Body Adiposity Indices, Adipokines Profile, and CNR1 Polymorphisms in Atypical Phenotypes of Obesity

<b>Background/Objectives:</b> Insulin-Resistant Normal Weight and Insulin-Sensitive Obesity are atypical cardiometabolic phenotypes whose clinico-biological features, management, and prognosis are a subject of extensive scientific debate. The current study aimed to assess the prevalence of metabolic phenotypes of obesity and to evaluate their association with markers related to diabesity, adipokines profile, and two single nucleotide polymorphisms of CNR1 gene. <b>Methods:</b> We performed a cross-sectional analysis in a random sample of 487 individuals (53.03 ± 13.71 years, 48.3% male) which were classified based on body mass index (</≥25 kg/m²) and insulin resistance (HOMA-IR cut-off value 2.5) as Insulin-Sensitive/Insulin-Resistant Normal Weight (ISNW/IRNW) and Insulin-Sensitive/Insulin-Resistant Obesity (ISO/IRO). <b>Results:</b> The ISO phenotype frequency was 24.2%, with a higher prevalence in the 40-60 years age group (47.0%) and in men (44.9%), while the prevalence of IRNW was 7.0%, predominating in women (61.8%). Participants with IRNW had a more altered glycoregulation profile (fasting and 2 h OGTT blood glucose, prediabetes, and hyperinsulinism), hypercholesterolemia, and adiposity indices (ABSI) than those with ISNW, but comparable to those with IRO. Participants with ISO had a more favorable glycoregulation profile, lipid profile, adipocytokines, and adiposity indices than those with IRO. IRNW had higher odds of being associated with prediabetes (OR 10.75; <i>p</i> < 0.001) than ISNW, while younger age, CUN-BAE, and ABSI were independently associated with both ISO and IRNW phenotypes. <b>Conclusions:</b> The IRNW phenotype should be actively evaluated to intervene on the cardiometabolic risk, while further studies are needed to confirm the sustainability of the favorable cardiometabolic profile of the ISO phenotype.