PNNL

Abstract

Both lipodystrophy and obesity are accompanied by dysregulated energy balance associated with insulin resistance and metabolic syndrome. Here, we show that SerpinA1 expression in liver is increased during recovery from lipodystrophy caused by adipocyte-specific loss of insulin signaling in mice. SerpinA1 induces proliferation of white and brown preadipocytes and increases the expression of uncoupling protein 1 (UCP1) to promote mitochondrial activation in mature white and brown adipocytes. Liver-specific SerpinA1 transgenic mice exhibit increased browning of adipose tissues, leading to higher energy expenditure, reduced adiposity and improved glucose tolerance. Conversely, SerpinA1 knockout mice exhibit decreased adipocyte mitochondrial function, impaired thermogenesis, obesity, and systemic insulin resistance. In adipocytes, SerpinA1 forms a complex with the EphB2 receptor and regulates its downstream signaling. Together these data demonstrate that SerpinA1 is an important hepatokine that improves obesity, energy expenditure and glucose metabolism by promoting preadipocyte proliferation and activating mitochondrial UCP1 expression in adipocytes.