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Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor-alpha, and inflammation

Journal article
Authors Petter Isakson
Ann Hammarstedt
Birgit Gustafson
Ulf Smith
Published in Diabetes
Volume 58
Issue 7
Pages 1550-7
ISSN 1939-327X (Electronic)
Publication year 2009
Published at Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 1550-7
Language en
Keywords Abdomen/*pathology, Adipocytes/*cytology/*pathology/transplantation, Adult, Aged, Antigens, CD/analysis, Bariatric Surgery, Biopsy, Biopsy, Needle, Body Mass Index, Cell Differentiation, Cell Size, Enzyme-Linked Immunosorbent Assay, Glycoproteins/analysis, Humans, Inflammation/pathology/*physiopathology, Middle Aged, Obesity/*pathology, Peptides/analysis, Polymerase Chain Reaction, Tumor Necrosis Factor-alpha/*physiology, Wnt Proteins/*physiology
Subject categories Medical and Health Sciences


OBJECTIVE: We examined preadipocyte differentiation in obese and nonobese individuals and the effect of cytokines and wingless-type MMTV (mouse mammary tumor virus) integration site family, member 3A (Wnt3a) protein 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. After 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 CD45-negative preadipocytes were cultured with tumor necrosis factor (TNF)-alpha, interleukin (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, whereas 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 mitogen-activated protein 4 kinase 4 (MAP4K4), which is known to inhibit peroxisome proliferator-activated receptor-gamma induction. TNF-alpha, 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 that can undergo differentiation is reduced in obesity with enlarged fat cells, possibly because of increased MAP4K4 levels. TNF-alpha 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.

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