Introduction: The cytokine Tumour Necrosis Factor Superfamily Member 14 (TNFSF14, or LIGHT) is a controversial player in numerous diseases as it may exert beneficial or detrimental effects. We investigated the role of TNFSF14 in high fat diet-induced obesity using a combination of both in vitro and in vivo studies. Specifically, we studied the effects of a global deletion of the TNFSF14 gene on the development of obesity, glucose intolerance, insulin resistance and hepatosteatosis. Secondly, we examined the role of TNFSF14 expression in hematopoietic cells on obesity and insulin sensitivity.
Methods: Male TNFSF14 knockout (KO) and wildtype mice were fed chow or high fat diet (HFD) for 12 weeks and metabolically phenotyped. In other experiments, wildtype mice were reconstituted with bone marrow cells from TNFSF14 KO mice and were fed chow or HFD for 12 weeks and metabolically phenotyped. These in vivo studies were complemented by mechanistic experiments in skeletal muscle myotubes.
Results: We show that HFD fed wildtype mice had elevated circulating levels of the cytokine TNFSF14 in their serum. Interestingly, it appears that liver and white adipose tissue are sources of this elevated TNFSF14. Excitingly, TNFSF14 deficient mice displayed markedly increased obesity, glucose intolerance, insulin resistance and hepatosteatosis compared to wildtype controls when placed on a HFD. Cellular experiments indicated that TNFSF14 may have a role in promoting insulin sensitivity. Hepatic cytokine profiling pointed to a potential novel role of decreased IL-6 in the metabolic disturbances in TNFSF14 KO mice on a HFD. Finally, bone marrow cells from TNFSF14 deficient mice were able to contribute to promoting diet-induced obesity and insulin resistance.
Conclusions: Our novel data suggest that TNFSF14 deficiency exacerbates parameters of the metabolic syndrome under high fat feeding conditions and provides further evidence to support the development of TNFSF14 agonists as potential therapeutics in diet-induced obesity.