Unpicking the mechanisms: Could there be something in it?
It is hard for epidemiologic associations to retain credibility for long without a plausible biologic basis, and metabolically healthy obesity did indeed have some potential explanations beyond the methodological ones.
One of these is a throwback to the original fit–fat concept, with the suggestion that cardiorespiratory fitness could protect obese people against metabolic ill health. For example, a 1999 study showed low fitness to be as strong a predictor for cardiovascular and all-cause mortality as the more traditional risk factors of smoking, diabetes, hypertension, and hyperlipidemia . And another study, involving over 43,000 adults, looked more specifically at fitness in the metabolically healthy obese, defined as the presence of no more than one metabolic abnormality and, notably, by percent body fat rather than BMI. The findings showed that the increased risk for cardiovascular, cancer, and all-cause mortality in the metabolically healthy obese became nonsignificant after adjusting for fitness, implying that obesity on its own could be a benign condition .
However, this likely makes sense of only a very small part of the picture, because, says Hamer, genuine fat but fit people are very rare. “When you try to go out and recruit these people to do a study it’s really hard to find them, because the bottom line is if you’re training hard enough to improve your fitness over a long period of time then you’re not going to stay obese.”
Another explanation to have garnered some support is that visceral adiposity, rather than subcutaneous fat, is the real driver of poor outcomes in obese people, with the theory being that people who are able to markedly expand their subcutaneous fat in the presence of excess calories can avoid accumulating fat around insulin-sensitive organs such as the liver. This would therefore allow for a subset of people – “pears” as opposed to “apples” – who remain in good metabolic health despite an increased BMI.
Supporting this are studies showing, for instance, that obese adults who are insulin-sensitive have around half the quantity of visceral fat as those who are insulin-resistant . In line with this, findings from the Dallas Heart Study showed that, among obese participants, insulin resistance and excess abdominal fat increased the risk for developing prediabetes and type 2 diabetes, whereas general adiposity did not . And in an analysis of the Framingham Heart Study Third Generation cohort, increases in fat mass were associated with an elevated risk for developing hypertension, high triglyceride levels, and the metabolic syndrome, with the associations being stronger for visceral than subcutaneous fat mass .
Hamer believes that there may be something in the theory. However, he cautions: “If you look at weight loss interventions in people that are initially healthy obese and those that are unhealthy obese you will see some interventions show that you can reduce visceral fat in both groups to a similar degree.
“So I’m not totally convinced about that argument.”
More interesting, he feels, is the research into the effects of liver fat, which, being closely linked to visceral adiposity, could partly account for the latter’s observed association with metabolic health. Fatty liver has been pinpointed as a common feature of obesity and metabolic ill health; one study of more than 12,000 South Korean people showed ultrasound-detected fatty liver in 45% of adults who had no metabolic syndrome components but were obese, compared with 18% of lean and metabolically healthy adults. Of note, fatty liver was also highly prevalent in metabolically unhealthy lean people, at 43%, although the rate was far higher in the metabolically unhealthy obese, at 75% . High as these rates are, one of the authors of that study, Christopher Byrne (University of Southampton, UK), when discussing the data at this year’s EASD conference, noted that the true prevalence of fatty liver could have been considerably higher, because ultrasound detects it only from a threshold of around 25% fat, whereas fatty liver on magnetic resonance imaging is defined as greater than 5% fat.
Other studies have shown that the presence of fatty liver predicts the onset of prediabetes  and people’s progression from a healthy to an unhealthy metabolic profile, the latter regardless of bodyweight . Another analysis by Byrne’s team, in the same South Korean cohort, showed that insulin resistance and fatty liver each independently increased people’s risk for developing type 2 diabetes, by 3.7- and 2.7-fold, respectively. But when combined with overweight/obesity, which itself increased risk 1.3-fold, they appeared to have a synergistic effect, increasing risk 14-fold . Yet neither of these factors is routinely accounted for when defining metabolically healthy or unhealthy obesity.
On a positive note, the team also showed that the risk for diabetes was not increased for people who had fatty liver that later resolved .
But again, it seems that fatty liver is not the whole story, as illustrated by a recent study from the same group, involving nearly 75,000 adults with no components of the metabolic syndrome except for a proportion with increased waist circumference . The risk for developing diabetes during follow-up was increased in overweight or obese participants with fatty liver, but also in those without, suggesting that obesity per se remains a risk factor for poor metabolic health. In line with this, another publication reported that the presence of overweight or obesity predicted the development of fatty liver in insulin-sensitive people with no metabolic syndrome components .
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