Intrinsic expression of viperin regulates thermogenesis in adipose tissues

Abstract

Viperin is an interferon (IFN)-inducible multifunctional protein. Recent evidence from high-throughput analyses indicates that most IFN-inducible proteins, including viperin, are intrinsically expressed in specific tissues; however, the respective intrinsic functions are unknown. Here we show that the intrinsic expression of viperin regulates adipose tissue thermogenesis, which is known to counter metabolic disease and contribute to the febrile response to pathogen invasion. Viperin knockout mice exhibit increased heat production, resulting in a reduction of fat mass, improvement of high-fat diet (HFD)-induced glucose tolerance, and enhancement of cold tolerance. These thermogenic phenotypes are attributed to an adipocyte-autonomous mechanism that regulates fatty acid β-oxidation. Under an HFD, viperin expression is increased, and its function is enhanced. Our findings reveal the intrinsic function of viperin as a novel mechanism regulating thermogenesis in adipose tissues, suggesting that viperin represents a molecular target for thermoregulation in clinical contexts.

ddhCTP produced by the radical‐SAM activity of RSAD2 (viperin) inhibits the NAD+‐dependent activity of enzymes to modulate metabolism

“…Inhibition of the NAD + ‐dependent enzymes such as 2‐OGDH, which catalyses transformation of 2‐OG in TCA cycle, can reduce mitochondrial respiration and affects metabolism of nucleotides causing a reduction in viral replication. (iv) It is reported that the radical‐SAM activity of RSAD2 reduces activity of the β‐oxidation pathway [16]. ddhCTP may inhibit the NAD + ‐dependent activity of enzyme 3‐hydroacyl‐CoA dehydrogenase reducing the flux through the β‐oxidation pathway.…”

“…In addition to the widely studied broad‐spectrum antiviral function of RSAD2 [7–14], emerging evidence suggests the enzyme may play a role in a range of different cellular processes. RSAD2 plays a role in optimal Th2 response [15], regulates thermogenesis in adipose tissue [16], is required for Golgi trafficking of TNF‐α in activated microglia [17], and regulates chondrogenic differentiation via CXCL10 protein secretion [18]. The radical‐SAM activity of RSAD2 can abolish metabolism of amino acids and mitochondrial respiration [19].…”

Targeting Viperin to the Mitochondrion Inhibits the Thiolase Activity of the Trifunctional Enzyme Complex

“…Immunoprecipitation using the HEK 293T cell lysates was performed with anti-Myc tagged magnetic beads according to the manufacturers' protocol, as detailed previously (32).…”

“…Our results provide support for the hypothesis that HCMV co-opts viperin to inhibit HADHB and thereby facilitate the escape of viral particles from the cell. They also throw light on the recent and intriguing observation that viperin is involved in regulating thermogenesis in murine adipose tissue (32).…”

“…It is also involved in regulating innate immune signaling (28) and lipid metabolism (29)(30)(31). Intriguingly, very recent studies on mice in which viperin was knocked out have implicated the enzyme in regulating thermogenesis in adipose tissues through regulation of fatty acid b-oxidation (32).…”