Growth Differentiation Factor-5 Promotes Brown Adipogenesis in Systemic Energy Expenditure

Abstract

Although growth differentiation factor-5 (GDF5) has been implicated in skeletal development and joint morphogenesis in mammals, little is known about its functionality in adipogenesis and energy homeostasis. Here, we show a critical role of GDF5 in regulating brown adipogenesis for systemic energy expenditure in mice. GDF5 expression was preferentially upregulated in brown adipose tissues from inborn and acquired obesity mice. Transgenic overexpression of GDF5 in adipose tissues led to a lean phenotype and reduced susceptibility to diet-induced obesity through increased systemic energy expenditure. Overexpression of GDF5 facilitated the development of brown fat-like cells, called brite or beige cells, along with the expression of uncoupling protein-1 in inguinal subcutaneous white adipose tissue. In mutant mice harboring the dominant-negative GDF5, marked impairment in energy expenditure and thermogenesis was seen under obesogenic conditions. Recombinant GDF5 promoted brown adipogenesis through the mothers against decapentaplegic homolog (Smad) and peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α) pathways after activation of bone morphogenetic protein receptor (BMPR). These results suggest that brown adipogenesis and energy homeostasis are both positively regulated by the GDF5/BMPR/Smad/PGC-1α signaling pathway in adipose tissues. Modulation of these pathways might be an effective therapeutic strategy for obesity and type 2 diabetes.

Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis

“…A number of endocrine regulators for brown/beige adipocytes have been identified. As listed in Figure 3, such factors include BMP4 (66), BMP7 (67,68), BMP8b (69), FGF19 (70,71), FGF21 (72,73), growth differentiation factor-5 (GDF5) (74), natriuretic peptides (75), prostaglandins (76,77), VEGF (78,79), and β-aminoisobutyric acid (BAIBA) (80). Indeed, these factors are able to increase whole-body energy expenditure, protect animals from diet-induced body weight gain, and improve systemic glucose homeostasis and/or insulin sensitivity.…”

Brown Adipose YY1 Deficiency Activates Expression of Secreted Proteins Linked to Energy Expenditure and Prevents Diet-Induced Obesity

“…Recently, systemic factors have been shown to regulate brown and beige adipose tissue thermogenesis, including fibroblast growth factor 21 (FGF21) (26), bone morphogenetic protein 4 (BMP4) (27), BMP7 (28), BMP8b (29), FGF19 (30), growth differentiation factor 5 (GDF5) (31), natriuretic peptides (32), prostaglandins (33,34), vascular endothelial growth factor (VEGF) (35), ␤-aminoisobutyric acid (BAIBA) (36), meteorin-like (14), and irisin (37). These factors are involved in the control of energy expendi-ture and body weight through modulation of BAT or beige fat.…”

Genomic profiling screens small molecules of metastatic prostate carcinoma

“…Certain signaling pathway changes, such as changes in the advanced glycation end products (AGE)-receptor for AGE pathway, the androgen receptor signaling pathway, the transforming growth factor β signaling pathway and the nuclear receptors pathway, can result in the changes of downstream genes. The angiogenesis pathway is likely to provide convenience for the transfer of cancer cells, while adipogenesis is associated with energy regulation (27,28). The changes to the lymphocyte TarBase aid the migrated cells in escaping immune attack (29).…”