Dysregulation of iron metabolism is associated with various metabolic diseases, such as Metabolic dysfunction-associated fatty liver disease (MAFLD), insulin resistance (IR) and Type 2 diabetes (T2DM). Conversely, weight gain and total body fat distribution influence iron metabolism. A common association between liver iron and liver triglycerides levels has been mapped on a region of chromosome 7 that contains the histone methyltransferase Suv420h2. Interestingly, Suv420h2 deletion, in conjunction with Suv420h1 downregulation, inhibits Ppar, a key transcription factor involved in glucose and lipid metabolism, and counteracts diet-induced obesity.

We then decided to dissect the role of these methyltransferases in a mouse model of obesity, insulin resistance, and T2DM, the db/db mice, focusing on Suv420h2. Db/db mice recapitulate the T2DM main features, displaying an obese and steatotic profile characterized by a substantial increase in body weight and adipose tissue, as well as insulin resistance and hyperglycemia. Hepatomegaly is associated with decreased liver iron concentration and elevated serum iron levels, indicating deregulated hepcidin function. Interestingly, deletion of Suv420h2 in db/db leads to decreased body weight, reduced white adipose tissue hypertrophy and a trend towards a decrease in hepatomegaly. This is accompanied by decreased serum iron levels and increased liver iron concentration. Hyperglycemia is also improved while IR is not affected by the deletion of Suv420h2.

Overall, these data suggest that global Suv420h2 deletion counteracts obesity and partially improves T2DM but does not correct IR. Further studies are underway to fully characterize the mechanism(s) involved.