Angiopoietin‐like protein 4 (ANGPTL‐4) regulates plasma lipoprotein levels, but its relevance in human obesity and type 2 diabetes (T2D) is largely unknown. We aim to investigate the regulation of circulating ANGPTL‐4 levels in obesity, T2D, and after changes in body weight.

Circulating ANGPTL‐4 levels were measured in two different cohorts. First, in a cross‐sectional study, we evaluated ANGPTL‐4 levels in lean and obese patients with normoglycemia or with altered glucose tolerance (AGT; n = 282). Second, in a longitudinal intervention study, 51 obese participants were evaluated. A hypocaloric diet was prescribed, with follow‐up 2 years later. ANGPTL‐4 levels were significantly increased in obese patients with AGT compared to lean participants. Moreover, ANGPTL‐4 was positively correlated with BMI, waist circumference, fat mass, HbA1c, HOMA‐IR, fasting triglycerides, and with inflammatory markers. Participants gaining weight after the follow‐up showed increased ANGPTL‐4 levels in parallel to increased BMI, fat mass, and fasting glucose, while ANGPTL‐4 levels were reduced in participants losing weight.

Our data support a relevant role of ANGPTL‐4 in human obesity and its involvement in long‐term body weight changes.