Direct control of hepatic glucose production by interleukin-13 in mice

Abstract

Hyperglycemia is a result of impaired insulin action on glucose production and disposal, and a major target of antidiabetic therapies. The study of insulin-independent regulatory mechanisms of glucose metabolism may identify new strategies to lower blood sugar levels. Here we demonstrate an unexpected metabolic function for IL-13 in the control of hepatic glucose production. IL-13 is a Th2 cytokine known to mediate macrophage alternative activation. Genetic ablation of Il-13 in mice (Il-13 -/-) resulted in hyperglycemia, which progressed to hepatic insulin resistance and systemic metabolic dysfunction. In Il-13 -/-mice, upregulation of enzymes involved in hepatic gluconeogenesis was a primary event leading to dysregulated glucose metabolism. IL-13 inhibited transcription of gluconeogenic genes by acting directly on hepatocytes through Stat3, a noncanonical downstream effector. Consequently, the ability of IL-13 to suppress glucose production was abolished in liver cells lacking Stat3 or IL-13 receptor α1 (Il-13rα1), which suggests that the IL-13Rα1/Stat3 axis directs IL-13 signaling toward metabolic responses. These findings extend the implication of a Th1/Th2 paradigm in metabolic homeostasis beyond inflammation to direct control of glucose metabolism and suggest that the IL-13/Stat3 pathway may serve as a therapeutic target for glycemic control in insulin resistance and type 2 diabetes.

Myokines in insulin resistance and type 2 diabetes

“…Furthermore, Jiang et al suggested a role for IL-13 in skeletal muscle glucose metabolism by showing that treatment of myotubes with this protein increased basal glucose uptake and oxidation and glycogen synthesis (Table 1) [28]. Moreover, a study using IL-13-deficient mice has suggested an implication for IL-13 in suppression of hepatic glucose production [29]. To date, data regarding the regulation of IL-13 release and expression by exercise are not available.…”

“…As summarised in Table 1, in vitro studies have shown that IL-6 increases myotube fatty acid oxidation and lipolysis via AMPK activation [32,33]. [46] No data available regarding endocrine metabolic effects of muscle-derived BDNF IL-6 ↑ GLUT4 translocation [19,20] ↑ Glucose uptake [15,19] ↑ Glycogen synthesis [18,20] ↑ Fatty acid oxidation [18][19][20] ↑ Lipolysis [32][33][34] Liver: ↑ Glucose production [23] Intestine: ↑ GLP-1 secretion of L cells [52] Pancreas: ↑ Beta cell proliferation [52] ↑ GLP-1 secretion of alpha cells [52] ↑ Proliferation and ↓ apoptosis of alpha cells [51] IL-13 ↑ Glucose uptake [28] ↑ Glucose oxidation [28] ↑ Glycogen synthesis [28] Liver: ↓ Glucose production [29] IL-15 ↑ Fatty acid oxidation [43] Adipose tissue: ↓ Lipid accumulation [44,45] ↑ Adiponectin secretion [44] Irisin No data available Adipose tissue: ↑ White to brown shift [98,111] No effect on browning [100] FGF21 ↑ Glucose uptake [99,136] Adipose tissue: ↑ White to brown shift [99] ↑ Glucose uptake [99] ↑ Adiponectin secretion [127,128] Liver: ↑ Fatty acid oxidation [137] ↑ Gluconeogenesis [137] Recently, a study using isolated mouse muscle reported that IL-6...…”

ITCH Deficiency Protects From Diet-Induced Obesity

“…In livers from Itch 2/2 mice, we found high levels of IL-13, which could contribute to explain the glucose control in Itch 2/2 mice; indeed, recently, a role for IL-13 in controlling glucose tolerance was proposed. IL-13 suppresses hepatic glucose production through signal transducer and activator of transcription 3 (STAT3) activation, and then the IL-13 deficiency leads to hyperglycemia and insulin resistance (26). Next, in order to evaluate whether the effect of ITCH deficiency in mice may be translated in human specimens we analyzed human biopsies of adipose tissue.…”

The benefits of restraint: a pivotal role for IL-13 in hepatic glucose homeostasis

“…In the current study, when isolated hepatocytes were treated with recombinant IL-13, p-STAT3 accumulated and suppressed gluconeogenic gene expression, resulting in reduced hepatocyte glucose production. The actions of IL-13 were abrogated in STAT3-deficient hepatocytes, but unaltered in STAT6-deficient cells (6). The authors' results therefore revealed that IL-13 is one of the master regulators of glucose metabolism, acting by directly inhibiting the transcription of hepatic genes that encode key gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6P).…”

“…The study by Stanya et al in this issue advances our understanding of the intricate relationships between the immune system and metabolism (6). By studying two different strains of mice genetically deficient in IL-13, a key cytokine in the antiinflammatory (also known as Th2 or M2) arm of the immune system, the authors demonstrated that IL-13 is required for normal postprandial suppression of hepatic glucose production.…”