The work by Joshua Tam and collaborators [1] provide a number of significant and interesting data on specificities of VEGF receptors, and on the origin of new blood vessels that accompany adipose tissue expansion induced by fat diet. But we think their results deserve further discussion.
Although the authors put some caution toward adapting anti-angiogenic measures to clinical therapy of obesity, they limit the argument for this to a rather drastic, genetic model, with harmful lipodistrophic effects [2]. However, after that publication more than ten years ago, a lot of observations and thinking led to the formulation of the adipose tissue expandability limit hypothesis [3,4]. This hypothesis sustains that there are limits to overall capacity of an individual to expand his fat mass, and beyond that capacity fat will deposit in inconvenient tissues and organs, thus giving origin to diverse pathological events. Furthermore, the adipocyte capacity to hypertrophy has also limits, as big adipocytes have a high tendency to rupture [5].
In the paper by Tam et al an increase in adipocyte dimensions along time is shown for diet induced obese mice. It would have been interesting to know the evolution of adipocyte size in mice treated with the VEGFR2 antibody, as well as the putative adipocyte hyperplasia in both cases. We guess that without new blood vessels hyperplasia will be blunted, and when adipocytes reach a critical diameter, no further fat can be deposited in adipose tissue. This could explain the VEGFR2 antibody treated mice weight increase up to six weeks, in parallel with control mice under the same high fat diet, with phenotype diversion from that period on. According to the adipose tissue expandability limit hypothesis, with fat deposition beyond adipose tissue, and the increasing adipocyte rupture, inflammatory cytokines do probably reach quite high levels. It would have been also of great importance to know those cytokine levels. That evidence would clarify the extension of antiangiogenic therapy adverse effects in obesity, and could eventually explain the decrease in appetite exhibited by treated animals [6].

[1] Tam J, Duda DG, Perentes JY, Quadri RS, Fukumura D, et al. (2009) Blockade of VEGFR2 and Not VEGFR1 Can Limit Diet-Induced Fat Tissue Expansion: Role of Local versus Bone Marrow-Derived Endothelial Cells. PLoS ONE 4(3): e4974. doi:10.1371/journal.pone.0004974

[2] Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, et al. (1998) Life without white fat: a transgenic mouse. Genes Dev 12: 3168–3181.

[3]Virtue S, Vidal-Puig A (2008) It's not how fat you are, it's what you do with it that counts. PLoS BIOL 6(9): e237.doi:10.1371/journal.pbio.0060237

[4] Azevedo I, Monteiro R, Calhau C, Alçada MNP (2008) Don't fill adipocytes beyond their capacity. PLoS BIOL 6(9): e237.doi:10.1371/journal.pbio.0060237#r2382

[5] Monteiro R, de Castro PM, Calhau C, Azevedo I (2006) Adipocyte size and liability to cell death. Obes Surg 16: 804-806.

[6] Steinberg GR, Watt MJ, Febbraio MA (2009) Cytokine regulation of AMPK signalling. Front Biosci 14: 1902-1916.



Submitted by: Isabel Azevedo
E-mail: isabelaz@med.up.pt
Occupation: Professor of Biochemistry
Depart Biochemistry, Fac. Medicine, University of Porto, Portugal

Additional authors: Rosário Monteiro, Conceição Calhau, Manuel Nuno Alçada