Journal Club Summary

Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation.

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In this paper, Anthony Ferrante's group at Columbia University explore the roles of lysosomal biogenesis in white adipose tissue. There was also a news and views review associated with this article penned by my former colleagues Shannon Reilly and Alan Saltiel. In this paper they performed a meta-analysis of factors which correlate with BMI in a variety of mouse strains and found that transcriptional pathways involved in lysosomal biogenesis are up-regulated. They then show that there is an accumulation of lysosomes in the macrophages which infiltrate adipose tissue from obese mice. Using FACS they sort out the adipose tissue macrophages into M1 and M2 subtypes based on CD11c immunoreactivity and show that the lysosomes are particularly unregulated in the CD11c+ macrophages.

They went on to examine the M1 and M2 macrophages, and surprisingly they found very little indication that these subtypes of macrophages differ substantially in polarization. This is contrary to several other reports which support that CD11c- and CD11c+ cells express markers suggestive of different polarization (Lumeng et al 2007, Fujisaka et al 2009, Shaul et al 2010), including several of the same markers examined in this study. One thing they did not present in this work though, which would have been helpful in deciphering these differences is a comparison of CD11c- vs CD11c+ cells from obese animals. Their conclusion, though is that one major difference between CD11c- and CD11c+ cells is that the latter tends to accumulate lipids and lysosomes in the obese state.

They show that co-differentiation of monocytes with adipose tissue leads to increased lysosomes and lipid accumulation, and expression of the CD11c marker. This suggests that adipose tissue breakdown might induce the polarization of cells into CD11c+ cells, potentially to act as a buffer for excessive fat release from adipose tissue. It stands to reason that the lysosomal accumulation might be a mechanism by which these cells will deal with this influx of lipid.

Whether these lysosomes are functional in the pathophysiologies associated with macrophage infiltration is not clear. To test this, Xu et al inhibited lysosomal function in vitro and found that this lead to more lipid accumulation and higher expression of lipid biosynthesis genes, and the CD11c marker. This supports the idea that something in adipose tissue is able to drive lipid accumulation in macrophages and drive them towards CD11c+ cells, and that inhibition of lysosomal function exaggerates that effect. Whether this is simply due to the presence of excessive lipid was not tested, but remains an interesting hypothesis. They also found that ex vivo, treatment with the lysosomal inhibitor chloroquine enhanced lipid release, consistent with the catabolic role of these organelles.

This study also performs most of its experiments on a genetic model of obesity, the ob/ob mouse. These mice are hyperphagic and obese due to a loss of leptin, a satiety hormone. It will be interesting to see if these effects are extendable into high fat diet or other genetic models of obesity or are specifically related to the loss of leptin signaling. The key question going forward is going to be whether inhibition of lysosomal function, specifically in adipose tissue macrophages plays a key role in adipose function and whole animal lipid homeostasis.


  • Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, et al. 2009 Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 58:2574–2582
  • Lumeng CN, Bodzin JL, Saltiel AR 2007 Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117:175–184
  • Shaul ME, Bennett G, Strissel KJ, Greenberg AS, Obin MS 2010 Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet--induced obesity in mice. Diabetes 59:1171–1181
  • Reilly SM, Saltiel AR 2014 Obesity: A complex role for adipose tissue macrophages. Nat. Rev. Endocrinol. Nature Publishing Group; 1–2

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