Normal adipose tissue function is necessary for maintaining proper energy balance, as both
excess and absence of this tissue lead to metabolic disturbances, such as insulin resistance.
Adipose tissue can be dysfunctional in many ways, including disturbances in adipocyte size,
lipolysis rate, adipokine secretion, inflammation, fibrosis or oxidative stress. Recently
ceramides have been proposed as candidate molecules that mediate the development of
adipocyte insulin resistance. The aim of this thesis is to evaluate different aspects of
dysfunctionality in human adipose depots in relation to their potential contribution to insulin
resistance and cardiovascular disease.
Paper I and II focus on the role of ceramides in human adipose tissue. We show that in obese
women with high liver fat increased ceramide content in the subcutaneous adipose depot is
most probably due to the increased sphingomyelin hydrolysis rather than de novo production.
Moreover, sphingomyelinases, that are responsible for this reaction, are present in areas rich
in apolipoprotein B, which may suggest that circulating lipoproteins may be a source of
sphingomyelin for the local ceramide production within adipose tissue. Additionally, we
show increased ceramide levels in the mediastinal as compared to the subcutaneous adipose
tissue and show that ceramides in this depot are associated with inflammatory processes. In
our unpublished data we demonstrate that ceramide induces inflammatory cytokine
expression in both macrophages and adipocytes. Paper III investigates whether the
mediastinal depot shows characteristics of brown adipose tissue. A comparison of several
markers of brown and white fat between subcutaneous and mediastinal adipose tissue reveals
that the mediastinal fat has higher expression levels of some brown (UCP1, PPARGC1A) and
lower expression levels of white (SHOX9, HOXC8) markers. Gene ontology analysis
indicates that mediastinal depot is enriched in genes related to mitochondrial function. In
some sections of mediastinal fat positive UCP1 staining and presence of multilocular cells are
observed. In Paper IV we investigate whether adipose tissue in patients with chronic kidney
disease is dysfunctional. We report that subcutaneous adipose tissue in patients with kidney
failure is characterized by higher numbers of phagocytic cells and smaller adipocytes, but
shows no signs of fibrosis as compared to healthy subjects. Additionally, proteomic analysis
shows differential expression patterns between the patients and controls. Among the proteins
expressed at higher levels in the patients, alpha-1-microglobulin/bikunin precursor is the most
significant and among those expressed at lower levels in the patients, the most significant is
vimentin – a protein known to be involved in lipid droplet metabolism.
In summary, the work presented in this thesis demonstrates that adipose tissue ceramides can
promote local inflammation, a process strongly linked to insulin resistance. Moreover, the
mediastinal adipose depot shows some signs of brown fat, however the functional
consequences remain to be evaluated. Finally, uremic adipose tissue shows adverse protein
composition, which together with an increased number of phagocytic cells and smaller
adipocyte size indicates that uremic adipose tissue is dysfunctional, which could lead to
increased cardiovascular risk in chronic kidney disease patients
