RGS16 adenovirus

Caloric restriction and intermittent fasting are emerging therapeutic strategies for obesity, insulin resistance, and their complications. However, the effectors driving this response are not fully defined. Here, we identify arginase 2 (Arg2), a fasting-induced hepatokine that prevents hepatic and peripheral fat accumulation, hepatic inflammatory responses, and insulin and glucose intolerance in a mouse model of obesity. Arg2 was upregulated under fasting conditions and after treatment with the hepatocyte glucose transporter inhibitor trehalose. Hepatocyte-specific overexpression of Arg2 enhanced basal thermogenesis and prevented weight gain, insulin resistance, glucose intolerance, hepatic steatosis, and hepatic inflammation in a diabetic mouse model. Arg2 inhibited expression of regulator of G protein signaling (RGS) 16, and genetic reconstitution of RGS16 reversed the effects of Arg2 overexpression. These results suggest that hepatocyte Arg2 is a key effector of the hepatic glucose fasting response and identify a therapeutic target to mitigate complications of obesity and nonalcoholic fatty liver disease.

Here, researchers treated db/db AAV8-Control and AAV8-Arg2 mice with adenovirus encoding GFP (Ad-Control) or adenovirus encoding RGS16 (Ad-Rgs16). In the liver, Arg2 reduced hepatic triglycerides (TG), cholesterol, free fatty acids (FFA), and low-density lipoprotein cholesterol (LDL-C) in db/db Arg2 mice, while these effects were significantly reversed after Rgs16 reconstitution in db/db AAV8-Arg2 mice (Figure 1a), and no significant changes were detected in serum triglycerides, cholesterol, free fatty acids, and low-density lipoprotein cholesterol (LDL-C). H&E and Oil Red O histological analysis showed that Arg2 overexpression reduced hepatic lipid accumulation, and this phenomenon was reversed in db/db mice that also expressed Ad-RGS16 (Figure 1b). Similarly, db/db AAV8-Arg2 mice expressing Ad-Rgs16 had significantly increased serum ALT and AST as well as liver inflammatory markers compared with db/db AAV8-Arg2 Ad-Control littermates (Figure 1c, d). Rgs16 overexpression reversed the effect of Arg2 on Igfbp1 expression, while Rgs16 overexpression generally increased genes involved in de novo hepatic lipogenesis, including Chrebp, Acc1, Gpam, and Pparγ (Figure 1e). However, hepatic Arg2 overexpression or Rgs16 reconstitution had little effect on the expression of mRNAs encoding β-oxidation and fatty acid uptake and export.

Figure 1. Hepatic RGS16 reconstitution reverses Arg2-mediated improvements in hepatic fat accumulation. (Zhang Y, et al., 2019)