Lipids and glucose homeostasis upon metabolic challenge: Extracellular matrix takes the stage

Paolo Bonaldo and Matilde Cescon

Department of Molecular Medicine, University of Padova, Padova, Italy.

Correspondence: Paolo Bonaldo (bonaldo@bio.unipd.it) or Matilde Cescon

(matilde.cescon@unipd.it), Department of Molecular Medicine, University of Padova, Via Ugo Bassi
58/B, I-35131 Padova, Padova, Italy.

Many human diseases and syndromes deal with dysregulation of glucose and lipid homeostasis.
Among these, metabolic syndrome is defined as a pathological condition in which at least three
conditions out of visceral obesity, hyperglycemia, hypertension, insulin resistance or dyslipidemia
occur simultaneously (Alberti et al. 2005). With a prevalence of 20-25 % worldwide in adults,
metabolic syndrome parallels the incidence of obesity and of type 2 diabetes in many countries.
Despite its wide diffusion and the increasing understanding of the involved mechanisms, the primary
causes of this syndrome remain obscure. Challenging animal models with diets impinging on the
global energy status or affecting glucose and lipid homeostasis, such as a prolonged high fat diet
(HFD), represent useful tools to assess whether certain genetic backgrounds can predispose to
metabolic syndrome, thus helping to understand the relevance of genetic risk factors (Kennedy et al.
2010).

Upon persistent caloric intakes, as assuming a HFD for a long time, the whole body metabolism
is challenged by affecting glucose and lipid metabolism and their regulation through hormones.
Induction of adipose tissue expansion requires the activation of multiple processes, including cell
proliferation and differentiation, angiogenesis, inflammation and extracellular matrix (ECM)
remodeling. It is well known that increased ECM deposition in adipose tissue and liver is also linked
to the onset of insulin resistance. Studies in animal models revealed that several types of collagens are
relevant in the tissue response to metabolic challenges, and changes in collagen expression can
directly impact on the capability to enhance a systemic metabolic adaptation, in terms of increased
body mass, adiposity relocation and insulin sensitivity (Ruiz-Ojeda et al. 2019). Collagens take part in
various processes linked to adipocyte growth. Expressed by adipocytes, preadipocytes and endothelial
cells, different collagen types are required to sustain the mechanical stress induced by adipocyte
expansion when accumulating lipids, and they also play a primary role in regulating cell

This is an Accepted Article that has been peer-reviewed and approved for publication in The Journal
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'Accepted Article'; doi: 10.1113/JP280226.

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differentiation, adhesion and migration. In this context, some of the major players are collagen IV,
necessary for adipocyte survival, as well as collagen types I, III, V and VI, which are involved in
adipocyte differentiation and whose expression increases upon HFD (Ruiz-Ojeda et al. 2019).

Some years ago, T. Pihlajaniemi and coll. highlighted a novel role for collagen XVIII in the
adipocyte differentiation program (Aikio et al. 2014). This ubiquitous collagen contributes to the
architecture of vascular and epithelial basement membranes, and mutations of the human COL18A1
gene cause Knobloch syndrome, a rare disorder characterized by heavy myopia, retinal degeneration
and less frequently by occipital encephalocele. Collagen XVIII is produced in three different isoforms
of variable length, a shorter form mostly expressed in skeletal muscle and two longer ones abundant
in white adipose tissue and in liver sinusoids. Interestingly, in 2014 the authors demonstrated that
mice lacking the long collagen XVIII isoforms display reduced adiposity associated with defects in
the adipocyte progenitor cell differentiation, elevated triglyceride blood levels and ectopic fat
deposition in liver (Aikio et al. 2014). The findings of that study allowed to include collagen XVIII in
the context of adipose tissue regulation and opened the field for the elucidation of novel mechanisms
in the onset of visceral obesity.

A further study by the same team, published in this issue of J. Physiol. et al. 2020),
makes a step forward in the understanding of how the altered expression of the longer collagen XVIII
isoforms can influence the response to HFD metabolic challenge. The dyslipidemia caused by
deficiency of long collagen XVIII isoforms is enhanced upon HFD, with a decrease in general
adiposity, elevation of serum triglycerides and increased ectopically developed fat in liver. The
decreased mass of white adipose tissue, resembling lipodystrophy, despite lipid accumulation in liver
and blood serum, is in accordance with the onset of insulin resistance and impaired glucose tolerance
et al. 2020). These findings the basis for taking into account collagen XVIII as a candidate
for the identification of the genetic etiology of disorders including metabolic syndrome,
lipodystrophies and dyslipidemia. In addition, this work underlines once more the central role of ECM
in adipose tissue homeostasis, a process in which the ECM not only provides a growth constraint and
a structural scaffold, but it directly regulates signaling pathways governing lipid and glucose
metabolism.

References

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