Comparative Transcriptomic Analysis of Obesity and Lipodystrophy Reveals Shared Mechanisms and Novel Targets in Adipose Tissue Dysfunction

Abstract

The global rise in obesity poses a major public health challenge. While chronic energy surplus is a well-established driver of weight gain and obesity, the mechanisms linking adipose tissue (AT) expansion to cardiometabolic complications remain incompletely understood. In obese individuals, dysfunctional AT loses its capacity to store excess lipids, leading to ectopic fat accumulation and contributing to cardiometabolic complications such as type 2 diabetes. However, the molecular events that drive the transition from healthy to dysfunctional adipocytes are poorly defined. At the opposite end of the adiposity spectrum, lipodystrophies represent a heterogeneous group of disorders characterized by selective loss of AT, often accompanied by severe metabolic disturbances. Despite these contrasting adipose phenotypes, both obesity and lipodystrophy result in similar metabolic complications. In this study, we investigated whether AT in these two contrasting conditions shares a common molecular signature. We performed an unbiased comparative transcriptomic analysis of AT from lipodystrophic BSCL2-deficient and obese mice, identifying a shared signature of 129 genes. Using publicly available datasets, we replicated this signature and refined it to 102 genes whose expression is consistently altered in both obese and lipodystrophic adipose tissue. Correlation network analysis, gene ontology, and literature-based refinement revealed that these genes fall into nine functional categories: lipogenesis, adipocyte differentiation, carbohydrate metabolism, mitochondrial function, amino acid metabolism, reactive oxygen species, metabolic processes, immune response, and a group with no clear functional association. Most of these genes expression levels correlated strongly with insulin sensitivity across lipodystrophic and obese mice, as well as human samples. Finally, 52 genetic loci containing these genes harbor variants associated with type 2 diabetes, including 11 loci where genetic associations directly influence candidate gene expression levels. In conclusion, our findings demonstrate that a shared "energetic collapse" of adipocytes, characterized by profound metabolic inflexibility in pathways spanning glucose utilization, lipogenesis, and amino acid catabolism, represents a common pathogenic mechanism underlying adipose tissue dysfunction in both obesity and lipodystrophy. This convergent molecular signature underscores the critical role of intrinsic adipocyte metabolic health in systemic energy homeostasis and insulin sensitivity.