Adipocyte caspase-8 but not RIPK3 promotes adiposity.

Abstract

Adipocyte death is a key event in the development of white adipose tissue (WAT) inflammation, a major driver of obesity-associated metabolic dysfunction. Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis, a recently discovered mode of regulated necrosis. Necroptosis has been implicated in several inflammatory pathologies; however, the role of adipocyte necroptosis in obesity remains unclear. In the present study, we sought to investigate the role of adipocyte RIPK3 in obesity and glucose homeostasis. We demonstrated that necroptotic signalling was upregulated in WAT of mice with diet-induced obesity and was associated with body-mass index in human WAT. We also demonstrated that caspase-8, a central regulator of apoptosis, suppresses adipocyte necroptosis both in vitro and in vivo. Adipocyte-specific deletion of caspase-8 in mice reduced adiposity compared to control mice. This difference was not observed with concomitant global deletion of RIPK3. Furthermore, adipocyte-specific deletion of the RIPK3 receptor-interacting protein homotypic interaction motif (RHIM), which is required for necroptotic induction, did not influence weight gain, adiposity, or glucose homeostasis in mice with diet-induced obesity. Caspase-8 knockdown by siRNA or pharmacological inhibition in 3T3-L1 adipocytes suppressed adipogenesis, which may be independent of adipocyte Ripk3. Collectively, our findings suggest that adipocyte RIPK3 RHIM does not play a critical role in obesity and glucose homeostasis. Alternatively, we provide further evidence that caspase-8 plays an essential role in adipocyte differentiation, offering insight into the molecular mechanisms underlying obesity and metabolic dysfunction.