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. 2015 Jul;58(7):1601-9.
doi: 10.1007/s00125-015-3594-8. Epub 2015 May 12.

The limited storage capacity of gonadal adipose tissue directs the development of metabolic disorders in male C57Bl/6J mice

Lianne van Beek  1 , Jan B van Klinken, Amanda C M Pronk, Andrea D van Dam, Eline Dirven, Patrick C N Rensen, Frits Koning, Ko Willems van Dijk, Vanessa van Harmelen
Affiliations

The limited storage capacity of gonadal adipose tissue directs the development of metabolic disorders in male C57Bl/6J mice

Lianne van Beek et al. Diabetologia. 2015 Jul.

Abstract

Aims/hypothesis: White adipose tissue (WAT) consists of various depots with different adipocyte functionality and immune cell composition. Knowledge of WAT-depot-specific differences in expandability and immune cell influx during the development of obesity is limited, therefore we aimed to characterise different WAT depots during the development of obesity in mice.

Methods: Gonadal WAT (gWAT), subcutaneous WAT (sWAT) and mesenteric WAT (mWAT) were isolated from male C57Bl/6J mice with different body weights (approximately 25-60 g) and analysed. Linear and non-linear regression models were used to describe the extent of WAT depot expandability and immune cell composition as a function of body weight.

Results: Whereas mouse sWAT and mWAT continued to expand with body weight, gWAT expanded mainly during the initial phase of body weight gain. The expansion diminished after the mice reached a body weight of around 40 g. From this point on, gWAT crown-like structure formation, liver steatosis and insulin resistance occurred. Mouse WAT depots showed major differences in immune cell composition: gWAT consisted mainly of macrophages, whereas sWAT and mWAT primarily contained lymphocytes.

Conclusions/interpretation: Marked inter-depot differences exist in WAT immune cell composition and expandability. The limited storage capacity of gWAT seems to direct the development of metabolic disorders in male C57Bl/6J mice.

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Figures

Fig. 1
Fig. 1
Correlation of HFD-induced changes in body composition and organ weight with body weight. Correlations with body weight in male C57Bl/6J mice (ranging from approximately 25 to 60 g) are shown for lean mass (a), fat mass (b), and different organ weights: liver (c), heart (d), spleen (e) and interscapular BAT (f). Associations were modelled using either a linear model or non-linear function, 95% CIs are shown as grey bands. See ESM Table 2 for equations, correlations and p values
Fig. 2
Fig. 2
Correlation of HFD-induced changes in plasma glucose and insulin levels with body weight. The correlation between body weight and plasma glucose (a, r = 0.67, p < 0.0001, p  lin = 0.0044) and insulin (b, r = 0.93, p < 0.0001, p  lin < 0.0001) levels in male C57Bl/6J mice. Associations were modelled using either a linear model or non-linear function; 95% CIs are shown as grey bands. A significant p value provides evidence of a non-zero slope in the linear model; a significant p  lin value provides evidence that the association is non-linear
Fig. 3
Fig. 3
Correlation of HFD-induced changes in fat pad weight and adipocyte size with body weight. Fat pad weight (a, c, e) and adipocyte size (b, d, f) of gWAT, sWAT and mWAT in relation to body weight in male C57Bl/6J mice. For gWAT and sWAT, one fat pad is representative. Associations were modelled using either a linear model or non-linear function; 95% CIs are shown as grey bands. See Table 1 and ESM Table 2 for equations, correlations and p values
Fig. 4
Fig. 4
Correlation of insulin responsiveness of adipocytes and macrophage phenotype in gWAT with body weight. Percentage inhibition of lipolysis by insulin of gonadal adipocytes correlated with body weight (a, r = −0.47, p = 0.0010). Insulin responsiveness of the adipocytes was determined by measuring the response of the adipocytes to 8-bromo-cAMP-stimulated lipolysis and the percentage inhibition thereof by insulin. F4/80-stained macrophages in gWAT (b), a ×20 magnification is used, CLS are indicated by arrows. CLS counts/mm2 WAT correlated with body weight of male C57Bl/6J mice (c, r = 0.71, p < 0.0001, p  lin < 0.0001). Macrophage type 1 (CD11B+CD11C+; black circles; r = 0.77, p < 0.0001) and 2 (CD11B+CD11C−; grey squares; r = −0.76, p < 0.0001) as percentage of F4/80+ cells in SVF of gWAT by flow cytometry (d) correlated with body weight of male C57Bl/6J mice. Associations were modelled using either a linear or non-linear function; 95% CIs are shown as grey bands. A significant value of p provides evidence of a non-zero slope in the linear model; a significant value of p  lin provides evidence that the association is non-linear
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