This editorial refers to ‘Association between regional body fat and cardiovascular disease risk among postmenopausal women with normal body mass index’†, by G.-C. Chen et al., on page 2849.
The simplicity of the common opinion ‘fat is bad’ has been challenged from the perspective of both dietary fat intake and body composition.1–5 While obesity is clearly associated with an increased risk for atherosclerotic cardiovascular disease (ASCVD), individuals with very low body weight are not characterized by reduced ASCVD events.2 Indeed, body weight and ASCVD show a U-shaped association.6 The lower turning point of this U-curve for ASCVD or total mortality has increased over the years to a body mass index (BMI) of 26–27, depicting an increase of risk not only for higher but similarly for lower body weight.6 In addition, not everybody with obesity develops premature atherosclerosis and there is substantial variation in cardiovascular risk even in individuals with normal BMI.7 Independently of other risk factors including smoking, LDL-cholesterol, hypertension, diabetes, and others, an unfavourable fat distribution characterized by increased central, abdominal, or trunk fat emerged as a stronger predictor for ASCVD and mortality than BMI or body fat mass.2 , 3 In contrast, predominant fat accumulation in the lower body as measured by a higher leg to total body fat ratio is associated with a lower ASCVD risk.4 Collectively, there is epidemiological evidence that fat distribution determines cardiovascular morbidity and mortality more strongly than increased fat mass itself.2–4
In the current issue of the European Heart Journal, Chen and co-workers now provide further support for the importance of fat distribution compared with overall fat mass as a determinant of ASCVD risk.5 A total of 2683 post-menopausal women with normal BMI (18.5 to <25 kg/m2) and without known ASCVD at baseline were selected from the Women’s Health Initiative and followed for a median duration of 17.9 years.5 The first occurrence of a major ASCVD manifestation was defined as the primary outcome parameter, and fat mass and distribution was determined by dual-energy X-ray absorptiometry.5 In normal weight post-menopausal women, whole body fat mass was not associated with incident ASCVD after adjustment for several potential risk factors.5 However, the authors found an increased ASCVD incidence associated with higher trunk fat, while higher leg fat predicted lower ASCVD risk.5 Importantly, the highest ASCVD risk was detected in those women with both an increased trunk and reduced leg fat deposition, suggesting that unfavourable (trunk) and protective (leg) fat depots are counteractively regulated. The study may inspire novel concepts of how a dysbalance between ‘atherogenic’ and ‘anti-atherogenic’ fat depots may indirectly contribute to vascular damage (Figure 1). Importantly, the study identifies a positive effect of leg fat on ASCVD risk.5 Although the study by Chen and colleagues supports the concept that adverse fat distribution may increase ASCVD risk, it also stimulates questions.
Concept for a mechanistic link between regional body fat depots and cardiovascular risk. Cardiovascular risk factors including genetic predisposition (e.g. raised LDL-cholesterol), behavioural factors (e.g. smoking, unhealthy diet patterns, physical inactivity), hypertension, diabetes, and obesity may contribute to vascular damage and atherosclerosis through direct and indirect mechanisms. Adverse fat distribution, rather than BMI or total body fat mass, may explain the variable cardiovascular risk for a given BMI category. Chen et al.5 provide direct evidence that despite normal BMI, elevated trunk fat and reduced leg fat are associated with increased cardiovascular risk in post-menopausal women. However, the mechanisms underlying these associations are not entirely understood. The interplay of behavioural and environmental factors in genetically susceptible individuals may cause ectopic fat deposition in visceral fat depots, the liver, and potentially abdominal subcutaneous fat and adipose tissue dysfunction (e.g. hypertrophied adipocytes, immune cell infiltration). Through adipokine and cytokine secretion, the release of metabolites (e.g. free fatty acids) or increasing intraperitoneal pressure causing local stress, inflammation, and insulin resistance in the liver, ectopic fat depots may indirectly contribute to an atherogenic, pro-inflammatory, hypercoagulation state. These mechanisms may explain how trunk fat increases cardiovascular risk independently of BMI. In addition, ectopic fat deposition may be related to an inability to ‘safely’ store excess energy in, for example, femoro-gluteal (leg) fat depots. ‘Safe fat depots’ could exert cardiovascular protective effects through the release of anti-atherogenic and anti-inflammatory factors, and/or simply by representing ‘inert’ fat depots characterized by normal adipose tissue function.
Are these associations specific to post-menopausal normal weight women?
