Vascular endothelial growth factor B-role in metabolism, lipotoxicity and disease

Vascular Endothelial Growth Factor B (VEGF-B) was previously shown to control lipid uptake from the bloodstream via the endothelium into tissue cells, and when ablating Vegfb, intra-tissue lipid accumulation was reduced. However, very little is known regarding the metabolic role of VEGF-B in physiologic, or pathophysiologic conditions.

In paper I, we characterized the upstream regulatory mechanism controlling VEGF-B expression. We showed in vitro and in vivo that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a major regulator of mitochondrial biogenesis, controls the expression of VEGF-B. The tight regulation of VEGF-B via PGC-1α enables the coordination of lipid uptake with mitochondrial biogenesis and β-oxidation, and hence the prevention of lipotoxicity.

Lipotoxicity and insulin resistance are suggested as key pathologies in type 2 diabetes (T2D). In paper II we analysed the effects of reduced VEGF-B signalling on lipotoxicty and disease progression in different rodent models of T2D. VEGF-B signalling was reduced by either genetic, or pharmaceutical means, and this reduced lipotoxicity, increased glucose uptake into peripheral tissues, improved dyslipidaemia and enhanced sensitivity to insulin, in rodent models of T2D. Therefore, targeting VEGF-B signalling is a promising therapeutic method for the treatment of T2D.

Lipotoxicity has also lately been attributed a larger role in the pathogenesis of diabetic nephropathy (DN), a comorbidity of both type 1 diabetes (T1D) and T2D. Therefore, in paper III, we investigated the effects of reducing VEGF-B signalling in mouse models of DN. We showed that renal lipotoxicity was an important element of DN in these models, and by reducing VEGF-B signalling renal lipotoxicity was ameliorated. Also, renal function, morphology and the filtration capacity were enhanced. Furthermore, VEGF-B signalling was present and activated in patients with DN in comparison to healthy individuals. Thus, targeting VEGF-B signalling represents a novel therapeutic approach for DN.

Finally, in paper IV, a protocol for detecting and imaging of intra-tissue neutral lipids is presented. This protocol enables the exact quantification of neutral lipids and was crucial for all papers discussed above.

To conclude, our data show that lipotoxicity is a major driving force for the development and progression of T2D and DN. Hence, VEGF-B could be a novel target for the treatment of both T2D and DN.

List of scientific papers

I. PGC-1alpha coordinates mitochondrial respiratory capacity and muscular fatty acid uptake via regulation of VEGF-B. Annika Mehlem, Isolde Palombo, Xun Wang, Carolina E Hagberg, Ulf Eriksson and Annelie Falkevall. [Submitted]

II. Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Hagberg CE, Mehlem A, Falkevall A, Muhl L, Fam BC, Ortsäter H, Scotney P, Nyqvist D, Samén E, Lu L, Stone-Elander S, Proietto J, Andrikopoulos S, Sjöholm A, Nash A, Eriksson U. Nature. 2012 490:426-30.
https://doi.org/10.1038/nature11464

III. Reducing VEGF-B signalling ameliorates renal lipotoxicity and protects against diabetic nephropathy. Annelie Falkevall, Annika Mehlem, Isolde Palombo, Benjamin Heller-Sahlgren, Lwaki Ebarasi, Liqun He, Jimmy Ytterberg, Jaakko Patrakka, Pierre Scotney, Andrew Nash and Ulf Eriksson. [Submitted]

III. Imaging of neutral lipids by oil red O for analyzing the metabolic status in health and disease. Mehlem A, Hagberg CE, Muhl L, Eriksson U, Falkevall A. Nature Protocols. 2013 6:1149-54.
https://doi.org/10.1038/nprot.2013.055