Lack of collagen XVIII leads to lipodystrophy and perturbs hepatic glucose and lipid homeostasis

Obesity is often associated with comorbidities, such as type 2 diabetes, as a result of insulin resistance and glucose intolerance. Due to the continuously increasing prevalence of obesity worldwide, current research efforts have focused on the discovery of novel therapeutic strategies against this metabolic disorder. Contrary to obesity, in which adiposity levels are elevated, lipodystrophy is distinguished by a diminished overall adipose tissue mass leading to abnormal/ectopic fat deposition (Aikio et al. 2014). White adipose tissue (WAT) functions as an energy reservoir and thus impaired white adipose storage, in the case of lipodystrophy, may result in metabolic dysregulation (Aikio et al. 2014; Petäistö et al. 2020). The inability to store fat safely in WAT can lead to ectopic lipid deposition particularly in the liver along with elevated triglyceride levels in the bloodstream, which ultimately results in the development of insulin resistance and impaired glucose regulation (Aikio et al. 2014; Petäistö et al. 2020). Collagen XVIII has been determined to promote adipogenesis by way of influencing adipogenic progenitor cells, specifically in epididymal WAT (eWAT) (Aikio et al. 2014). Collagen XVIII is expressed as three isoforms coming from two gene promotors: small from P1, and medium and large from P2 (Aikio et al. 2014; Petäistö et al. 2020). Knocking out the various isoforms, specifically the medium and long variants, causes lipodystrophy with which mice exhibit reduced adiposity, increased serum triglyceride (TG) levels and ectopic accumulation of fat in the liver (Aikio et al. 2014). In a recent study by Petäistö et al. (2020) in The Journal of Physiology, the authors sought to assess the metabolic consequences of this lipodystrophic phenotype (from a lack of collagen XVIII) when challenged with a long-term high fat diet (HFD). Consistent with previous findings, mice lacking medium and long isoforms of collagen XVIII displayed reduced adiposity while maintaining comparable food intake and activity levels to wild-type mice. The HFD induced a marked increase in serum TG in both the total and medium/long isoform knockout mice accompanied by increased fat accumulation in the liver. Further investigation showed significant liver damage in these mutant mice, likely a result of impaired adipogenesis and increased fat accumulation in the liver. With both liver and adipose tissue being important regulators of glucose and lipid homeostasis, it is important to understand the metabolic consequences of the aforementioned phenotype. Reduced circulating and eWAT adiponectin levels were observed in the total, long, and medium isoform knockout mice along with significant reductions in the insulin-regulated glucose transporter, which is indicative of impaired lipid homeostasis (Petäistö et al. 2020). Evidence of altered glucose homeostasis was also observed. Levels of both Glut2 and Glut4 RNA, found in liver and adipose/muscle tissues, respectively, were altered in the mutant mice, in which Glut2 was increased in the total, medium and long isoform knockout but decreased in the short isoform knockout, and Glut4 in eWAT was significantly reduced in all knockout mice. Additionally, when fed a HFD, the total, medium and long isoform knockout mice showed signs of increased gluconeogenesis in the liver and impaired glucose tolerance. Reduced insulin sensitivity was also observed in the liver and there were trending reductions in eWAT, but not in muscle. Thus, it is likely the changes in liver and adipose tissue that are leading to the insulin resistance and glucose intolerance in these lipodystrophic mice. Notably, the knockout (total, medium and long isoform) mice showed reduced adiposity and slower weight gain on a HFD with no outwardly apparent cause. Non-shivering thermogenesis in brown adipose tissue (BAT) increases energy consumption and can be activated through cold exposure and caloric excess. The mutant mice, when exposed to cold temperatures, showed increased heat production and respiratory exchange rate, indicative of the utilization of carbohydrates over lipids, whereas the wild-type mice increased lipid consumption (Petäistö et al. 2020). Together this suggests that enhanced thermogenesis may be contributing to the lipodystrophic phenotype in these mice, and that their inability to store fat causes a shift towards using carbohydrates. In support of this, further investigation showed increased BAT content as well as increases in thermogenic markers, such as UCP-1; however, there was no difference in BAT activity in response to noradrenaline injection between genotypes (Petäistö et al. 2020). The authors also investigated the expression of sarcolipin (SLN) – a well-known uncoupler of the sarco(endo)plasmic reticulum Ca2+-ATPase pump – as another potential thermogenic mechanism. Though they found no differences in mRNA, this is overall difficult to interpret given the lack of protein determination and identification of muscle type. In adult mice, SLN expression is limited to muscles with a more tonic activation pattern (i.e. soleus, gluteus minimus and diaphragm) (Bombardier et al. 2013; Fajardo et al. 2018). Other potential thermogenic mechanisms could also be explored in the future including SERCA cycling in brown/beige adipose tissue and creatine cycling (Roesler & Kazak, 2020). With this work, the authors determined the role of collagen XVIII variants in the regulation of glucose, lipids and fat deposition in mice. They concluded that the medium and long variants of collagen XVIII played a more substantial role in these pathways compared to the short variant. By investigating potential mechanisms underlying their results, they showed that non-shivering thermogenesis may have played a role in increased energy expenditure contributing to the observed lipodystrophy in these transgenic mice. Although the induction of thermogenesis is often considered an attractive therapeutic strategy to combat obesity and type 2 diabetes, these results perhaps highlight the importance of balancing thermogenesis since limiting WAT storage can also cause insulin and glucose intolerance through ectopic lipid storage. The authors have none to declare. All 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. J.L.B. has an NSERC USRA award and S.I.H. has an NSERC CGS M.

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