Understanding the role of visceral fat in metabolically healthy versus unhealthy obesity: a sex-based analysis of the transcriptome

Abstract

Background: The term “metabolically healthy obesity” is used to define those patients with obesity that do not present elements of metabolic syndrome. The causes behind this temporary reduction of the cardiovascular risk are still unknown, although these patients are characterized by a conserved expansion capacity of the adipose tissue, preventing ectopic accumulation of fat. Since hormones are key regulators in adipogenesis, we hypothesize that there are sex-specific differences in visceral white adipose tissue (vWAT) biology that may contribute to metabolic health disparities between men and women. Methods: 60 patients attending the Morbid Obesity Unit from the Hospital Universitario de Getafe for elective bariatric surgery were enrolled. Prior to the surgery, a full biochemical panel was carried out. During the procedure, a portion of vWAT was excised and snap-frozen for histological analysis and for the study of the transcriptomic fingerprint in 8 metabolically healthy (MH) and 8 metabolically unhealthy (MU) patients using a transcript expression microarray. The results were validated by qPCR. Results: Functional enrichment analysis of the differentially expressed transcripts (DETs) revealed a similar vWAT transcriptome between MH and MU patients, with differences related to immune response and metabolism homeostasis. However, when we stratified the patients by sex, the number of DETs multiplied by 10, showing sex-specific signatures. MH men presented a reduced pro-inflammatory and oxidative stress profile in comparison to MU men. Thus, the transition from MH to a MU state in men led to a disruption of the normal biology of the tissue, which correlates to the apparition of comorbidities. Surprisingly, MH females exhibited the most deleterious profile, with alterations of key pathways related to inflammation, extracellular matrix organization and metabolism in comparison to MU females. Even those common processes (extracellular remodeling and inflammation) that were observed in men and women cohorts presented a unique signature. These results suggest that vWAT in females suffers an exaggerated pathological state in response to the increased demand to store energy in comparison to men. Conclusion: These findings suggest that obesity should be treated as a different entity in men and women and highlight the need of early intervention in female patients with obesity, even in the absence of comorbidities. Plain english summary: Obesity is often linked to metabolic problems, but some patients with obesity do not show typical signs of metabolic syndrome, a situation referred to as "metabolically healthy obesity." The reasons behind this are not fully understood, but it is thought that these individuals have healthier adipose tissue that prevents the accumulation of fat in other organs. Since hormones play an important role in fat storage, we examined if there are gender differences in how adipose tissue responds to fat accumulation. In this study, we analyzed the genes that were expressed in the visceral adipose tissue of patients with obesity who were metabolically healthy (MH) and those who were metabolically unhealthy (MU). When we compared the results, we found that men and women had different gene activity patterns. For men, MH adipose tissue had less inflammation and stress compared to MU adipose tissue. However, MH women tissue showed worse signs of inflammation, fibrosis and metabolism problems than MU women. Between genders, there are several differences in the pathways that are triggered by obesity, with women having a more pathological profile. Even those processes that were common had a worst profile than in men. This suggests that women adipose tissue does not adapt equally to the increased demand for energy storage, even in the absence of metabolic abnormalities. These results suggest that obesity should be treated differently in men and women and emphasize the importance of early intervention for women, even if they do not show metabolic alterations.