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Factors limiting maximal adipose tissue mass.

Posted by pbio on 07 May 2009 at 22:27 GMT

Author: Sam Virtue
Position: No occupation was given
Institution: IMS, Cambridge University
Additional Authors: Antonio Vidal-Puig
Submitted Date: October 16, 2008
Published Date: October 21, 2008
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

The adipose tissue expansion hypothesis that we postulate states the capacity of an individual to expand their fat mass is the key determinant as to whether obesity leads to metabolic complications. In the article we did not discuss what limits adipose tissue expansion in any detail. We thank Azevedo et al for highlighting this aspect and pointing out one particular potential mechanism that limits adipose tissue mass, that of mechanical adipocyte rupture.

Most examples of mouse models with altered adipose tissue expansion capacity have focussed on factors that alter the processes of adipogenesis. While adipogenesis is undoubtedly important there are undoubtedly other factors that affect the capacity of adipose tissue to expand. For example, in humans, considerable work has focussed on the ability of hormones, such as glucocorticoids, to regulate adipose tissue mass and adipose tissue distribution.

In addition to adipogenic and hormonal factors several other processes have been implicated in regulating adipose tissue mass. To increase fat mass requires the activation of programs including angiogenesis, to supply new blood vessels (which may be driven by hypoxic signals and require Hif signalling), as well as matrix metalloproteases to allow remodelling of the extracellular matrix to physically allow expansion of adipose tissue. While there have been studies looking at the effect of ablating tissue inhibitor of metalloproteinases (TIMP) they have principally focussed on adipose tissue mass in response to high fat diet, and show a decrease in adipose tissue mass (1). Given that loss of TIMP-1 would be expected to increase matrix metalloproteinase (MMP) activity and allow unrestrained expansion of adipose tissue it is surprising these mice lose weight. Furthermore, the reduction of fat mass in response to loss of TIMP-1 is doubly unexpected, as pharmacologically inhibiting MMPs in vitro blocks adipogenesis (2).

Inhibitors of angiogenesis also have some surprising results; TNP470 a drug that prevents endothelial cell proliferation, reduces fat mass in ob/ob mice (3,4). Surprisingly this fat-mass loss seems to be caused by a reduction in food intake (this also appears to be an effect common to other blockers of angiogenesis such angiostatin (4)) suggesting modulating processes involved in the physical expansion of adipose tissue may activate feedback loops that modulate food intake and energy expenditure. Finally the recent publication by Rodeheffer identifying adipose tissue resident stem cells points to a further area of potential modulation of adipose tissue expansion; that of at the level of preadipocyte formation from stem cells (5).

Clearly there is much to learn about how adipose tissue mass can be limited and we welcome helpful suggestions as to other possible mechanisms that may be involved.

1. Lijnen HR, Demeulemeester D, Van Hoef B, Collen D, Maquoi E.
Deficiency of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) impairs nutritionally induced obesity in mice. Thromb Haemost. 2003 Feb;89(2):249-55.

2. Bourlier V, Zakaroff-Girard A, De Barros S, Pizzacalla C, de Saint Front VD, Lafontan M, Bouloumié A, Galitzky J.Protease inhibitor treatments reveal specific involvement of matrix metalloproteinase-9 in human adipocyte differentiation.
J Pharmacol Exp Ther. 2005 Mar;312(3):1272-9.

3. Rupnick MA, Panigrahy D, Zhang CY, Dallabrida SM, Lowell BB, Langer R, Folkman MJ. Adipose tissue mass can be regulated through the vasculature.
Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10730-5. Epub 2002 Jul 29.

4. Bråkenhielm E, Cao R, Gao B, Angelin B, Cannon B, Parini P, Cao Y. Angiogenesis inhibitor, TNP-470, prevents diet-induced and genetic obesity in mice. Circ Res. 2004 Jun 25;94(12):1579-88. Epub 2004 May 20.

5. Rodeheffer MS, Birsoy K, Friedman JM. Identification of White Adipocyte Progenitor Cells In Vivo. Cell. 2008 Oct 1.

No competing interests declared.