BMP4 and BMP Antagonists Regulate Human White and Beige Adipogenesis

Area of Science:

• Adipose tissue biology
• Obesity research
• Cell differentiation signaling

Background:

• Subcutaneous adipose tissue expansion is limited in obesity due to impaired adipocyte recruitment and differentiation, leading to hypertrophic obesity.
• Bone morphogenetic protein-4 (BMP4) is crucial for adipogenic precursor cell commitment and differentiation.
• Increased BMP4 levels are observed in large adipocytes, but precursor cells show resistance due to elevated levels of the BMP inhibitor Gremlin-1 (GREM1).

Purpose of the Study:

• To investigate the role of BMP4 and GREM1 in regulating adipocyte differentiation and phenotype, particularly in the context of hypertrophic obesity.
• To explore the potential of manipulating BMP4 and GREM1 signaling to influence white and beige/brown adipose tissue development.

Main Methods:

• Investigated BMP4 and GREM1 expression and secretion in differentiated adipocytes and precursor cells.
• Utilized BMP4 treatment and GREM1 silencing to assess effects on adipogenic differentiation and gene expression.
• Analyzed markers of white and beige/brown adipose phenotypes, including peroxisome proliferator-activated receptor γ (PPARγ), mitochondrial content, and PGC1α.

Main Results:

• BMP4 is induced and secreted by differentiated adipocytes and is increased in hypertrophic obesity.
• Precursor cells exhibit BMP4 resistance due to GREM1 secretion, which inhibits BMP4 and BMP7.
• BMP4 treatment or GREM1 silencing promoted a beige/brown adipose phenotype, characterized by increased oxidative markers and PGC1α.
• Manipulation of GREM1 and BMP4 during white adipogenesis reactivated beige/brown markers, indicating BMP4's preferential regulation of this phenotype.

Conclusions:

• BMP4, secreted by white adipocytes, acts as a feedback regulator of both white and beige adipogenic commitment and differentiation.
• Resistance to BMP4 signaling, mediated by GREM1, is a key characteristic of hypertrophic obesity.
• Targeting the BMP4/GREM1 axis may offer therapeutic strategies for managing obesity and metabolic dysfunction.