Non-Hematopoietic Il-4r Alpha Expression Contributes To Fructose-Driven Obesity And Metabolic Sequelae

Objective The risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4R alpha regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4R alpha to sugar rich diet-driven obesity and metabolic sequelae remains unknown. Methods WT, IL-4R alpha-deficient (IL-4R alpha(-/-)) and STAT6-deficient mice (STAT6(-/-)) male mice were fed low-fat chow, high fat (HF) or HF plus high carbohydrate (HC/fructose) diet (HF + HC). Analysis included quantification of: (i) body weight, adiposity, energy expenditure, fructose metabolism, fatty acid oxidation/synthesis, glucose dysmetabolism and hepatocellular damage; (ii) the contribution of the hematopoietic or non-hematopoietic IL-4R alpha expression; and (iii) the relevance of IL-4R alpha downstream canonical STAT6 signaling pathway in this setting. Results We show that IL-4R alpha regulated HF + HC diet-driven weight gain, whole body adiposity, adipose tissue inflammatory gene expression, energy expenditure, locomotor activity, glucose metabolism, hepatic steatosis, hepatic inflammatory gene expression and hepatocellular damage. These effects were potentially, and in part, dependent on non-hematopoietic IL-4R alpha expression but were independent of direct STAT6 activation. Mechanistically, hepatic ketohexokinase-A and C expression was dependent on IL-4R alpha, as it was reduced in IL-4R alpha-deficient mice. KHK activity was also affected by HF + HC dietary challenge. Further, reduced expression/activity of KHK in IL-4R alpha mice had a significant effect on fatty acid oxidation and fatty acid synthesis pathways. Conclusion Our findings highlight potential contribution of non-hematopoietic IL-4R alpha activation of a non-canonical signaling pathway that regulates the HF + HC diet-driven induction of obesity and severity of obesity-associated sequelae.