Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction

Abstract

We recently identified endotrophin as an adipokine with potent tumour-promoting effects. However, the direct effects of local accumulation of endotrophin in adipose tissue have not yet been studied. Here we use a doxycycline-inducible adipocyte-specific endotrophin overexpression model to demonstrate that endotrophin plays a pivotal role in shaping a metabolically unfavourable microenvironment in adipose tissue during consumption of a high-fat diet (HFD). Endotrophin serves as a powerful co-stimulator of pathologically relevant pathways within the ‘unhealthy’ adipose tissue milieu, triggering fibrosis and inflammation and ultimately leading to enhanced insulin resistance. We further demonstrate that blocking endotrophin with a neutralizing antibody ameliorates metabolically adverse effects and effectively reverses metabolic dysfunction induced during HFD exposure. Collectively, our findings demonstrate that endotrophin exerts a major influence in adipose tissue, eventually resulting in systemic elevation of pro-inflammatory cytokines and insulin resistance, and the results establish endotrophin as a potential target in the context of metabolism and cancer.

Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes

“…Accordingly, suppression of endotrophin improves insulin sensitivity and attenuated adipose tissue inflammation in animals [8]. This correlates well with our findings that elevated serum endotrophin levels are indicative of a response to PPARγ agonists.…”

“…Endotrophin is predominantly produced by adipose tissue and induces upregulation of TGF-β, adipose tissue fibrosis, angiogenesis and inflammation [8]. In animal models, it has also been shown to unfavourably modulate several metabolic functions, such as insulin sensitivity, food intake, energy balance [8][9][10] and adipose tissue inflammation [11,12]. These findings suggest that levels of endotrophin in the blood may be useful for classifying and/or monitoring patients with metabolic dysfunction, especially those with type 2 diabetes.…”

“…In animal models, endotrophin levels have been shown to reflect insulin sensitivity, food intake and energy balance, as well as angiogenesis [4,5,8]. Accordingly, suppression of endotrophin improves insulin sensitivity and attenuated adipose tissue inflammation in animals [8].…”

“…Moreover, the ECM can serve as an endocrine organ due to the signalling potential of certain fragments released by proteolysis, creating ligands with paracrine and potential endocrine functions [3]. Endotrophin (Pro-C6) is a soluble fragment of the C-terminal α3 chain of type VI procollagen that is released by naturally occurring proteolysis [4,8,22,26]. Here we demonstrate that serum endotrophin levels are predictive of a response to the insulin sensitisers, pioglitazone and balaglitazone, in patients with type 2 diabetes.…”

“…Here, further cleavage of the C-terminal propeptide of the α3(VI) chain generates endotrophin (also known as Pro-C6), a newly identified adipokine. Endotrophin is predominantly produced by adipose tissue and induces upregulation of TGF-β, adipose tissue fibrosis, angiogenesis and inflammation [8]. In animal models, it has also been shown to unfavourably modulate several metabolic functions, such as insulin sensitivity, food intake, energy balance [8][9][10] and adipose tissue inflammation [11,12].…”