GDF-11 triggers cold-induced browning and metabolic activation of adipose tissue

White adipose tissue (WAT) browning enhances energy expenditure and represents a promising target for metabolic disease. Growth differentiation factor 11 (GDF-11), a circulating member of the TGF-β superfamily, has been implicated in metabolic regulation, but its role in adipose tissue plasticity remains unclear. This study investigated whether GDF-11 regulates WAT browning and the underlying mechanisms.

Mice were exposed to cold to induce browning, and GDF-11 expression and SMAD2/3 activation were assessed in brown adipose tissue (BAT), visceral and subcutaneous WAT, and skeletal muscle. We combined in vivo results to in vitro approaches, 3T3-L1 cells were differentiated into white or brown adipocytes and treated with recombinant GDF-11 to evaluate gene expression and cellular phenotype.

Cold exposure increased GDF-11 expression and activated SMAD2/3 signaling, particularly in BAT and subcutaneous WAT. This was associated with upregulation of thermogenic and metabolic genes, including Ucp1, Ucp3, Dio2, and PGC-1α. In vitro, GDF-11 enhanced thermogenic and adipogenic gene expression and induced morphological features consistent with browning. GDF-11 also increased SmyD1 expression, supporting a role in metabolic activation.

GDF-11 promotes adipose tissue thermogenic remodeling through SMAD2/3 signaling and may represent a potential therapeutic target for metabolic diseases.