Improvements in vascular health by a low-fat diet, but not a high-fat diet, are mediated by changes in adipocyte biology

Obesity is a key risk factor for the development of coronary heart disease (CHD). Patients who are obese often exhibit increased LDL cholesterol and triglyceride concentrations, reduced HDL cholesterol concentrations, and increased blood pressure [1]. Carrying this extra weight also leads to abnormal endothelial function marked by reduced vasodilation to an increased blood flow (endothelium-dependent flow-mediated dilation; FMD) [2]. Endothelial dysfunction is an early hallmark and prognostic indicator of future CHD, and most vascular disease risk factors are associated with reduced FMD [3].

Weight loss has been shown to improve plasma lipids, blood pressure, and endothelial function in obese subjects [4]. However, some controversy exists as to the optimal macronutrient composition of the weight loss diet to improve vascular health. For instance, in a study by Phillips et al. [5], 6 weeks of a calorie-restricted high-fat (HF), low carbohydrate diet (60% of kcal as fat, 25% kcal as saturated fat) impaired FMD, while an isocaloric low-fat diet (LF) (25% of kcal as fat, 7% kcal as saturated fat) was shown to improve FMD. In contrast, Volek et al. [5], report increases in FMD with a HF diet, and decreases with a LF diet, while Keogh et al. [6, 7] demonstrate no effect of either diet on vascular endothelial function during weight loss. In view of these contradictory findings, more work in this area is evidently required before solid conclusions can be reached.

The mechanisms that link weight loss to improvements in endothelial function are still unclear. However, recent evidence suggests that adipose tissue physiology (i.e. adipokine profile and visceral adiposity) may play a role. Adiponectin is a fat cell-derived hormone that protects the endothelium by decreasing oxidative stress [8]. This hormone has been shown to increase with weight loss and is inversely related to waist circumference (indirect measure of visceral fat mass) [9]. Leptin and resistin, in contrast, are pro-atherogenic hormones derived from adipocytes that have been shown to cause endothelial dysfunction by promoting oxidative stress [10, 11]. Leptin and resistin decrease with weight loss and are positively correlated to visceral fat mass [9]. As such, weight loss interventions that reduce visceral fat mass generally result in increased plasma adiponectin, and decreased leptin and resistin. This favorable adipokine profile has a protective effect on the vascular endothelium, which results in increased FMD [12]. An important question that has yet to be tested is whether the enhancements in FMD that occur with either LF or HF diets during weight loss, are mediated in part by improvements in adipocyte parameters.

Accordingly, the objective of this study was to examine the intermediate role of adipocyte parameters in mediating the effects of HF versus LF diets on vascular health during weight loss.

This study is the first to show that improvements in endothelial function by LF diets during weight loss may be mediated in part by changes in adipose tissue biology. More specifically, we show here that improved brachial artery FMD during LF diets is associated with decreased visceral fat mass and improved adipokine profile (i.e. increased plasma adiponectin, and decreased leptin and resistin). These benefits of LF diets on vascular health were paralleled by improvements in several CHD risk factors. In contrast, weight loss by HF diets, were shown to impair FMD, with no concomitant improvement in parameters of adipocyte biology.

Brachial artery FMD is a noninvasive index of endothelial function [15], and is an independent predictor of cardiovascular events [16]. Diet-induced weight loss has been shown to be an effective strategy to help obese individuals increase FMD, however, the optimal macronutrient composition of the diet remains unknown. While some studies indicate that LF diets may benefit vascular health more than HF diets [17, 18], other studies show that HF diets are superior [5]. In the present study, we demonstrate that weight loss resulting from an LF diet improves FMD, while weight loss resulting from a HF diet impairs FMD. Although these findings are similar to that of Phillips et al. [17], they are in contrast to the results of Keogh et al. [6, 7] and Volek et al. [5]. The reason for these conflicting data remain unclear since trial design in each study was similar with respect to sample population, trial length, and dietary macronutrient distribution. One key difference, however, is the dietary protocols used. In our study, as well as in the study by Phillips et al. [17], all meals were provided to the subjects so that macronutrient distribution would be carefully controlled. In the trials by Keogh et al. [6, 7] and Volek et al. [5], subjects were instructed how to consume the HF or LF diets by a dietician, and dietary adherence was assessed by means of food records. Since macronutrient distribution was not carefully controlled in the studies by Keogh et al. [6, 7] and Volek et al. [5], it is possible that the subjects were consuming something closer to a standard diet (i.e. 50% kcal as carbohydrate, 15% kcal as protein, and 35% kcal as fat), rather than a HF or LF diet. As such, the lack of standardization of the feeding protocols may partly explain these inconsistent findings. The reason why the HF diet impaired FMD is not certain, but may involve the increased consumption of saturated fat. Subjects in the HF group consumed 26% of energy as saturated fat, which is similar to that consumed with Atkins'-like diets. Evidence suggests that a high intake of saturated fat directly impairs arterial endothelial function by reducing the anti-inflammatory potential of HDL [19]. Therefore, the increased saturated fat intake may have contributed to the decreased FMD observed in the HF group. It should also be noted that the diets varied greatly in dietary fiber content (HF diet: 11 g/d, LF diet: 30 g/d). Recent findings by Rallidis et al. [20] indicate that increasing fiber consumption may augment FMD in obese volunteers. As such, this discrepancy in dietary fiber content between the two groups may have contributed to the beneficial alterations in FMD observed by the LF diet, but not the HF diet.

