Background/Objectives: 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. Methods: 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). Results: 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; p < 0.001) than ISNW, while younger age, CUN-BAE, and ABSI were independently associated with both ISO and IRNW phenotypes. Conclusions: 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.

Glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists, originally introduced for the management of type 2 diabetes mellitus and obesity, are increasingly recognized for their broader actions within the central nervous system, with emerging implications in neuropsychiatry and neurodegeneration. This review integrates current preclinical and clinical evidence, emphasizing their pharmacodynamic profile, central receptor distribution, and the molecular pathways linking metabolic signaling to neural function. Evidence suggests that GLP-1 receptor activation across key brain regions involved in energy balance and reward modulates multiple neurotransmitter systems, including dopamine and serotonin, as well as glutamatergic and GABAergic transmission, thereby influencing behavior, affective processes, and cognitive function. In parallel, these agents exhibit neuroprotective properties through improved neuronal insulin sensitivity, attenuation of neuroinflammatory pathways, and support of neuroplasticity, alongside effects on limiting pathological protein aggregation. Dual GIP/GLP-1 agonism may further potentiate these central actions through complementary metabolic and synaptic mechanisms. Although pharmacovigilance data have identified isolated neuropsychiatric adverse events, current clinical evidence does not support a consistent causal association. Collectively, incretin-based therapies represent a promising translational approach at the interface of metabolic and neuropsychiatric disorders, warranting further investigation into their long-term central safety, therapeutic efficacy, and clinical relevance.