Adiposity and disease
Why is adiposity important?
Excess of body fat, or adiposity, is a major cause of death and disability in most human populations. Adiposity overall (i.e., general adiposity) is most commonly measured, both in large epidemiological studies and in clinical practice, using the body-mass index (BMI). There are many reasons for this, including that it is really easy to measure - all that is needed is weight and height. It is also useful to measure: BMI is very strongly associated with a higher risk of all-cause mortality, with each 5 kg/m2 higher BMI increasing mortality risk by about one-third. However, BMI does not capture where in the body adipose tissue accumulates and it contains other contributors to weight such as muscle.
Does it matter where adiposity accumulates?
In fact, disease risk may vary depending on whether fat accumulates overall, in the middle of the body, or around the hips. For example, a previous study showed that general and abdominal adiposity (measured using BMI and waist circumference, respectively) are strongly and independently associated with mortality. To put it another way, a higher level of waist circumference is associated with an increased mortality risk over and above any information provided by BMI. Notably, a subsequent study showed that for a given amount of general and abdominal adiposity, higher gluteo-femoral adiposity (measured as the hip circumference) was associated with lower mortality due to vascular and metabolic causes. These findings provided support to the hypothesis that body fat accumulation in the upper versus lower parts of the body have opposing effects on the risk of vascular and metabolic causes of death.
What do we know about adiposity and lipids?
It is unclear how much of the effects on mortality of different types of adiposity are driven by how they alter the metabolic pathways of lipids (and other metabolic groups), in part because of limitations in the ways in which the implicated metabolites are routinely measured. Traditionally, such measurements have been rather crude quantifications (or estimations) of cholesterol (the total amount circulating in blood, or the proportion carried in the atherogenic low-density lipoproteins) and triglycerides.
What are blood lipids anyway?
Lipids are essential biomolecules used for energy storage and consumption (among many other functions). Because lipids are non-soluble, they are transported in the blood in the form of lipoproteins. These are spherical macromolecules formed by an outer layer of phospholipids (making lipoproteins soluble), apolipoproteins, and other proteins and a lipidic core of cholesterol and triglycerides.
Lipoproteins are classified according to their biochemical composition and density. Very low-density lipoproteins (VLDLs) are large, with vast quantities of triglycerides and proportionally not much cholesterol. As VLDLs lose triglycerides (due to their physiological use), they become intermediate-density or low-density lipoproteins (IDLs, or LDLs). These lipoproteins have proportionally much more cholesterol, and fewer triglycerides, than VLDLs. They are also smaller, which makes them prone to infiltrate the tunica intima of blood vessels to form atherosclerotic plaques placing these lipoproteins at the core of atherosclerotic cardiovascular disease. Notably, VLDLs, IDLs, and LDLs have one apolipoprotein B anchored to their surface. High-density lipoproteins (HDLs) have the smallest lipid core of all lipoproteins and have between 2 and 3 Apolipoprotein-AI on their surface. Although their role in atherosclerosis is poorly understood, it is generally accepted that their main function is to collect cholesterol in peripheral tissue and bring it back to the liver for metabolic repurposing.
New ways of measuring lipids
Blood-based nuclear magnetic resonance (NMR) spectroscopy metabolomics provides a fine-grain quantitative profile of lipoprotein lipids, including the concentrations of these particles across 14 different size-based subclasses: 6 VLDLs, IDL, 3 LDLs, and 4 HDLs, as well as the lipid content of each lipoprotein subclass (including cholesterol, triglycerides, and phospholipids). This platform also provides information on apolipoproteins, fatty acids, cholines, glycolysis-related metabolites, amino acids, ketone bodies, creatinine, albumin, and glycoprotein acetyls (a marker of chronic inflammation).
Modern NMR spectroscopy platforms offer high-throughput (ie, fast) ways to provide standardised metabolic profiling, making them a great asset for population-based epidemiological research.
What did we do?
We compared the NMR-measured metabolic profiles related to general (ie, BMI), abdominal (ie, waist circumference and the waist to hip ratio), and gluteo-femoral (ie, hip circumference) adiposity among ~30,000 Mexican adults from the Mexico City Prospective Study. We did this by estimating the individual association of each marker of adiposity with each of about 140 biomarkers measured by NMR while adjusting for relevant confounders (ie, age, sex, socio-economic factors, alcohol intake, and smoking).
As the different measures of adiposity are correlated (eg, on average, those with higher BMI levels are likely to also have a larger waist circumference), the overall association of each adiposity marker in isolation may be inflated, reduced, or even reversed due to their correlations with other adiposity markers. Therefore, we repeated the main analysis further adjusting for other adiposity markers. Such adjustments allow an assessment of how higher or lower than expected levels of a particular adiposity marker (ie expected given other adiposity markers) predict levels of NMR biomarkers.
What did we find?
Higher adiposity relates to numerous molecules in the blood linked to type 2 diabetes and heart disease
We found that markers of general, abdominal, and gluteo-femoral adiposity all display similar and strong associations with biomarkers that increase cardiometabolic risk. More specifically, higher adiposity associates with higher levels of Apolipoprotein-B, higher levels of VLDLs (and the cholesterol, triglycerides, and phospholipids linked to these lipoproteins), higher levels of various types of fatty acids (particularly mono-unsaturated fatty acids), and multiple changes in other metabolic biomarkers including higher levels of the branched-chain amino acids leucine (Leu), isoleucine (Iso), and valine (Val) and higher levels of the inflammation biomarker glycoprotein acetyls (Glyc-A).
Body-fat accumulation around the hips shows a favourable metabolic profile
We also found that associations for general and abdominal adiposity are fairly independent of each other (ie, after adjustment for each other). However, given general and abdominal adiposity, higher gluteo-femoral adiposity is associated with a strongly favourable cardiometabolic lipid profile. For example, given waist circumference and BMI, higher levels of hip circumference associate with lower levels of Apolipoprotein-B, of VLDLs, and of triglycerides, lower levels of fatty acids and branched-chain amino acids, and lower Glyc-A.
Why is our study relevant?
Our findings reinforce and provide further insight into previous evidence suggesting that body-fat accumulation around the hips could be linked to a lower risk of cardiometabolic disease. The observational nature of our study, however, did not allow us to formally assess causation. This is a clear line of research we will be pursuing using Mendelian randomisation approaches.
For population health
In Mexico, obesity and type 2 diabetes are common but at the time of our study use of lipid-lowering drugs was low (thereby allowing us to make an unbiased assessment of the impact of adiposity on blood lipids). Our findings reinforce the need in Mexico for ongoing efforts to reduce population levels of overweight and obesity, but also have relevance to population health strategies in other parts of the world where obesity and diabetes are increasing but have not yet reached the levels seen in Mexico.
Data availability and equity in science
The Mexico City Prospective Study was set up in the late 1990s by scientists at Universidad Nacional Autónoma de México in collaboration with scientists at the University of Oxford (with the two groups collaborating together on the study ever since). If you are interested in obtaining data from the study for research purposes, or in collaborating with MCPS investigators on a specific research proposal, please visit the study website where you can download the study’s Data and Sample Access Policy in English or Spanish. The policy aims to promote equity in science by giving Mexican scientists and institutions a 2-year exclusivity period to new data ahead of scientists in other parts of the world. The NMR data used in our analyses were added to the data already available to researchers from Mexico in October 2022. Full details of the data available may also be viewed at the study’s Data Showcase.