The differences in endothelial function observed between HF and LF groups may also be related to changes in body composition. We show here that HF subjects lost more weight (-6.6 ± 0.5 kg) than LF subjects (-4.7 ± 0.6 kg). However, fat mass and waist circumference were significantly decreased in LF subjects only. It was also observed that the decreases in fat mass and waist circumference by LF diets were correlated to improvements in FMD post-treatment. Accumulating evidence suggests that visceral fat mass is inversely correlated to FMD [21]. A mechanism linking visceral adiposity to the onset and progression of endothelial dysfunction may involve free fatty acids (FFA) [22]. In vitro studies demonstrate that excessive release of FFA by visceral fat into the bloodstream can enhance the production of reactive oxygen species, which may induce endothelial dysfunction [23]. In view of these relationships, it is possible that the decrease in visceral fat mass in the LF group contributed to the improvements in FMD observed here. It is important to note, however, that this study is limited in that waist circumference was used to assess visceral fat mass. Waist circumference is only an indirect indicator of visceral adiposity, and is strongly operator dependent. As such, future studies in this area should implement computed tomography (CT) scans to distinguish between visceral and subcutaneous fat mass, and to confirm the association of visceral adiposity with FMD.

Favorable changes in adipokine profile may have also played a role in the improvements in FMD observed with LF diets. After 6-weeks of treatment, subjects in the LF group experienced a 16% increase in plasma adiponectin from baseline, which was paralleled by a 48% and 26% decrease in leptin and resistin concentrations, respectively. We also observed that the increases in adiponectin, and decreases in leptin and resistin were associated with improved FMD. Although a causal link between adiponectin and FMD has yet to be established, we speculate that modulations in nitric oxide (NO) by adiponectin may be involved. Nitric oxide, released from the endothelium, is important in regulating vascular tone. Plasma adiponectin can stimulate the phosporylation of endothelial nitric oxide synthase (eNOS), thereby increasing NO-dependent endothelial vasodilation [24]. Therefore, higher circulating concentrations of adiponectin in the LF group may contribute to enhanced endothelial function. As with adiponectin, we hypothesize that the mechanism linking decreased leptin and resistin to increased FMD may involve changes in the production of NO. Both leptin and resistin have been shown to blunt NO production [11, 25] likely through the stimulation of reactive oxygen species that scavenge NO and impair eNOS function. Since these adipokines were significantly decreased post-intervention in the LF group, there would be less leptin and resistin in the circulation to inhibit NO. Therefore, more NO may have been produced, resulting in an enhancement in endothelium-dependent vasodilation. Visceral fat mass loss is a major determinant of adipokine profile improvement with diet [26]. In the present study, significant reductions in visceral fat mass were noted in the LF group, but not the HF group. As such, it can be hypothesized that this reduction in abdominal fat mass by the LF regimen contributed to the increases in adiponectin, and decreases in leptin and resistin observed.

Several previous studies have evaluated the effects of HF and LF energy restricted diets on cardiometabolic disease risk factors [5–7, 17]. In general, both of these diets have been shown to improve blood pressure, CRP, glucose, and insulin concentrations [5–7, 17]. We show here that HF and LF diets were equally as effective in reducing blood pressure (systolic and diastolic) and insulin. However, differential effects for each diet on plasma lipids were observed. For instance, in the LF group, total and LDL cholesterol concentrations were reduced post-intervention. In contrast, in the HF group, total cholesterol increased while LDL cholesterol remained unchanged. These effects of HF diets on cholesterol concentrations are in line with previous findings [27]. Diets that are high in saturated fat are thought to increase total and LDL cholesterol concentrations by affecting LDL receptor activity, protein, and mRNA abundance [28]. These mechanisms may therefore account for the increased total cholesterol concentrations observed with HF diets.

There are several limitations to our study that warrant discussion. Firstly, our study is limited in that it employed a small sample size (HF diet: n = 9, LF diet: n =8). This imposes risk of a type 2 error, and as such, non-significant results may be merely the result of low statistical power. An example of this would be the lack of significant difference for FMD at baseline between groups. If a larger sample size was employed, it can be postulated that a significant difference in FMD between groups at this time point would be observed. Secondly, our experimental design is limited in that no control group was implemented. The omission of a control group makes it difficult to ascertain whether these effects were truly due to treatment, and not the result of an unidentified confounder. Future studies in this area should include a control group to ensure that these effects can be solely attributed to diet. Thirdly, our findings cannot be generalized to all HF and LF diets. Since not all HF and LF diets are created equal, it is possible that these effects may have occurred in response to the specific diets and food items provided here.

In sum, our findings suggest that weight loss with LF diets may be superior to that of HF diets for improving endothelial function and cardiometabolic risk variables. Our results also show that these vascular benefits of LF diets may be mediated, in part, by improvements in adipose tissue parameters (i.e. body fat distribution and adipokine profile). Further research is warranted to determine the impact of both dietary patterns on long-term cardiovascular outcomes, and the role that adipose tissue may play in mediating these effects.