A Novel TGFß Receptor Inhibitor, IPW-5371, Prevents Diet-induced Hepatic Steatosis and Insulin Resistance in Irradiated Mice.

As the number of cancer survivors increases and the risk of accidental radiation exposure rises, there is a pressing need to characterize the delayed effects of radiation exposure and develop medical countermeasures. Radiation has been shown to damage adipose progenitor cells and increase liver fibrosis, such that it predisposes patients to developing metabolic-associated fatty liver disease (MAFLD) and insulin resistance. The risk of developing these conditions is compounded by the global rise of diets rich in carbohydrates and fats. Radiation persistently increases the signaling cascade of transforming growth factor ß (TGFß), leading to heightened fibrosis as characteristic of the delayed effects of radiation exposure. We investigate here a potential radiation medical countermeasure, IPW-5371, a small molecule inhibitor of TGFßRI kinase (ALK5). We found that mice exposed to sub-lethal whole-body irradiation and chronic Western diet consumption but treated with IPW-5371 had a similar body weight, food consumption, and fat mass compared to control mice exposed to radiation. The IPW-5371 treated mice maintained lower fibrosis and fat accumulation in the liver, were more responsive to insulin and had lower circulating triglycerides and better muscle endurance. Future studies are needed to verify the improvement by IPW-5371 on the structure and function of other metabolically active tissues such as adipose and skeletal muscle, but these data demonstrate that IPW-5371 protects liver and whole-body health in rodents exposed to radiation and a Western diet, and there may be promise in using IPW-5371 to prevent the development of MAFLD.

Delayed effects of radiation in adipose tissue reflect progenitor damage and not cellular senescence.

The pathogenesis of many age-related diseases is linked to cellular senescence, a state of inflammation-inducing, irreversible cell cycle arrest. The consequences and mechanisms of age-associated cellular senescence are often studied using in vivo models of radiation exposure. However, it is unknown whether radiation induces persistent senescence, like that observed in ageing. We performed analogous studies in mice and monkeys, where young mice and rhesus macaques received sub-lethal doses of ionizing radiation and were observed for ~ 15% of their expected lifespan. Assessments of 8-hydroxy-2' -deoxyguanosine (8-OHdG), senescence-associated beta-galactosidase (SAß-gal), and p16Ink4a and p21 were performed on mitotic and post-mitotic tissues - liver and adipose tissue - 6 months and 3 years post-exposure for the mice and monkeys, respectively. No elevations in 8-OHdG, SA-ßgal staining, or p16 Ink4a or p21 gene or protein expression were found in mouse and monkey liver or adipose tissue compared to control animals. Despite no evidence of senescence, progenitor cell dysfunction persisted after radiation exposure, as indicated by lower in situ CD34+ adipose cells (p = 0.03), and deficient adipose stromal vascular cell proliferation (p < 0.05) and differentiation (p = 0.04) ex vivo. Our investigation cautions that employing radiation to study senescence-related processes should be limited to the acute post-exposure period and that stem cell damage likely underpins the dysfunction associated with delayed effects of radiation.