Blocking Fas-signaling in adipocytes and hepatocytes prevents obesity-associated inflammation, insulin resistance, and hepatosteatosis.

[Display omitted] • Obese mice exhibit increased Fas-signaling in adipocytes and liver. • Fas-signaling plays a pivotal role in obesity-associated consequences. • Systemic delivery of Fas-blocking peptide to adipose tissue and liver in obese mice. • The FBP treatment reduces apoptosis, inflammation, free fatty acids and triglycerides. • The FBP treatment improves liver steatosis and metabolic dysfunction in obese mice. Fas-mediated apoptosis in the adipose tissue and the liver plays a pivotal role in the onset of obesity-associated inflammation, insulin resistance, hepatic steatosis, and metabolic dysfunction. Concurrent aberrant Fas signaling in adipose tissue and the liver, particularly during obesity, activates several inflammatory pathways and thus impairs metabolic and liver function. Here, we report the discovery of a small octameric Fas-blocking peptide (FBP) that specifically inhibits Fas signaling in dietary-induced obese mouse models. Systemic delivery of FBP to Fas-expressing adipose tissue and the liver significantly reduced apoptosis and pro-inflammatory cytokine secretion in adipose tissue as well as the concentration of systemic free fatty acids and hepatic triglycerides, and thereby alleviated liver steatosis and metabolic dysfunction in obese mouse models. This approach may be a promising strategy for reversing inflammation, hepatic steatosis, and insulin resistance due to obesity. [ABSTRACT FROM AUTHOR]