ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 12.10 | DOI: 10.1530/ey.18.12.10

Nat Metab. 2021 Feb;3(2):228–243. doi: 10.1038/s42255-021-00346-2. PMID: 33619380.

In brief: In this genome-wide association study, the authors were able to disentangle the mechanism that uncouples adiposity from its known cardiometabolic complications. They identified 62 genomic loci, at which the same allele is associated with both higher adiposity and lower cardiometabolic risk. Functional analyses implicated several underlying mechanisms. These 62 loci clustered into three functional groups: favourable fat distribution, favourable lipid levels, and lower fasting glucose and lower risk for T2DM.

Comment: There is ongoing controversy regarding the ‘fat but fit’ paradox, as a substantial proportion of individuals with obesity do not have cardiometabolic comorbidities, and some normal-weight individuals have high risk. Previous studies focused on lifestyles and suggested that fitness might mitigate the negative effects of excess body weight on heart health, and that being “fat but fit” might be associated with similar cardiovascular health to being “thin but unfit.” The current study adopted a different approach to explain this paradox.

Data on several traits were analysed in the UK Biobank study, including: BMI, body fat, waist-hip ratio, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, systolic blood pressure and non-fasting glucose. 62 genomic loci were significantly associated with higher body fat, but that also conferred protection from the negative health impacts of obesity. Function analyses showed that the underlying genes had a range of functions, including the regulation and differentiation of adipocytes, and increased peripheral distribution of body fat; also glucose-insulin signalling, inflammation, energy expenditure, fatty acid oxidation and browning of white adipose tissue.

In light of the seeming futility of weight loss interventions for many people, it is of utmost importance to distinguish individuals with excess body weight who are at high risk of developing cardiometabolic diseases, from those who have genetic protection from developing diabetes and cardiovascular diseases.

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