Expansion of a WAT depot occurs through hypertrophy of mature adipocytes and/or through hyperplasia. The creation of new, mature adipocytes, or adipogenesis, involves the replication and differentiation of preadipocyte cells into mature, lipid storing adipoctyes and recent data demonstrate that the degree to which mature adipocytes can be formed depends upon the phenotype of the preadipocyte found within the depot [79
]. Isakson et al. (2009) have further established that the phenotype of resident preadipocytes can be changed based on the composition of the inflammatory proteins found in the depot [142
]. Moreover, whereas healthy, non-obese omental WAT contains preadipocytes with a reduced capacity for replication and differentiation [79
], the preferred modality for healthy subcutaneous WAT expansion is through adipogenesis [82
]. Because non-visceral depots constitute the bulk of total body fat mass, it therefore follows that a diminutive reduction in the adipogenic potential of subcutaneous WAT would negatively affect body fat distribution [82
]. In support of our hypothesis that IL-1β could dampen the adipogenic potential of subcutaneous WAT, Lu et al. (2010) reported that the presence of as little as 5.0
pg/mL of IL-1β (equivalent to basal concentrations in visceral rat WAT) in the culture medium of 3T3-L1 preadipocytes inhibited adipogenesis [155
]. Lu et al. (2010) further demonstrated that preadipocyte differentiation was also impaired upstream of IL-1β at the level of NF-кB due to its effect on the adipogenic transcription factor, PPARγ [155
]. These data support other studies in which a rise in NF-κB activity leads to a reduction in PPARγ expression/activity and impairments in adipogenesis [156
]. In this manner stress-induced IL-1β signaling could drive ectopic lipid deposition and visceral fat expansion by reducing the adipogenic potential of subcutaneous WAT. Contrary to this postulation, however, are data from Weise et al. (2008) suggesting that IL-1β stimulates the expression of tissue inhibitor of metalloproteinase (TIMP)-1, a protein thought to promote preadipocyte differentiation [158
] and shown to be elevated in the serum of viscerally obese subjects [159
]. Though Weise et al. (2008) demonstrated increased TIMP-1 secretion from mature 3T3-L1 adipocyte cells, concentrations of 0.5-20.0
ng/mL of IL-1β were required to induce this response [160
] which may be outside of the physiological range for WAT. For example, as shown in Figure
, stressed subcutaneous WAT concentrations rose to only 0.02
ng/mg total tissue. In addition, Weise et al. (2008) failed to demonstrate that IL-1β induced TIMP-1 synthesis leads to an increase in preadipocyte differentiation [160
]. Consequently, the physiological relevance of their in vivo data in this study is unclear.
Finally, because glucocorticoid activation and signaling is known to stimulate early preadipocyte differentiation [161
], an IL-1β induced rise in glucocorticoid activity seemingly contradicts the hypothesis that repeated exposure to IL-1β impairs the adiopogenic potential of adipose tissue. Interestingly, however, a transgenic study done by Masuzaki et al. (2001) demonstrated that depot specific increases in 11β-HSD1 activity did not, in fact, stimulate the differentiation of preadipocytes in either subcutaneous or visceral adipose tissue [12
]. Instead, gains in adiposity instigated through transgenic over-expression of the enzyme were predominantly due to hypertrophy of the visceral adipocytes [12
] suggesting that the effects of this enzyme are site dependent. While the authors speculated that exaggerated visceral fat deposition was due to enhanced glucocorticoid receptor expression, they did not provide a reason for the lack of hyperplasia found in the depots [12
]. Although inflammatory proteins were not assessed in this study, our data along with the aforementioned studies [155
] suggest that a rise in IL-1β activity and/or the activity of its primary transcription factor NF-кB may be involved in modulating the site specific effects of 11β-HSD1 and/or glucocorticoids on preadipocyte differentiation and adipocyte metabolism.
Despite conflicting evidence it is clear that sustained impairment of subcutaneous expansion or an increase in the capacity of visceral preadipocytes to expand or replicate in the face of positive energy balance could have momentous consequences on body fat distribution. As to which of these maladaptive events occurs first and where, though, remains unclear. Current data demonstrate that the inherent differences among the phenotypes of cells found within WAT depots contribute toward the interdepot variations seen in response to intrinsic and extrinsic stimuli such as IL-1β. Future research must therefore aim to understand the unique and adaptive functions of WAT and WAT proteins relative to time and depot location.