Lipids and glucose homeostasis upon metabolic challenge: extracellular matrix takes the stage (2020)

Many human diseases and syndromes involve 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, hyperglycaemia, hypertension, insulin resistance and dyslipidaemia 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), represents 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 with a HFD over a long time span, 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) remodelling. 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 differentiation, adhesion and migration. In this context, some of the major players are collagen IV, necessary for adipocyte survival, and collagens 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 colleagues highlighted a novel role for collagen XVIII in the adipocyte differentiation programme (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 the inclusion of 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 The Journal of Physiology (Petäistö et al. 2020), marks 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 dyslipidaemia 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 (Petäistö et al. 2020). These findings form the basis for taking into account collagen XVIII as a candidate for the identification of the genetic aetiology of disorders including metabolic syndrome, lipodystrophies and dyslipidaemia. 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 directly regulates signalling pathways governing lipid and glucose metabolism. None declared. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. This work was supported by the Italian Ministry of Education, University and Research (grant 201742SBXA), the Telethon Foundation (grant GGP19229), and the University of Padova (STARS grant WRAPS).