Identification of BMP and Activin Membrane-Bound Inhibitor (BAMBI) as a Potent Negative Regulator of Adipogenesis and Modulator of Autocrine/Paracrine Adipogenic Factors

Abstract

Adipose tissue dysfunction underpins the association of obesity with type 2 diabetes. Adipogenesis is required for the maintenance of adipose tissue function. It involves the commitment and subsequent differentiation of preadipocytes and is coordinated by autocrine, paracrine, and endocrine factors. We previously reported that fibroblast growth factor-1 (FGF-1) primes primary human preadipocytes and Simpson Golabi Behmel syndrome (SGBS) preadipocytes and increases adipogenesis through a cascade involving extracellular signal–related kinase 1/2 (ERK1/2). Here, we aimed to use the FGF-1 system to identify novel adipogenic regulators. Expression profiling revealed bone morphogenetic protein (BMP) and activin membrane-bound inhibitor (BAMBI) as a putative FGF-1 effector. BAMBI is a transmembrane protein and modulator of paracrine factors that regulate adipogenesis, including transforming growth factor (TGF) superfamily members (TGF-β and BMP) and Wnt. Functional investigations established BAMBI as a negative regulator of adipogenesis and modulator of the anti- and proadipogenic effects of Wnt3a, TGF-β1, and BMP-4. Further studies showed that BAMBI expression levels are decreased in a mouse model of diet-induced obesity. Collectively, these findings establish BAMBI as a novel, negative regulator of adipogenesis that can act as a nexus to integrate multiple paracrine signals to coordinate adipogenesis. Alterations in BAMBI may play a role in the (patho)physiology of obesity, and manipulation of BAMBI may present a novel therapeutic approach to improve adipose tissue function.

Transcriptional Repression of the Transforming Growth Factor β (TGF-β) Pseudoreceptor BMP and Activin Membrane-bound Inhibitor (BAMBI) by Nuclear Factor κB (NF-κB) p50 Enhances TGF-β Signaling in Hepatic Stellate Cells

“…BAMBI protects the murine heart from pressure overload biomechanical stress by restraining TGF-␤ signaling (20). BAMBI has also been reported as a negative regulator of adipogenesis and modulator of the antiand proadipogenic effects of TGF-␤ (21). BAMBI blocks the differentiation of human bone marrow mesenchymal stem cells to carcinoma-associated fibroblasts via inhibition of TGF-␤ signaling (22).…”

Fibroblast growth factor-1 (FGF-1) promotes adipogenesis by downregulation of carboxypeptidase A4 (CPA4) – a negative regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity

“…We previously described an FGF-1/BAMBI/PPAR adipogenic network as a potent driver of adipogenesis of human PAs (Kim et al 2016, Luo et al 2012). In the current study we have extended our understanding of this adipogenic network.…”

“…More recently we identified a key role for BMP and activin membrane-bound inhibitor (BAMBI) as a downstream effector of FGF-1 situated upstream of PPAR (Luo et al 2012). FGF-1 reduced BAMBI expression in preadipocytes and subsequent functional investigations revealed BAMBI knockdown was sufficient to recapitulate the adipogenic effects of FGF-1, including induction of PPAR, thereby establishing BAMBI as a negative regulator of adipogenesis (Luo et al 2012).…”

“…More recently we identified a key role for BMP and activin membrane-bound inhibitor (BAMBI) as a downstream effector of FGF-1 situated upstream of PPAR (Luo et al 2012). FGF-1 reduced BAMBI expression in preadipocytes and subsequent functional investigations revealed BAMBI knockdown was sufficient to recapitulate the adipogenic effects of FGF-1, including induction of PPAR, thereby establishing BAMBI as a negative regulator of adipogenesis (Luo et al 2012). In addition, we also recently identified a role for carboxypeptidase X-1 (CPX-1), a catalytically inactive member of the carboxypeptidase family, as an FGF-1 effector and positive regulator of adipogenesis situated downstream of FGF-1/BAMBI but independent of PPAR (Kim et al 2016).…”

“…Human Simpson-Golabi-Behmel syndrome (SGBS) preadipocytes (PAs) or primary human PAs were cultured and differentiated as described (Luo et al 2012, Newell et al 2006, Widberg et al 2009). Cells were cultured and differentiated with or without FGF-1 (1ng/mL) and heparin (90 μg/mL) as indicated.…”