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


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.
Lundberg Laboratory for Diabetes Research, Center of Excellence for Metabolic and Cardiovascular Research, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Petter
P
Isakson
Ann
A
Hammarstedt
Birgit
B
Gustafson
Ulf
U
Smith
D000071916:AC133 Antigen; D000005:Abdomen / Q000473:pathology*; D017667:Adipocytes / Q000166:cytology* / Q000473:pathology* / Q000637:transplantation; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D050110:Bariatric Surgery; D001706:Biopsy; D001707:Biopsy, Needle; D015992:Body Mass Index; D002454:Cell Differentiation; D048429:Cell Size; D004797:Enzyme-Linked Immunosorbent Assay; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology*; D008875:Middle Aged; D009765:Obesity / Q000473:pathology*; D010455:Peptides / Q000032:analysis; D016133:Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse