Impaired preadipocyte differentiation in human abdominal obesity -- role of Wnt, TNFα and inflammation

Abstract

Objective To examine preadipocyte differentiation in obese and non-obese individuals and the effect of cytokines and Wnt3a on preadipocyte differentiation and phenotype.

Research Design and Methods Abdominal, subcutaneous adipose tissue biopsies were obtained from a total of 51 donors with varying BMI. Following isolation of the adipose and stromalvascular cells, inflammatory cells (CD14- and CD45-positive cells) were removed by immune magnetic separation. CD133-positive cells, containing early progenitor cells, were also isolated and quantified. The CD14- and 45-negative preadipocytes were cultured with TNFα, IL-6, resistin or Wnt3a with or without a differentiation cocktail.

Results The number of preadipocytes able to differentiate to adipose cells was negatively correlated with both BMI and adipocyte cell size of the donors while the number of CD133 -- positive cells was positively correlated with BMI suggesting an impaired differentiation of preadipocytes in obesity. Cultured preadipocytes, like freshly isolated mature adipocytes, from obese individuals had an increased expression of MAP4K4 which is known to inhibit PPARγ induction. TNFα, but not IL-6 or resistin, increased Wnt10b, completely inhibited the normal differentiation of the preadipocytes and, instead, induced a proinflammatory and macrophage-like phenotype of the cells.

Conclusions The apparent number of preadipocytes in the abdominal subcutaneous tissue which can undergo differentiation is reduced in obesity with enlarged fat cells, possibly due to increased MAP4K4 levels. TNFα promoted a macrophage-like phenotype of the preadipocytes, including several macrophage markers. These results document the plasticity of human preadipocytes and the inverse relationship between lipid storage and proinflammatory capacity.