Rheumatoid Arthritis Drug Kinnopin Reduces Leptin Levels and Exerts Anti-diabetic Effects

Recently, Sean M. Hartig's team from Baylor College of Medicine published an article in Cell Metabolism titled "The rheumatoid arthritis drug auranofin lowers leptin levels and exerts antidiabetic effects in obese mice". They found that the FDA-approved rheumatoid arthritis drug Auranofin accumulates in white adipose tissue, improves insulin sensitivity, and normalizes fatty liver disease in obesity. β-adrenergic receptors modulate leptin secretion to produce metabolic benefits superior to anti-inflammatory effects. This study reveals important metabolic properties of anti-inflammatory therapy and contributes to the idea of reducing peripheral leptin to treat obesity and T2DM.

Hypothesizing that small molecules driving immune and metabolic changes similar to miR-30a expression in WAT produce antidiabetic effects, the authors wanted to screen for small molecules with similar gene expression profiles. Among them, the FDA-approved drug Auranofin for rheumatoid arthritis caught their attention, so they administered intraperitoneal injections of Auranofin to obese mice and showed by mass spectrometry that it was mainly distributed in the epididymal WAT (eWAT) and inguinal fat compartment, and subsequently found that the obese mice were significantly more responsive to insulin.

To explore other functional similarities between Auranofin and miR-30a, the authors examined gene expression responses in human adipocytes treated with miR-30a mimics, Auranofin, or appropriate controls. Auranofin exhibited similar functions to miR-30a, being able to disrupt inflammatory signaling and promote the onset of metabolic changes that can enhance insulin sensitivity.

To identify the effects of Auranofin on gene expression in eWAT in obese mice, the authors identified metabolic pathways including oxidative phosphorylation, adipogenesis, and fatty acid metabolism, as well as elevated broad anti-inflammatory pathways by RNA-seq and GSEA analysis.

It is important to note that the authors found that Auranofin can lead to a significant decrease in serum leptin and leptin/lipocalin ratios in obese mice. The authors constructed an inducible leptin receptor knockout mouse (LepRKO) model with an increase of 17-19 g at 4 weeks post-Cre activation, at which point mice were randomly assigned to receive either Auranofin or vector treatment. LepR KO eWAT expressed significantly higher levels of Lep compared to wild-type mice, and subsequent hyperleptinemia resisted Auranofin treatment. Histology as well as targeting gene expression profiles and RPPA further indicated that LepR KO lacked a wild-type anti-inflammatory response to Auranofin in eWAT. Therefore, the authors concluded that the insulin-sensitizing effect of Auranofin requires intact leptin signaling.

Further analysis of RNA-seq data revealed that Auranofin significantly increased the expression of lipolytic genes including Adrb3, Atgl, and Lipe/Hsl in eWAT. In vivo, Auranofin treatment increased fasting serum free fatty acids (FFA), and eWAT oxygen consumption rate (OCR) in wild-type mice. The effect of leptin on eWAT sympathetic tone suggested that the effects of Auranofin may be dependent on bAR signaling, and as expected, β-less (i.e., lacking all three βARs) eWAT lacked a functional response to isoproterenol or Auranofin treatment. In order to further understand the effect of Auranofin on the leptin/βAR axis, the authors compared the lipolytic response in eWAT with that in obese wild-type and LepR KO mice and found that Auranofin increased sensitivity to βAR activation in wild-type eWAT.

These data suggest that Auranofin increases bAR sensitivity, thereby restoring lipolytic capacity and regulation of leptin secretion, further identifying Auranofin, an insulin sensitizer that acts on leptin secretion, for the treatment of obesity and its comorbidities.

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