Association of the PNPLA3 p.I148M common variant with increased resting energy expenditure in the context of cold adaptation in humans

Genome-wide association studies linked the common PNPLA3 variant p.I148M (rs738409) to increased hepatic steatosis. This variant is conserved in modern humans and was fixed in archaic humans, putatively due to advantages in cold-adaptation.

To investigate the role of this variant in the context of thermogenesis, we utilized data of the FREECE cohort that studied the effect of cold-exposure (CE) on resting energy expenditure (REE), metabolites and hormones across 140 individuals in the context of genetic variation. Additionally, brown adipocyte marker gene expression was assessed in 17 individuals.

Our results show a risk allele frequency for rs738409 of 0.18 across the study population (89 CC, 44 CG, 7 GG). We observed a numerically increased fat-free mass-adjusted REE after CE in normal-weight individuals with the largest delta increase in GG-carriers (median deltaREE±SD (kcal/d): 148±98(GG), 42±153(CG), 79±150(CC), p=0.1359). Simultaneously, median supraclavicular temperature was increased by+0,17°C in GG compared to CG and CC. We did not detect relevant differences in blood lipid concentrations. Analysis of mRNA levels points towards a small decrease of brown adipocyte marker genes in heterozygous but not homozygous risk allele carriers, suggesting a UCP1-independent mechanism. For validation, we analyzed RNAseq-data of subcutaneous adipocytes and found no difference in UCP1 expression but a genotype-dependent effect on the expression of lipid cycling genes.

In conclusion, our data suggests a potential thermogenic adaptation mechanism via increased REE in homozygous p.I148M carriers independent of changes in blood lipids and brown adipocyte marker gene expression, however further validation in a larger cohort is needed.

Publication History

Article published online:
20 January 2025