LLTH induces white adipose tissue browning via NF κB inhibition in ATM.

This study aimed to explore the role of macrophage polarization and TLR4/NF-κB pathway in promoting browning of white adipose tissue through different hypoxic exercises. (1) Fifty obese female rats were selected after 16 weeks of high-fat diet feeding and randomly divided into normoxic sedentary (NC), normoxic exercise (NE), hypoxic sedentary (HC), Living-High Training-High (HH), and Living-Low Training-High (LH) groups. Four weeks of hypoxic and exercise interventions were conducted to investigate changes in the expression of the TLR4/NF-κB pathway and inflammatory factors in obese rat adipose tissue and the expression of genes and proteins related to adipose tissue browning. (2) After the 4-week intervention, adipose tissue macrophages (ATM) were isolated from HH and LH groups, activated with NF-κB activator, and co-cultured with adipocyte-induced adipose-derived stem cells to explore the role of the TLR4/NF-κB pathway in promoting browning of white adipose tissue by inducing changes in macrophage polarization through different hypoxic exercise. (1) After 4 weeks of different hypoxic interventions, the proportion of M1 macrophages decreased (p < 0.01), and HH intervention increased the proportion of M2 macrophages (p < 0.05). The protein expression levels of TLR4, NF-κB, p-NF-κB, and MyD88 in ATM of the HH and LH groups were significantly lower than those of the NC group (p < 0.01). Four weeks of LH intervention significantly upregulated the protein expression levels of CIDEA, C/EBP-β, PPAR-γ, PGC-1α, PRDM-16, and UCP-1 in rat adipose tissue (p < 0.01). (2) NF-κB activator intervention for 24 h significantly upregulated the protein expression levels of TLR4, p-NF-κB, and MyD88 in adipose tissue of HH and LH group rats (p < 0.01). NF-κB activator intervention for 24 h downregulated the protein expression levels of CIDEA, C/EBP-β, PPAR-γ, PGC-1α, PRDM-16, and UCP-1 in co-cultured adipocytes for 48 h in ATM of the LH group rats (p < 0.05). Four weeks of HH and LH interventions could reduce M1 polarization of ATM, downregulate the expression levels of the TLR4-NF-κB pathway in ATM, and promote browning of white adipose tissue. The TLR4-NF-κB pathway plays a more critical role in promoting the browning of white adipose tissue by regulating macrophage polarization in LH intervention.