The understanding of the potential role of betatrophin in human metabolic disorders is a current challenge. The present research evaluated circulating betatrophin levels in obese patients with metabolic syndrome (MetSyn) features under energy-restricted weight-loss programs and in normal weight in order to establish the putative interplay between the levels of this hormone, diet and metabolic risk factors linked to obesity and associated comorbidities. One hundred forty-three participants were enrolled in the study (95 obese-MetSyn; age 49.5±9.4 years; body mass index (BMI) 35.7±4.5 kg m(-2) and 48 normal weight; age 35.71±8.8 years; BMI 22.9±2.2 kg m(-2)). A nutritional therapy consisting in two hypocaloric strategies (control diet based on the AHA recommendations and the RESMENA (MEtabolic Syndrome REduction in Navarra) diet, a novel dietary program with changes in the macronutrient distribution) was only prescribed to obese-MetSyn participants who were randomly allocated to the dietary strategies. Dietary records, anthropometrical and biochemical variables as well as betatrophin levels were analyzed before (pre-intervention, week 0), at 8 weeks (post-intervention, week 8) and after 4 additional months of self-control period (follow-up, week 24). Betatrophin levels were higher in obese-MetSyn patients than normal-weight subjects (1.24±0.43 vs 0.97±0.69 ng ml(-1), respectively, P=0.012), and levels were positively associated with body composition, metabolic parameters, leptin and irisin in all participants at baseline. Notably, low pre-intervention (week 0) betatrophin levels in obese patients were significantly associated with higher dietary-induced changes in atherogenic risk factors after 8 weeks. Moreover, protein intake, especially proteins from animal sources, was an independent determinant of betatrophin levels after dietary treatment (B=-0.27; P=0.012). Betatrophin is elevated in obese patients with MetSyn features and is associated with poorer nutritional outcomes of adiposity and dyslipidemia traits after a weight-loss program. Dietary protein intake could be a relevant modulator of betatrophin secretion and activity.