Data from the The Health Improvement Network (THIN) database suggest that ASCVD risk increases even in groups without known cardiometabolic abnormality with increasing BMI.7 In the THIN analysis, individuals with ‘metabolically healthy obesity’ (MHO; at BMI 34–35 kg/m2) had a higher ASCVD risk compared with both metabolically healthy overweight and lean.7 These data were to some extent unexpected from previous epidemiological cohorts and may be due to residual confounding factors (e.g. lack of diet, exercise, and behavioural data) and some additional study limitations [e.g. no data for LDL-cholesterol, blood pressure, or glycated haemoglobin (HbA1c)].8
MHO is more prevalent in pre-menopausal women, and a shift from MHO to a higher ASCVD risk in post-menopausal women could be related to increasing visceral fat mass.9 Because subcutaneous fat mass may also increase and energy expenditure decreases during menopausal transition,9 these potential confounders need to be considered in particular in post-menopausal women.
However, in individuals with obesity, the contribution of adverse fat distribution vs. BMI effects to ASCVD risk is more difficult to dissociate. In a recent cohort study of >296 000 white European adults, the magnitude of the association between ASCVD and abdominal fat distribution was only slightly superior to that of BMI.10 These data suggest that the importance of mechanisms linking adverse effects of abdominal fat and potential positive effects of leg fat to increased ASCVD risk are particularly pronounced in individuals with low BMI and may be attenuated with adverse factors associated with increasing total body fat mass.10
Is trunk fat dangerous and leg fat protective?
The study by Chen et al.5 supports the concept that abdominal fat distribution increases the cardiometabolic risk independently of BMI.2 , 3 , 11 Among other factors, decreased leg fat and increased visceral and liver fat may underly the approximatley three-fold increased risk for cardiovascular events in normal weight, but metabolically unhealthy individuals.11 Those individuals share several symptoms with lipodystrophy patients, including adipose tissue (AT) dysfunction and the inability to expand ‘safe’ fat depots (e.g. femoro-gluteal subcutaneous), leading to ectopic fat accumulation in visceral depots and the liver.11 Subcutaneous leg fat may exert its beneficial ASCVD effects through different mechanisms (Figure 1). First, leg fat may function as a metabolically ‘inert’ sink, which can store excessive calories without inducing harmful AT dysfunction. Impaired expandability of this healthy AT depot is considered a critical knot in the development of cardiometabolic diseases.11 Secondly, compared with visceral depots, leg fat may release lower concentrations of potentially harmful metabolites (e.g. free fatty acids).12 In addition—and so far still a hypothesis—leg fat may directly protect against ASCVD through anti-atherogenic and anti-inflammatory factors.
These potential mechanisms may contribute to the increased risk of ASCVD in individuals with low BMI, cachexia, or after weight loss.
If excess energy cannot be sufficiently stored in healthy fat depots such as leg fat, ectopic fat deposition may develop as a compensatory mechanism. Visceral obesity increases the cardiovascular risk by enhancing both direct (dyslipidaemia, hypertension, and hyperglycaemia) and indirect mechanisms.13 As an indirect mechanism, AT dysfunction (adipocyte hypertrophy and insulin resistance, immune cell infiltration of AT) causes an atherogenic secretion pattern including adipokines (e.g. leptin and adiponectin), pro-inflammatory cytokines (e.g. interleukin-6, tumour necrosis factor-α), pro-thrombotic (e.g. plasminogen activator inhibitor type 1), and vasoactive factors (e.g. angiotensinogen) which contributes to endothelial dysfunction.12 , 13 Ectopic fat accumulation including non-alcoholic fatty liver disease leads to impaired insulin sensitivity and increased release of fatty acids, with subsequent abnormalities in lipid and glucose metabolism.13
Taken together, an adverse fat distribution characterized by increased abdominal (trunk) and decreased lower body (leg) fat increases the ASCVD risk independently of body fat mass. Therefore, an intact balance between potentially harmful ectopic fat depots and safer or even beneficial healthy fat storage seems to be cardioprotective, although the exact mechanisms for the development of adverse fat distribution and how it is linked to atherosclerosis needs to be explored.
Conflicts of interest: M.B. received honoraria as a consultant and speaker from Amgen, AstraZeneca, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi. U.L. has served as a consultant for Amgen, Esperion, and Sanofi.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
Footnotes
doi:10.1093/eurheartj/ehz391.
References
