Metabolic syndrome (MetS) is a cluster of metabolic abnormalities, including visceral obesity, dyslipidemia, and insulin resistance. In this regard, visceral white adipose tissue (vWAT) plays a critical role, influencing energy metabolism, immunomodulation, and oxidative stress. Adipose-derived stem cells (ADSCs) are key players in these processes within vWAT. While second-generation antipsychotics (SGAs) have significantly improved treatments for mental health disorders, their chronic use is associated with an increased risk of MetS. In this study, we explored the impact of SGAs on ADSCs to better understand their role in MetS and identify potential therapeutic targets. Our findings reveal that olanzapine disrupts lipid droplet formation during adipogenic differentiation, impairing insulin receptor endocytosis, turnover, and signaling. SGAs also alter the endolysosomal compartment, leading to acidic vesicle accumulation and increased lysosomal biogenesis through TFEB activation. PKCζ is crucial for the SGA-induced nuclear translocation of TFEB and acidic vesicle formation. Notably, inhibiting PKCζ restored insulin receptor tyrosine phosphorylation, normalized receptor turnover, and improved downstream signaling following olanzapine treatment. This activation of PKCζ by olanzapine is driven by increased phosphatidic acid synthesis via phospholipase D (PLD), following G protein-coupled receptor (GPCR) signaling activation. Overall, olanzapine and clozapine disrupt endolysosomal homeostasis and insulin signaling in a PKCζ-dependent manner. These findings highlight SGAs as valuable tools for uncovering cellular dysfunction in vWAT during MetS and may guide the development of new therapeutic strategies to mitigate the metabolic side effects of these drugs.

Background The Novara Cohort Study (NCS) is the first multidisciplinary cohort study on aging in Northern Italy. It is designed to explore aging trajectories and health outcomes in the general population. This study involves the collection of biological samples and extensive data, including socioeconomic, medical history, lifestyle habits, quality of life and physical function. Objective This paper outlines the rationale, objectives, and preliminary findings of the NCS pilot phase. It discusses the baseline characteristics, initial biological characterization, and identifies key areas for improvement to ensure the successful implementation of the full-scale study. Methods The NCS pilot phase enrolled participants aged 35 and older residing in Novara, Italy. The study involved the collection of biological samples, medical examinations, questionnaires and functional tests. Data were collected included demographic information, physical activity, sleep quality, diet, quality of life, mental health, medical history, and medication use. Key blood parameters were analyzed alongside clinical data. Results The pilot phase enrolled 123 participants, 68 (55.3%) females and 55 (44.7%) males with a median age of 65 years old. The NCS pilot participants had higher education levels, lower smoking rates, and higher physical activity levels than the general population. Blood biomarker profiling showed significant variability across participants, providing a solid foundation for effectively analyzing aging trajectories. Conclusions The NCS pilot provided crucial insights into participant characteristics and identified areas for study protocol enhancement throughout all phases. These findings will guide refinements to optimize future study processes and outcomes, ultimately aimed at investigating the biological, social, and environmental determinants of aging in the Northern Italy area population.