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We examined whether relative concentrations of circulating triacylglycerols (TAGs) between carriers compared with noncarriers of [PNPLA3.sup.I148M] gene variant display deficiency of TAGs, which accumulate in the liver because of defective lipase activity. We also analyzed the effects of obesity-associated nonalcoholic fatty liver disease (NAFLD) independent of genotype, and of NAFLD due to either [PNPLA3.sup.I148M] gene variant or obesity on circulating TAGs. A total of 372 subjects were divided into groups based on PNPLA3 genotype or obesity. Absolute and relative deficiency of distinct circulating TAGs was observed in the [PNPLA3.sup.148MM/148MI] compared with the [PNPLA3.sup.148II] group. Obese and 'nonobese' groups had similar PNPLA3 genotypes, but the obese subjects were insulin-resistant. Liver fat was similarly increased in obese and [PNPLA3.sup.148MM/148MI] groups. Relative concentrations of TAGs in the obese subjects versus nonobese displayed multiple changes. These closely resembled those between obese subjects with NAFLD but without [PNPLA3.sup.I148M] versus those with the I148M variant and NAFLD. The etiology of NAFLD influences circulating TAG profiles. 'PNPLA3 NAFLD' is associated with a relative deficiency of TAGs, supporting the idea that the I148M variant impedes intrahepatocellular lipolysis rather than stimulates TAG synthesis. 'Obese NAFLD' is associated with multiple changes in TAGs, which can be attributed to obesity/insulin resistance rather than increased liver fat content per se. Diabetes 2014;63:312-322 | DOI: 10.2337/db13-0774, Nonalcoholic fatty liver disease (NAFLD) is defined as steatosis, which is not caused by excess alcohol consumption or other known causes (1). It refers to a spectrum of hepatic pathology, [...]