Metabolic syndrome (MetS) is a multicomponent risk condition that reflects the clustering of individual cardiometabolic risk factors related to abdominal obesity and insulin resistance. MetS increases the risk for cardiovascular diseases (CVD) and type 2 diabetes mellitus (T2DM). However, there still is not total clinical consensus about the definition of MetS, and its pathophysiology seems to be heterogeneous. Moreover, it remains unclear whether MetS is a single syndrome or a set of diverse clinical conditions conferring different metabolic and cardiovascular risks. Indeed, traditional biomarkers alone do not explain well such heterogeneity or the risk of associated diseases. There is thus a need to identify additional biomarkers that may contribute to a better understanding of MetS, along with more accurate prognosis of its various chronic disease risks. To fulfill this need, omics technologies may offer new insights into associations between sphingolipids and cardiometabolic diseases. Particularly, ceramides –the most widely studied sphingolipid class– have been shown to play a causative role in both T2DM and CVD. However, the involvement of simple glycosphingolipids remains controversial. This review focuses on the current understanding of MetS heterogeneity and discuss recent findings to address how sphingolipid profiling can be applied to better characterize MetS-associated risks.

Lipid-related disorders, which primarily affect metabolic tissues, including adipose tissue and the liver are associated with alterations in lysosome homeostasis. Obesity is one of the more prevalent diseases, which results in energy imbalance within metabolic tissues and lysosome dysfunction. Less frequent diseases include Niemann-Pick type C (NPC) and Gaucher diseases, both of which are known as Lysosomal Storage Diseases (LSDs), where lysosomal dysfunction within metabolic tissues remains to be fully characterized. Adipocytes and hepatocytes share common pathways involved in the lysosome-autophagic axis, which are regulated by the function of cathepsins and CD36, an immuno-metabolic receptor and display alterations in lipid diseases, and thereby impacting metabolic functions. In addition to intrinsic defects observed in metabolic tissues, cells of the immune system, such as B cells can infiltrate adipose and liver tissues, during metabolic imbalance favoring inflammation. Moreover, B cells rely on lysosomes to promote the processing and presentation of extracellular antigens and thus could also present lysosome dysfunction, consequently affecting such functions. On the other hand, growing evidence suggests that cells accumulating lipids display defective inter-organelle membrane contact sites (MCSs) established by lysosomes and other compartments, which contribute to metabolic dysfunctions at the cellular level. Overall, in this review we will discuss recent findings addressing common mechanisms that are involved in lysosome dysregulation in adipocytes and hepatocytes during obesity, NPC, and Gaucher diseases. We will discuss whether these mechanisms may modulate the function of B cells and how inter-organelle contacts, emerging as relevant cellular mechanisms in the control of lipid homeostasis, have an impact on these diseases.

Upon interaction with immobilized antigens, B cells form an immune synapse where actin remodeling and re-positioning of the microtubule-organizing center (MTOC) together with lysosomes can facilitate antigen extraction. B cells have restricted cytoplasmic space, mainly occupied by a large nucleus, yet the role of nuclear morphology in the formation of the immune synapse has not been addressed. Here we show that upon activation, B cells re-orientate and adapt the size of their nuclear groove facing the immune synapse, where the MTOC sits, and lysosomes accumulate. Silencing the nuclear envelope proteins Nesprin-1 and Sun-1 impairs nuclear reorientation towards the synapse and leads to defects in actin organization. Consequently, B cells are unable to internalize the BCR after antigen activation. Nesprin-1 and Sun-1-silenced B cells also fail to accumulate the tethering factor Exo70 at the center of the synaptic membrane and display defective lysosome positioning, impairing efficient antigen extraction at the immune synapse. Thus, changes in nuclear morphology and positioning emerge as critical regulatory steps to coordinate B cell activation.