CVDs in individuals with hypertension [29].

It is well accepted that the cardiovascular risk factors are excellent predictors of the CVDs and that their presence may lead to the abnormalities in the structure and function of the cardiovascular system, by a number of complex mechanisms [11, 30‐34].

We believe that, if confirmed by further investigations, also high RQ may have a role in the clinical practice because it has the potential to identify the effect of the modification in the nutrients utilization on the vascular system. Understanding this concept may give a new view on the mechanisms of the organ damage and their prevention and treatment. Consequently, the RQ measurement may contribute to important changes in the prediction of cardiovascular disease. RQ evaluation probably may identify the individuals needing special therapeutic strategies, like individuals with hypertension. However, because our findings were obtained from cross-sectional data, this hypothetical clinical impact can be emphasized but it is not definitely proved. The RQ measurement offers the potential of a fast analyses using a low cost instrument that is easy to use after a short period of training. However, due to the complexity of the various ways in which different diet may be metabolized, actually there is the need to perform the experiments in the same controlled conditions in all individuals (for example, the same diet).